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  • 1.
    Ahlgren, Kerstin M
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    von Euler, Henrik
    Sundberg, Katarina
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hedhammar, Åke
    Andersson, Göran
    Hansson-Hamlin, Helene
    Lernmark, Åke
    Kämpe, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 8, s. e105473-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS/HYPOTHESIS:

    Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.

    METHODS:

    Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.

    RESULTS:

    None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.

    CONCLUSIONS/INTERPRETATIONS:

    Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

  • 2.
    Almqvist, Catarina
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Karolinska Univ Hosp, Lung & Allergy Unit, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    Olsson, Henrik
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lundholm, Cecilia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Sibship and risk of asthma in a total population: A disease comparative approach2016Inngår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 138, nr 4, s. 1219-1222Artikkel i tidsskrift (Fagfellevurdert)
  • 3.
    Arendt, Maja
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Axelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes2014Inngår i: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 45, nr 5, s. 716-722Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus.

  • 4.
    Beijer, Kristina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Nowak, Christoph
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Ärnlöv, Johan
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden;Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study2019Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, nr 11, s. 1998-2006Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims/hypothesis: The pathogenesis of type 2 diabetes is not fully understood. We investigated whether circulating levels of preselected proteins were associated with the outcome 'diabetes' and whether these associations were causal.

    Methods: In 2467 individuals of the population-based, cross-sectional EpiHealth study (45-75 years, 50% women), 249 plasma proteins were analysed by the proximity extension assay technique. DNA was genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip. Diabetes was defined as taking glucose-lowering treatment or having a fasting plasma glucose of >= 7.0 mmol/l. The associations between proteins and diabetes were assessed using logistic regression. To investigate causal relationships between proteins and diabetes, a bidirectional two-sample Mendelian randomisation was performed based on large, genome-wide association studies belonging to the DIAGRAM and MAGIC consortia, and a genome-wide association study in the EpiHealth study.

    Results: Twenty-six proteins were positively associated with diabetes, including cathepsin D, retinal dehydrogenase 1, alpha-l-iduronidase, hydroxyacid oxidase 1 and galectin-4 (top five findings). Three proteins, lipoprotein lipase, IGF-binding protein 2 and paraoxonase 3 (PON-3), were inversely associated with diabetes. Fourteen of the proteins are novel discoveries. The Mendelian randomisation study did not disclose any significant causal effects between the proteins and diabetes in either direction that were consistent with the relationships found between the protein levels and diabetes.

    Conclusions/interpretation: The 29 proteins associated with diabetes are involved in several physiological pathways, but given the power of the study no causal link was identified for those proteins tested in Mendelian randomisation. Therefore, the identified proteins are likely to be biomarkers for type 2 diabetes, rather than representing causal pathways.

  • 5.
    Beijer, Kristina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala Univ, Med Sci, Uppsala, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Arnlöv, J.
    Karolinska Inst, Stockholm, Sweden.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ingelsson, E.
    Stanford Univ, Palo Alto, CA 94304 USA.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    A targeted proteomic profile of prevalent diabetes in a population-based sample2018Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, s. S252-S252Artikkel i tidsskrift (Annet vitenskapelig)
  • 6.
    Burgess, Stephen
    et al.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England..
    Bowden, Jack
    Univ Bristol, Sch Social & Community Med, Med Res Council, Integrat Epidemiol Unit, Bristol, Avon, England..
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Thompson, Simon G.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England..
    Sensitivity Analyses for Robust Causal Inference from Mendelian Randomization Analyses with Multiple Genetic Variants2017Inngår i: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 28, nr 1, s. 30-42Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Mendelian randomization investigations are becoming more powerful and simpler to perform, due to the increasing size and coverage of genome-wide association studies and the increasing availability of summarized data on genetic associations with risk factors and disease outcomes. However, when using multiple genetic variants from different gene regions in a Mendelian randomization analysis, it is highly implausible that all the genetic variants satisfy the instrumental variable assumptions. This means that a simple instrumental variable analysis alone should not be relied on to give a causal conclusion. In this article, we discuss a range of sensitivity analyses that will either support or question the validity of causal inference from a Mendelian randomization analysis with multiple genetic variants. We focus on sensitivity analyses of greatest practical relevance for ensuring robust causal inferences, and those that can be undertaken using summarized data. Aside from cases in which the justification of the instrumental variable assumptions is supported by strong biological understanding, a Mendelian randomization analysis in which no assessment of the robustness of the findings to violations of the instrumental variable assumptions has been made should be viewed as speculative and incomplete. In particular, Mendelian randomization investigations with large numbers of genetic variants without such sensitivity analyses should be treated with skepticism.

  • 7.
    Censin, J. C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nowak, Christoph
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cooper, Nicholas
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England..
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Todd, John A.
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England.;Univ Oxford, NIHR Oxford Biomed Res Ctr, Wellcome Trust Ctr Human Genet,Nuffield Dept Med, JDRF,Wellcome Trust Diabet & Inflammat Lab, Oxford, England..
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study2017Inngår i: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, nr 8, artikkel-id e1002362Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations. Methods and findings We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2-10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study. Conclusions This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.

  • 8. Dahl, A. K.
    et al.
    Reynolds, C. A.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Magnusson, P. K. E.
    Pedersen, N. L.
    Multifactorial analysis of changes in body mass index across the adult life course: a study with 65 years of follow-up2014Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 38, nr 8, s. 1133-1141Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Although the negative consequences on health of being obese are well known, most adults gain weight across the lifespan. The general increase in body mass index (BMI) is mainly considered to originate from behavioral and environmental changes; however, few studies have evaluated the influence of these factors on change in BMI in the presence of genetic risk. We aimed to study the influence of multifactorial causes of change in BMI, over 65 years. METHODS AND FINDINGS: Totally, 6130 participants from TwinGene, who had up to five assessments, and 536 from the Swedish Adoption/Twin Study of Aging, who had up to 12 assessments, ranging over 65 years were included. The influence of lifestyle factors, birth cohort, cardiometabolic diseases and an individual obesity genetic risk score (OGRS) based on 32 single nucleotide polymorphisms on change in BMI was evaluated with a growth model. For both sexes, BMI increased from early adulthood to age of 65 years, after which the increase leveled off; BMI declined after age of 80 years. A higher OGRS, birth after 1925 and cardiometabolic diseases were associated with higher average BMI and a steeper increase in BMI prior to 65 years of age. Among men, few factors were identified that influence BMI trajectories in late life, whereas for women type 2 diabetes mellitus and dementia were associated with a steeper decrease in BMI after the age of 65 years. CONCLUSIONS: There are two turning points in BMI in late adulthood, one at the age of 65 years and one at the age 80 years. Factors associated with an increase in BMI in midlife were not associated with an increase in BMI after the age of 65 years. These findings indicate that the causes and consequences of change in BMI differ across the lifespan. Current health recommendations need to be adjusted accordingly.

  • 9. Dahl, A. K.
    et al.
    Reynolds, C. A.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Magnusson, P. K.
    Pederson, N. L.
    A multifactorial life course perspective on change in body mass index: a longitudinal study with 65 years of follow-up2013Inngår i: The Gerontologist, ISSN 0016-9013, E-ISSN 1758-5341, Vol. 53, nr Suppl. 1, s. 158-159Artikkel i tidsskrift (Annet vitenskapelig)
  • 10.
    Diamanti, Klev
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Visvanathar, Robin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Cavalli, Marco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pan, Gang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Kumar, Chanchal
    Translational Science & Experimental Medicine, Early Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca; Karolinska Institute/AstraZeneca Integrated CardioMetabolic Centre (KI/AZ ICMC), Department of Medicine.
    Stanko, Stanko
    Pharmaceutical Technology & Development, AstraZeneca AB; Department of Medicine, Sahlgrenska University Hospital, Gothenburg.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Lind, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Eriksson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wadelius, Claes
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Komorowski, Jan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Integration of whole-body PET/MRI with non-targeted metabolomics provides new insights into insulin sensitivity of various tissuesManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Alteration of various metabolites has been linked to type 2 diabetes (T2D) and insulin resistance. However, identifying significant associations between metabolites and tissue-specific alterations is challenging and requires a multi-omics approach. In this study, we aimed at discovering associations of metabolites from subcutaneous adipose tissue (SAT) and plasma with the volume, the fat fraction (FF) and the insulin sensitivity (Ki) of specific tissues using [18F]FDG PET/MRI.

    Materials and Methods: In a cohort of 42 subjects with different levels of glucose tolerance (normal, prediabetes and T2D) matched for age and body-mass-index (BMI) we calculated associations between parameters of whole-body FDG PET/MRI during clamp and non-targeted metabolomics profiling for SAT and blood plasma. We also used a rule-based classifier to identify a large collection of prevalent patterns of co-dependent metabolites that characterize non-diabetes (ND) and T2D.

    Results: The plasma metabolomics profiling revealed that hepatic fat content was positively associated with tyrosine, and negatively associated with lysoPC(P-16:0). Ki in visceral adipose tissue (VAT) and SAT, was positively associated with several species of lysophospholipids while the opposite applied to branched-chain amino acids (BCAA) and their intermediates. The adipose tissue metabolomics revealed a positive association between non-esterified fatty acids and, VAT and liver Ki. On the contrary, bile acids and carnitines in adipose tissue were inversely associated with VAT Ki. Finally, we presented a transparent machine-learning model that predicted ND or T2D in “unseen” data with an accuracy of 78%.

    Conclusions: Novel associations of several metabolites from SAT and plasma with the FF, volume and insulin senstivity of various tissues throughout the body were discovered using PET/MRI and a new integrative multi-omics approach. A promising computational model that predicted ND and T2D with high certainty, suggested novel non-linear interdependencies of metabolites.

  • 11.
    Fall, Tove
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ekberg, Sara
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Lundholm, Cecilia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Fang, Fang
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Almqvist, Catarina
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Unit Pediat Allergy & Pulmonol, Stockholm, Sweden.
    Dog characteristics and future risk of asthma in children growing up with dogs2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 16899Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is observational evidence that children exposed to dogs in early life are at lower risk of asthma. It is unknown whether this association is modified by dog characteristics such as sex, breed, number of dogs, and dog size. The aim of this study was to determine whether different dog characteristics modify the risk of asthma among children exposed to dogs during their first year of life. In the main analysis, we used national register data for all children born in Sweden from Jan 1st 2001 to Dec 31st 2004 with a registered dog in the household during their first year of life (n = 23,585). We used logistic regression models to study the association between dog characteristics and the risk of asthma or allergy diagnosis and medication at age six. The prevalence of asthma at age six was 5.4%. Children exposed to female dogs had lower risk of asthma compared to those exposed to male dogs, odds ratio, OR= 0.84 (95% confidence interval, CI 0.74 to 0.95). Children with two dogs or more had lower risk of asthma than those with one dog only, OR= 0.79 (95%Cl 0.65 to 0.95). Children whose parents had asthma and allergy had a higher frequency of exposure to dog breeds anecdotally described as "hypoallergenic" compared to those parents without asthma or allergy (11.7% vs 7.6%, p < 0.001). Exposure to these breeds were associated with higher risk of allergy OR= 1.27 (95% CI 1.02 to 1.59) but not asthma. In conclusion, we found evidence of an association between the sex of dog and the number of dogs with a lower risk of childhood asthma in dog-exposed children.

  • 12.
    Fall, Tove
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Gustafsson, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA USA.
    Genome-wide association study of coronary artery disease among individuals with diabetes: the UK Biobank2018Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, nr 10, s. 2174-2179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Coronary artery disease (CAD) is a common complication among individuals with diabetes. A better understanding of the genetic background of CAD in this population has the potential to suggest novel molecular targets for screening, risk assessment and drug development. We performed a genome-wide association study of CAD in 15,666 unrelated individuals (3,968 CAD cases and 11,698 controls) of white British ancestry with diabetes at inclusion in the UK Biobank study. Our results were compared with results from participants without diabetes. We found genome-wide significant evidence for association with CAD at the previously well-established LPA locus (lead variant: rs74617384; OR 1.38 [95% CI 1.26, 1.51], p = 3.2 x 10(-12)) and at 9p21 (lead variant: rs10811652; OR 1.19 [95% CI 1.13, 1.26], p = 6.0 x 10(-11)). Moreover, other variants previously associated with CAD showed similar effects in the participants with and without diabetes, indicating that the genetic architecture of CAD is largely the same. Our results indicate large similarities between the genetic architecture of CAD in participants with and without diabetes. Larger studies are needed to establish whether there are important diabetes-specific CAD loci.

  • 13.
    Fall, Tove
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hedman, Anna
    Karolinska Institutet.
    Pershagen, Göran
    Karolinska Institutet.
    Andolf, Ellika
    Karolinska Institutet.
    Almqvist, Catarina
    Karolinska Institutet.
    Helmersson-Karlqvist, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Reference Intervals for Fecal Calprotectin in Pregnant Women Using a Particle Enhanced Turbidimetric Assay2019Inngår i: Clinical Laboratory, ISSN 1433-6510, Vol. 65, nr 7, s. 1293-1297Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Fecal calprotectin is widely used as a marker for inflammatory bowel diseases (IBD). IBD often affects women during their reproductive years, but there are no established reference intervals during pregnancy. The aim of the present study was to define reference values during pregnancy and in the postpartum period to allow comparisons between patient results and reference values.

    METHODS: Fecal samples were collected from 84 healthy females during pregnancy week 26 to 28 and a second sample was collected six months after delivery. The samples were weighed, extracted, and centrifugated to remove debris. The extracted samples were then analyzed on a chemistry analyzer using a particle enhanced turbidimetric immunoassay reagent.

    RESULTS: The calculated reference interval during pregnancy was < 127 μg/g (90% confidence interval, 90 - 164 μg/g) and the corresponding reference interval during the postpartum period was < 143 μg/g (60 - 226 μg/g). There were no significant statistical differences between F-calprotectin values analyzed at the two sampling times.

    CONCLUSIONS: The reference values are slightly higher than the cutoff values of 50 - 100 μg/g often used as General cutoff for fecal calprotectin.

  • 14.
    Fall, Tove
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hägg, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Maegi, Reedik
    Ploner, Alexander
    Fischer, Krista
    Horikoshi, Momoko
    Sarin, Antti-Pekka
    Thorleifsson, Gudmar
    Ladenvall, Claes
    Kals, Mart
    Kuningas, Maris
    Draisma, Harmen H. M.
    Ried, Janina S.
    van Zuydam, Natalie R.
    Huikari, Ville
    Mangino, Massimo
    Sonestedt, Emily
    Benyamin, Beben
    Nelson, Christopher P.
    Rivera, Natalia V.
    Kristiansson, Kati
    Shen, Huei-yi
    Havulinna, Aki S.
    Dehghan, Abbas
    Donnelly, Louise A.
    Kaakinen, Marika
    Nuotio, Marja-Liisa
    Robertson, Neil
    de Bruijn, Renee F. A. G.
    Ikram, M. Arfan
    Amin, Najaf
    Balmforth, Anthony J.
    Braund, Peter S.
    Doney, Alexander S. F.
    Doering, Angela
    Elliott, Paul
    Esko, Tonu
    Franco, Oscar H.
    Gretarsdottir, Solveig
    Hartikainen, Anna-Liisa
    Heikkila, Kauko
    Herzig, Karl-Heinz
    Holm, Hilma
    Hottenga, Jouke Jan
    Hypponen, Elina
    Illig, Thomas
    Isaacs, Aaron
    Isomaa, Bo
    Karssen, Lennart C.
    Kettunen, Johannes
    Koenig, Wolfgang
    Kuulasmaa, Kari
    Laatikainen, Tiina
    Laitinen, Jaana
    Lindgren, Cecilia
    Lyssenko, Valeriya
    Laara, Esa
    Rayner, Nigel W.
    Mannisto, Satu
    Pouta, Anneli
    Rathmann, Wolfgang
    Rivadeneira, Fernando
    Ruokonen, Aimo
    Savolainen, Markku J.
    Sijbrands, Eric J. G.
    Small, Kerrin S.
    Smit, Jan H.
    Steinthorsdottir, Valgerdur
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Taanila, Anja
    Tobin, Martin D.
    Uitterlinden, Andre G.
    Willems, Sara M.
    Willemsen, Gonneke
    Witteman, Jacqueline
    Perola, Markus
    Evans, Alun
    Ferrieres, Jean
    Virtamo, Jarmo
    Kee, Frank
    Tregouet, David-Alexandre
    Arveiler, Dominique
    Amouyel, Philippe
    Ferrario, Marco M.
    Brambilla, Paolo
    Hall, Alistair S.
    Heath, AndrewC.
    Madden, Pamela A. F.
    Martin, Nicholas G.
    Montgomery, Grant W.
    Whitfield, John B.
    Jula, Antti
    Knekt, Paul
    Oostra, Ben
    van Duijn, Cornelia M.
    Penninx, Brenda W. J. H.
    Smith, George Davey
    Kaprio, Jaakko
    Samani, Nilesh J.
    Gieger, Christian
    Peters, Annette
    Wichmann, H. -Erich
    Boomsma, Dorret I.
    de Geus, Eco J. C.
    Tuomi, TiinaMaija
    Power, Chris
    Hammond, Christopher J.
    Spector, Tim D.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Orho-Melander, Marju
    Palmer, Colin Neil Alexander
    Morris, Andrew D.
    Groop, Leif
    Jarvelin, Marjo-Riitta
    Salomaa, Veikko
    Vartiainen, Erkki
    Hofman, Albert
    Ripatti, Samuli
    Metspalu, Andres
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Pedersen, Nancy L.
    McCarthy, Mark I.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Prokopenko, Inga
    The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis2013Inngår i: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, nr 6, s. e1001474-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

  • 15.
    Fall, Tove
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hägg, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ploner, Alexander
    Mägi, Reedik
    Fischer, Krista
    Draisma, Harmen H M
    Sarin, Antti-Pekka
    Benyamin, Beben
    Ladenvall, Claes
    Åkerlund, Mikael
    Kals, Mart
    Esko, Tõnu
    Nelson, Christopher P
    Kaakinen, Marika
    Huikari, Ville
    Mangino, Massimo
    Meirhaeghe, Aline
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Kobl, Michael
    Grallert, Harald
    Dehghan, Abbas
    Kuningas, Maris
    de Vries, Paul S
    de Bruijn, Renée F A G
    Willems, Sara M
    Heikkilä, Kauko
    Silventoinen, Karri
    Pietiläinen, Kirsi H
    Legry, Vanessa
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Goumidi, Louisa
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Strauch, Konstantin
    Koenig, Wolfgang
    Lichtner, Peter
    Herder, Christian
    Palotie, Aarno
    Menni, Cristina
    Uitterlinden, André G
    Kuulasmaa, Kari
    Havulinna, Aki S
    Moreno, Luis A
    Gonzalez-Gross, Marcela
    Evans, Alun
    Tregouet, David-Alexandre
    Yarnell, John W G
    Virtamo, Jarmo
    Ferrières, Jean
    Veronesi, Giovanni
    Perola, Markus
    Arveiler, Dominique
    Brambilla, Paolo
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Kaprio, Jaakko
    Hofman, Albert
    Stricker, Bruno H
    van Duijn, Cornelia M
    Ikram, M Arfan
    Franco, Oscar H
    Cottel, Dominique
    Dallongeville, Jean
    Hall, Alistair S
    Jula, Antti
    Tobin, Martin D
    Penninx, Brenda W
    Peters, Annette
    Gieger, Christian
    Samani, Nilesh J
    Montgomery, Grant W
    Whitfield, John B
    Martin, Nicholas G
    Groop, Leif
    Spector, Tim D
    Magnusson, Patrik K
    Amouyel, Philippe
    Boomsma, Dorret I
    Nilsson, Peter M
    Järvelin, Marjo-Riitta
    Lyssenko, Valeriya
    Metspalu, Andres
    Strachan, David P
    Salomaa, Veikko
    Ripatti, Samuli
    Pedersen, Nancy L
    Prokopenko, Inga
    McCarthy, Mark I
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Age- and sex-specific causal effects of adiposity on cardiovascular risk factors2015Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 5, s. 1841-1852Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.

  • 16.
    Fall, Tove
    et al.
    Dept. of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Ingelsson, Erik
    Dept. of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Genome-wide association studies of obesity and metabolic syndrome2014Inngår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 382, nr 1, s. 740-757Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Until just a few years ago, the genetic determinants of obesity and metabolic syndrome were largely unknown, with the exception of a few forms of monogenic extreme obesity. Since genome-wide association studies (GWAS) became available, large advances have been made. The first single nucleotide polymorphism robustly associated with increased body mass index (BMI) was in 2007 mapped to a gene with for the time unknown function. This gene, now known as fat mass and obesity associated (FTO) has been repeatedly replicated in several ethnicities and is affecting obesity by regulating appetite. Since the first report from a GWAS of obesity, an increasing number of markers have been shown to be associated with BMI, other measures of obesity or fat distribution and metabolic syndrome. This systematic review of obesity GWAS will summarize genome-wide significant findings for obesity and metabolic syndrome and briefly give a few suggestions of what is to be expected in the next few years.

  • 17.
    Fall, Tove
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kuja-Halkola, Ralf
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Dobney, Keith
    Univ Liverpool, Dept Archaeol Class & Egyptol, Liverpool, Merseyside, England.
    Westgarth, Carri
    Univ Liverpool, Inst Infect & Global Hlth, Liverpool, Merseyside, England;Univ Liverpool, Inst Vet Sci, Liverpool, Merseyside, England.
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Evidence of large genetic influences on dog ownership in the Swedish Twin Registry has implications for understanding domestication and health associations2019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 7554Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dogs were the first domesticated animal and, according to the archaeological evidence, have had a close relationship with humans for at least 15,000 years. Today, dogs are common pets in our society and have been linked to increased well-being and improved health outcomes in their owners. A dog in the family during childhood is associated with ownership in adult life. The underlying factors behind this association could be related to experiences or to genetic influences. We aimed to investigate the heritability of dog ownership in a large twin sample including all twins in the Swedish Twin Registry born between 1926 and 1996 and alive in 2006. Information about dog ownership was available from 2001 to 2016 from national dog registers. The final data set included 85,542 twins from 50,507 twin pairs with known zygosity, where information on both twins were available in 35,035 pairs. Structural equation modeling was performed to estimate additive genetic effects (the heritability), common/shared environmental, and unique/non-shared environmental effects. We found that additive genetic factors largely contributed to dog ownership, with heritability estimated at 57% for females and 51% for males. An effect of shared environmental factors was only observed in early adulthood. In conclusion, we show a strong genetic contribution to dog ownership in adulthood in a large twin study. We see two main implications of this finding: (1) genetic variation may have contributed to our ability to domesticate dogs and other animals and (2) potential pleiotropic effects of genetic variation affecting dog ownership should be considered in studies examining health impacts of dog ownership.

  • 18.
    Fall, Tove
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lundholm, Cecilia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Ortqvist, Anne K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Fall, Katja
    Orebro Univ Hosp, Clin Epidemiol & Biostat, Orebro, Sweden.;Univ Orebro, Sch Hlth & Med Sci, SE-70182 Orebro, Sweden..
    Fang, Fang
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hedhammar, Ake
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Kampe, Olle
    Karolinska Inst, Dept Med, Ctr Mol Med, Stockholm, Sweden..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Almqvist, Catarina
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Lung & Allergy Unit, Stockholm, Sweden..
    Early Exposure to Dogs and Farm Animals and the Risk of Childhood Asthma2015Inngår i: JAMA pediatrics, ISSN 2168-6203, E-ISSN 2168-6211, Vol. 169, nr 11, artikkel-id e153219Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    IMPORTANCE The association between early exposure to animals and childhood asthma is not clear, and previous studies have yielded contradictory results. OBJECTIVE To determine whether exposure to dogs and farm animals confers a risk of asthma. DESIGN, SETTING AND PARTICIPANTS In a nationwide cohort study, the association between early exposure to dogs and farm animals and the risk of asthma was evaluated and included all children born in Sweden from January 1, 2001, to December 31, 2010 (N = 1 011 051), using registry data on dog and farm registration, asthma medication, diagnosis, and confounders for parents and their children. The association was assessed as the odds ratio (OR) for a current diagnosis of asthma at age 6 years for school-aged children and as the hazard ratio (HR) for incident asthma at ages 1 to 5 years for preschool-aged children. Data were analyzed from January 1, 2007, to September 30, 2012. EXPOSURES Living with a dog or farm animal. MAIN OUTCOMES AND MEASURES Childhood asthma diagnosis and medication used. RESULTS Of the 1 011 051 children born during the study period, 376 638 preschool-aged (53 460 [14.2%] exposed to dogs and 1729 [0.5%] exposed to farm animals) and 276 298 school-aged children (22 629 [8.2%] exposed to dogs and 958 [0.3%] exposed to farm animals) were included in the analyses. Of these, 18 799 children (5.0%) in the preschool-aged children's cohort experienced an asthmatic event before baseline, and 28 511 cases of asthma and 906 071 years at risk were recorded during follow-up (incidence rate, 3.1 cases per 1000 years at risk). In the school-aged children's cohort, 11 585 children (4.2%) experienced an asthmatic event during the seventh year of life. Dog exposure during the first year of life was associated with a decreased risk of asthma in school-aged children (OR, 0.87; 95% CI, 0.81-0.93) and in preschool-aged children 3 years or older (HR, 0.90; 95% CI, 0.83-0.99) but not in children younger than 3 years (HR, 1.03; 95% CI, 1.00-1.07). Results were comparable when analyzing only first-born children. Farm animal exposure was associated with a reduced risk of asthma in both school-aged children and preschool-aged children (OR, 0.48; 95% CI, 0.31-0.76, and HR, 0.69; 95% CI, 0.56-0.84), respectively. CONCLUSIONS AND RELEVANCE In this study, the data support the hypothesis that exposure to dogs and farm animals during the first year of life reduces the risk of asthma in children at age 6 years. This information might be helpful in decision making for families and physicians on the appropriateness and timing of early animal exposure.

  • 19.
    Fall, Tove
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Mandic-Havelka, Aleksandra
    Karolinska Univ Hosp, Karolinska Inst & Clin Chem, Dept Mol Med & Surg.
    Helmersson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundstrom, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Reference Intervals for Fecal Calprotectin in Adults Using Two Different Extraction Methods in the Uppsala-SCAPIS Cohort.2017Inngår i: Clinical Laboratory, ISSN 1433-6510, Vol. 63, nr 9, s. 1493-1496Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Fecal calprotectin measurement is generally recommended to exclude inflammatory bowel disease (IBD) in patients with suspected IBD. A problem with the fecal calprotectin assays so far has been the rather long test-turnaround times. Recently a particle enhanced turbidimetric immunoassay (PETIA) for fecal calprotectin with assay times of approximately 10 minutes has been introduced on the European market. The aim of this study was to define reference intervals for adults with this new fecal calprotectin PETIA using two different extraction methods.

    Methods: Samples were collected from 382 healthy individuals from the Swedish CArdioPulmonary bioImage Study (SCAPIS) Uppsala cohort in the age range 50 - 65 years. 202 samples were processed with CALEX® Cap extraction device (BÜHLMANN, Schönenbuch, Switzerland) and 180 samples were extracted using weighed samples. The extracted samples were analyzed on a Mindray BS-380 using the fCal Turbo PETIA reagent (BÜHLMANN).

    Results: The calculated reference values for the Calex device were < 199 µg/g for the whole cohort, < 184 µg/g for females, and < 215 µg/g for males, while the corresponding values for weighed samples were < 153 µg/g for the whole cohort, < 141 µg/g for females, and < 215 µg/g for males. There were no significant statistical differences for calprotectin levels in males and females.

    Conclusions: The CALEX device yielded slightly higher calprotectin values. As there were no significant gender differences, the study indicates gender independent reference intervals of < 199 µg/g feces for the CALEX device and < 153 µg/g feces for weighed samples in patients in the 50 - 65 year age range.

  • 20.
    Fall, Tove
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mendelson, Michael
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.;Boston Childrens Hosp, Dept Cardiol, Boston, MA USA..
    Speliotes, Elizabeth K.
    Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Recent Advances in Human Genetics and Epigenetics of Adiposity: Pathway to Precision Medicine?2017Inngår i: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 152, nr 7, s. 1695-1706Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obesity is a heritable trait that contributes to substantial global morbidity and mortality. Here, we summarize findings from the past decade of genetic and epigenetic research focused on unravelling the underpinnings of adiposity. More than 140 genetic regions now are known to influence adiposity traits. The genetics of general adiposity, as measured by body mass index, and that of abdominal obesity, as measured by waist-to-hip ratio, have distinct biological backgrounds. Gene expression associated with general adiposity is enriched in the nervous system. In contrast, genes associated with abdominal adiposity function in adipose tissue. Recent population-based epigenetic analyses have highlighted additional distinct loci. We discuss how associated genetic variants can lead to understanding causal mechanisms, and to disentangling reverse causation in epigenetic analyses. Discoveries emerging from population genomics are identifying new disease markers and potential novel drug targets to better define and combat obesity and related diseases.

  • 21.
    Fall, Tove
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Xie, Weijia
    Poon, Wenny
    Yaghootkar, Hanieh
    Maegi, Reedik
    Knowles, Joshua W.
    Lyssenko, Valeriya
    Weedon, Michael
    Frayling, Timothy M.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes2015Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 7, s. 2676-2684Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C ( = -0.12, P = 0.03) and T2D and genetically determined lower LDL-C ( = -0.21, P = 5 x 10(-6)) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.

  • 22.
    Feldreich, Tobias
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Nowak, Christoph
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Carlsson, Axel C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Carrero, Juan-Jesus
    Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Solna, Sweden.
    Ripsweden, Jonas
    Karolinska Inst, Div Med Imaging & Technol, Dept Clin Sci Intervent & Technol, Campus Flemingsberg, Stockholm, Sweden.
    Qureshi, Abdul Rashid
    Karolinska Univ Hosp, Div Renal Med, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.
    Heimburger, Olof
    Karolinska Univ Hosp, Div Renal Med, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.
    Barany, Peter
    Karolinska Univ Hosp, Div Renal Med, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.
    Stenvinkel, Peter
    Karolinska Univ Hosp, Div Renal Med, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.
    Vuilleumier, Nicolas
    Geneva Univ Hosp, Dept Genet Lab Med & Pathol, Geneva, Switzerland;Geneva Fac Med, Dept Med Specialties, Geneva, Switzerland.
    Kalra, Philip A.
    Univ Manchester, Manchester Acad Hlth Sci Ctr, Div Cardiovasc Sci, Manchester, Lancs, England;Salford Royal NHS Fdn Trust, Dept Renal, Med, Stott Lane, Salford, Lancs, England.
    Green, Darren
    Univ Manchester, Manchester Acad Hlth Sci Ctr, Div Cardiovasc Sci, Manchester, Lancs, England;Salford Royal NHS Fdn Trust, Dept Renal, Med, Stott Lane, Salford, Lancs, England.
    Arnlov, Johan
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Circulating proteins as predictors of cardiovascular mortality in end-stage renal disease2019Inngår i: JN. Journal of Nephrology (Milano. 1992), ISSN 1121-8428, E-ISSN 1724-6059, Vol. 32, nr 1, s. 111-119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Proteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n=183, 55% women, mean age 63years, 46 cardiovascular deaths during follow-up (mean 43months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n=186, 73% women, mean age 62years, 45 cardiovascular deaths during follow-up (mean 12months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n=89, 37% women, mean age 46years).

    Results

    In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26-2.69, p=0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C=0.777 to C=0.799 and C=0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03-2.05, p=0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort.

    Conclusions

    Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies.

  • 23.
    Figarska, Sylwia M.
    et al.
    Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA;Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr, Stanford, CA 94305 USA.
    Gustafsson, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden;Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden.
    Mälarstig, Anders
    Pfizer Worldwide Res & Dev, Stockholm, Sweden;Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.
    Elmstahl, Sölve
    Lund Univ, Malmo Univ Hosp, Dept Clin Sci, Div Geriatr Med, Lund, Sweden.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA;Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr, Stanford, CA 94305 USA.
    Associations of Circulating Protein Levels With Lipid Fractions in the General Population2018Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, nr 10, s. 2505-2518Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Revealing patterns of associations between circulating protein and lipid levels could improve biological understanding of cardiovascular disease (CVD). In this study, we investigated the associations between proteins related to CVD and triglyceride (TG), total cholesterol, LDL (low-density lipoprotein), and HDL (high-density lipoprotein) cholesterol levels in individuals from the general population.

    Approach and Results: We measured plasma protein levels using the Olink ProSeek CVD I or II+III arrays and analyzed 57 proteins available in 3 population-based cohorts: EpiHealth (n=2029; 52% women; median age, 61 years), PIVUS (Prospective Study of the Vasculature in Uppsala Seniors; n=790; 51% women; all aged 70 years), and ULSAM (Uppsala Longitudinal Study of Adult Men; n=551; all men aged 77 years). A discovery analysis was performed in EpiHealth in a regression framework (adjusted for sex, age, body mass index, smoking, glucose levels, systolic blood pressure, blood pressure medication, diabetes mellitus medication, and CVD history), and associations with false discovery rate <0.05 were further tested in PIVUS and ULSAM, where a P value of 0.05 was considered a successful replication (validation false discovery rate of 0.1%). We used summary statistics from a genome-wide association study on each protein biomarker (meta-analysis of EpiHealth, PIVUS, ULSAM, and IMPROVE [Carotid Intima-Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population]) and publicly available data from Global Lipids Genetics Consortium to perform Mendelian randomization analyses to address possible causality of protein levels. Of 57 tested proteins, 42 demonstrated an association with at least 1 lipid fraction; 35 were associated with TG, 15 with total cholesterol, 9 with LDL cholesterol, and 24 with HDL cholesterol. Among these associations, we found KIM-1 (kidney injury molecule-1), TNFR (TNF [tumor necrosis factor] receptor) 1 and 2, TRAIL-R2 (TRAIL [TNF-related apoptosis-inducing ligand] receptor 2), and RETN (resistin) to be associated with all 4 lipid fractions. Further, 15 proteins were related to both TG and HDL cholesterol in a consistent and biologically expected manner, that is, higher TG and lower HDL cholesterol or vice versa. Another common pattern of associations was concomitantly higher TG, total cholesterol, and LDL cholesterol, which is associated with higher CVD risk. We did not find evidence of causal links for protein levels.

    Conclusions: Our comprehensive analysis of plasma proteins and lipid fractions of 3370 individuals from the general population provides new information about lipid metabolism.

  • 24. Ganna, Andrea
    et al.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    1-acyl-sn-glycero-3-phosphocholine Levels are Related to Obesity and Several Markers of Subclinical CV Disease and its Biosynthesis is Associated With Genetic Variants in the 9p21 Region2013Inngår i: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 128, nr 22Artikkel i tidsskrift (Annet vitenskapelig)
  • 25.
    Ganna, Andrea
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lee, Woojoo
    Broeckling, Corey D.
    Kumar, Jitender
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Hägg, Sara
    Stenemo, Markus
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Magnusson, Patrik K.E.
    Prenni, Jessica E.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Pawitan, Yudi
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Large-scale non-targeted metabolomic profiling in three human population-based studies2016Inngår i: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, artikkel-id 4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-targeted metabolomic profiling is used to simultaneously assess a large part of the metabolome in a biological sample. Here, we describe both the analytical and computational methods used to analyze a large UPLC–Q-TOF MS-based metabolomic profiling effort using plasma and serum samples from participants in three Swedish population-based studies of middle-aged and older human subjects: TwinGene, ULSAM and PIVUS. At present, more than 200 metabolites have been manually annotated in more than 3600 participants using an in-house library of standards and publically available spectral databases. Data available at the metabolights repository include individual raw unprocessed data, processed data, basic demographic variables and spectra of annotated metabolites. Additional phenotypical and genetic data is available upon request to cohort steering committees. These studies represent a unique resource to explore and evaluate how metabolic variability across individuals affects human diseases.

  • 26.
    Ganna, Andrea
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Broeckling, Corey D
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America.
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Magnusson, Patrik K E
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Pedersen, Nancy L
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Zilmer, Mihkel
    Department of Biochemistry, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
    Prenni, Jessica
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease2014Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, nr 12, s. e1004801-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.

  • 27. Gao, He
    et al.
    Fall, Tove
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    van Dam, Rob M
    Flyvbjerg, Allan
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Hägg, Sara
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Evidence of a Causal Relationship Between Adiponectin Levels and Insulin Sensitivity: A Mendelian Randomization Study2013Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, nr 4, s. 1338-1344Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The adipocyte-secreted protein adiponectin is associated with insulin sensitivity in observational studies. We aimed to evaluate whether this relationship is causal using a Mendelian randomization approach. In a sample of Swedish men aged 71 years (n = 942) from the Uppsala Longitudinal Study of Adult Men (ULSAM), insulin sensitivity (M/I ratio) was measured by the euglycemic insulin clamp. We used three genetic variants in the ADIPOQ locus as instrumental variables (IVs) to estimate the potential causal effect of adiponectin on insulin sensitivity and compared these with results from conventional linear regression. The three ADIPOQ variants, rs17300539, rs3774261, and rs6444175, were strongly associated with serum adiponectin levels (all P ≤ 5.3 × 10−9) and were also significantly associated with M/I ratio in the expected direction (all P ≤ 0.022). IV analysis confirmed that genetically determined adiponectin increased insulin sensitivity (β = 0.47–0.81, all P ≤ 0.014) comparable with observational estimates (β = 0.50, all Pdifference ≥ 0.136). Adjustment for BMI and waist circumference partly explained the association of both genetically determined and observed adiponectin levels with insulin sensitivity. The observed association between higher adiponectin levels and increased insulin sensitivity is likely to represent a causal relationship partly mediated by reduced adiposity.

  • 28.
    Hillström, Anna
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Bylin, Jonas
    Evidensia Sodra Djursjukhuset, Stockholm, Sweden..
    Hagman, Ragnvi
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Björhall, Karin
    AstraZeneca R&D, RIA IMed, Dept Translat Sci, Molndal, Sweden..
    Tvedten, Harold
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Königsson, Kristian
    AstraZeneca R&D Sodertalje, Safety Assessment, Sodertalje, Sweden..
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kjelgaard-Hansen, Mads
    Novo Nordisk, Translat Haemophilia Pharmacol, Malov, Denmark..
    Measurement of serum C-reactive protein concentration for discriminating between suppurative arthritis and osteoarthritis in dogs2016Inngår i: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 12, artikkel-id 240Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In a dog with joint pain, it is important to determine whether it has suppurative joint disease, characterized by exudation of neutrophils in the synovial fluid, or not, as this affects choice of diagnostic tests and treatments. The aim of this study was to evaluate whether measurement of serum C-reactive protein (CRP) concentration could be used to discriminate between dogs with suppurative arthritis and osteoarthritis (OA). Furthermore, the concentrations of serum and synovial fluid interleukin (IL) 6 concentrations were measured in dogs with joint disease and in healthy dogs, and were correlated to serum CRP concentrations. Methods: Dogs with joint pain were enrolled prospectively and were classified to have suppurative arthritis or OA based on synovial fluid analysis and radiographic/arthroscopic findings. Healthy Beagles were enrolled as a comparative group. CRP and IL-6 concentrations were measured with canine-specific immunoassays. The performance of CRP concentration in discriminating between dogs with suppurative arthritis and OA was evaluated using a previously established clinical decision limit for CRP (20 mg/l), and by receiver operator characteristic (ROC) curve and logistic regression analysis. Comparisons of CRP and IL-6 concentrations between groups were performed using t-tests, and correlations by Spearman rank correlation coefficients. Results: Samples were obtained from 31 dogs with suppurative arthritis, 34 dogs with OA, and 17 healthy dogs. Sixty-two out of 65 dogs with joint disease were correctly classified using the clinical decision limit for CRP. Evaluation of ROC curve and regression analysis indicated that serum CRP concentrations could discriminate between suppurative arthritis and OA. Dogs with suppurative arthritis had higher serum CRP and serum and synovial fluid IL-6 concentrations compared to dogs with OA (p < 0.001). Dogs with OA had higher synovial fluid IL-6 concentrations (p < 0.001), but not higher serum CRP (p = 0.29) or serum IL-6 (p = 0.07) concentrations, compared to healthy dogs. There was a positive correlation between synovial fluid IL-6 and serum CRP concentrations (r(s) = 0.733, p < 0.001), and between serum IL-6 and serum CRP concentrations (r(s) = 0.729, p < 0.001). Conclusion: CRP concentration was found to discriminate well between dogs with suppurative arthritis and OA.

  • 29.
    Hägg, Sara
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ploner, Alexander
    Maegi, Reedik
    Fischer, Krista
    Draisma, Harmen H. M.
    Kals, Mart
    de Vries, Paul S.
    Dehghan, Abbas
    Willems, Sara M.
    Sarin, Antti-Pekka
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Havulinna, Aki S.
    de Bruijn, Renee F. A. G.
    Ikram, M. Arfan
    Kuningas, Maris
    Stricker, Bruno H.
    Franco, Oscar H.
    Benyamin, Beben
    Gieger, Christian
    Hall, Alistair S.
    Huikari, Ville
    Jula, Antti
    Jarvelin, Marjo-Riitta
    Kaakinen, Marika
    Kaprio, Jaakko
    Kobl, Michael
    Mangino, Massimo
    Nelson, Christopher P.
    Palotie, Aarno
    Samani, Nilesh J.
    Spector, Tim D.
    Strachan, David P.
    Tobin, Martin D.
    Whitfield, John B.
    Uitterlinden, Andre G.
    Salomaa, Veikko
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kuulasmaa, Kari
    Magnusson, Patrik K.
    Esko, Tonu
    Hofman, Albert
    de Geus, Eco J. C.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Perola, Markus
    Evans, Alun
    Ferrieres, Jean
    Virtamo, Jarmo
    Kee, Frank
    Tregouet, David-Alexandre
    Arveiler, Dominique
    Amouyel, Philippe
    Gianfagna, Francesco
    Brambilla, Paolo
    Ripatti, Samuli
    van Duijn, Cornelia M.
    Metspalu, Andres
    Prokopenko, Inga
    McCarthy, Mark I.
    Pedersen, Nancy L.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Adiposity as a cause of cardiovascular disease: a Mendelian randomization study2015Inngår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, nr 2, s. 578-586Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (beta = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.

  • 30.
    Kamble, Prasad G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Gustafsson, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Lundkvist, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Cook, Naomi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Franks, Paul W.
    Lund Univ, Diabet Ctr, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Genotype-based recall to study metabolic effects of genetic variation: a pilot study of PPARG Pro12Ala carriers2017Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, nr 4, s. 234-242Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: To assess practical implications of genotype-based recall (GBR) studies, an increasingly popular approach for in-depth characterization of genotype-phenotype relationships.

    METHODS: We genotyped 2500 participants from the Swedish EpiHealth cohort and considered loss-of-function and missense variants in genes with relation to cardiometabolic traits as the basis for our GBR study. Therefore, we focused on carriers and non-carriers of the PPARG Pro12Ala (rs1801282) variant, as it is a relatively common variant with a minor allele frequency (MAF) of 0.14. It has also been shown to affect ligand binding and transcription, and carriage of the minor allele (Ala12) is associated with a reduced risk of type 2 diabetes. We re-invited 39 Pro12Pro, 34 Pro12Ala, and 30 Ala12Ala carriers and performed detailed anthropometric and serological assessments.

    RESULTS: The participation rates in the GBR study were 31%, 44%, and 40%, and accordingly we included 12, 15, and 13 individuals with Pro12Pro, Pro12Ala, and Ala12Ala variants, respectively. There were no differences in anthropometric or metabolic variables among the different genotype groups.

    CONCLUSIONS: Our report highlights that from a practical perspective, GBR can be used to study genotype-phenotype relationships. This approach can prove to be a valuable tool for follow-up findings from large-scale genetic discovery studies by undertaking detailed phenotyping procedures that might not be feasible in large studies. However, our study also illustrates the need for a larger pool of genotyped or sequenced individuals to allow for selection of rare variants with larger effects that can be examined in a GBR study of the present size.

  • 31.
    Kamble, Prasad G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Gustafsson, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lundkvist, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Castillejo-Lopez, Casimiro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA..
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    PPARG Pro12Ala variant in relation to adipose tissue metabolism and differentiation: a small genotype-based recall study2017Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, nr S1, s. S173-S173, artikkel-id 375Artikkel i tidsskrift (Annet vitenskapelig)
  • 32.
    Kamble, Prasad G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Gustafsson, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lundkvist, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Castillejo-Lopez, Casimiro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Role of peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism in human adipose tissue: assessment of adipogenesis and adipocyte glucose and lipid turnover.2018Inngår i: Adipocyte, ISSN 2162-3945, E-ISSN 2162-397X, Vol. 7, nr 4, s. 285-296Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Protective mechanisms of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala polymorphism in type 2 diabetes (T2D) are unclear. We obtained adipose tissue (AT) before and 3 h after oral glucose (OGTT) in carriers and non-carriers of the Ala allele (12 Pro/Pro, 15 Pro/Ala, and 13 Ala/Ala). Adipogenesis, adipocyte glucose uptake and lipolysis as well as PPARγ target genes expression were investigated and compared between the genotype groups. On fasting and post-OGTT, neither basal nor insulin-stimulated adipocyte glucose uptake differed between genotypes. Compared to fasting, a decreased hormone-sensitive lipase gene expression in Pro/Pro (p<0.05) also accompanied with a higher antilipolytic effect of insulin post-OGTT (p<0.01). The adipocyte size was similar across groups. Preadipocyte differentiation rates between Pro/Pro and Ala/Ala were unchanged. In conclusion, no major differences in AT differentiation, glucose uptake, lipolysis or expression of PPARγ target genes were observed between different PPARγ Pro12Ala genotypes. Albeit small, our study may suggest that other pathways in AT or effects exerted in other tissues might contribute to the Pro12Ala-mediated protection against T2D.

  • 33. Klütsch, C F C
    et al.
    Seppälä, E H
    Fall, Tove
    Department of Clinical Sciences, Swedish University of Agricultural Sciences.
    Uhlén, M
    Hedhammar, Å
    Lohi, H
    Savolainen, P
    Regional occurrence, high frequency but low diversity of mitochondrial DNA haplogroup d1 suggests a recent dog-wolf hybridization in Scandinavia2011Inngår i: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 42, nr 1, s. 100-103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The domestic dog mitochondrial DNA (mtDNA)-gene pool consists of a homogenous mix of haplogroups shared among all populations worldwide, indicating that the dog originated at a single time and place. However, one small haplogroup, subclade d1, found among North Scandinavian/Finnish spitz breeds at frequencies above 30%, has a clearly separate origin. We studied the genetic and geographical diversity for this phylogenetic group to investigate where and when it originated and whether through independent domestication of wolf or dog-wolf crossbreeding. We analysed 582 bp of the mtDNA control region for 514 dogs of breeds earlier shown to harbour d1 and possibly related northern spitz breeds. Subclade d1 occurred almost exclusively among Swedish/Finnish Sami reindeer-herding spitzes and some Swedish/Norwegian hunting spitzes, at a frequency of mostly 60-100%. Genetic diversity was low, with only four haplotypes: a central, most frequent, one surrounded by two haplotypes differing by an indel and one differing by a substitution. The substitution was found in a single lineage, as a heteroplasmic mix with the central haplotype. The data indicate that subclade d1 originated in northern Scandinavia, at most 480-3000 years ago and through dog-wolf crossbreeding rather than a separate domestication event. The high frequency of d1 suggests that the dog-wolf hybrid phenotype had a selective advantage.

  • 34.
    Kumar, Jitender
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    No Evidence of a Causal Relationship between Plasma Homocysteine and Type 2 Diabetes: A Mendelian Randomization Study2015Inngår i: Frontiers in Cardiovascular Medicine, ISSN 1539-4565, E-ISSN 2296-701X, Vol. 2, artikkel-id 11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Several observational studies have shown an association between increased circulating homocysteine and risk of type 2 diabetes (T2D). We aimed to assess whether this relation is causal using genetic data from large populations of individuals of European descent.

    METHODS: We investigated the association between homocysteine concentrations and blood glucose, plasma insulin, T2D in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort (n = 1,016). A score of five previously published single nucleotide polymorphisms (SNPs) from genes involved in homocysteine metabolism were utilized as genetic instrument for homocysteine concentrations. The effect estimate of this genetic score with T2D was determined using results from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (including 34,840 cases and 114,981 controls). Further, the effects of the genetic score with fasting glucose and insulin were determined using results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (up to 38,238 non-diabetic participants).

    RESULTS: The genetic score provided a strong instrument for homocysteine concentrations (P = 2.7 × 10(-143), F = 650). In the PIVUS cohort, we found an association of homocysteine with fasting insulin [β = 0.056 (95% CI 0.021, 0.090), P = 0.001], but not with incident diabetes. We did not find any evidence of a causal effect of homocysteine on fasting glucose, fasting insulin, or T2D (P > 0.05 for all analyses) when using data from DIAGRAM or MAGIC studies.

    CONCLUSION: No evidence of a causal relationship of levels of plasma homocysteine with fasting glucose, fasting insulin, or T2D was observed.

  • 35.
    Landegren, Nils
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden.
    Rosen, Lindsey B.
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Freyhult, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Natl Bioinformat Infrastruct, Dept Med Sci, Uppsala, Sweden.
    Eriksson, Daniel
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Smith, Gustav
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden;MIT, Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02139 USA;Lund Univ, Ctr Diabet, Wallenberg Ctr Mol Med, Lund, Sweden.
    Ferre, Elise M. N.
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Brodin, Petter
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden;Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, Stockholm, Sweden;Karolinska Univ Hosp, Dept Newborn Med, Stockholm, Sweden.
    Sharon, Donald
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Snyder, Michael
    Lund Univ, Ctr Diabet, Wallenberg Ctr Mol Med, Lund, Sweden;Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Lionakis, Michail
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Anderson, Mark
    Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
    Kampe, Olle
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;Univ Bergen, KG Jebsen Ctr Autoimmune Dis, Bergen, Norway.
    Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'2019Inngår i: eLIFE, E-ISSN 2050-084X, Vol. 8, artikkel-id e43578Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    The AIRE gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with AIRE-deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with AIRE-deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion.

  • 36.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Penell, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Luttropp, Karin
    Nordfors, Louise
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    van Bavel, Bert
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, P Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population2013Inngår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 59, s. 456-461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p=0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p=0.009) only in subjects with one G-allele (n=103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p=0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross-sectional analysis.

  • 37.
    Ljungberg, Johan
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden..
    Janiec, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergdahl, Ingvar A.
    Umea Univ, Dept Biobank Res, Umea, Sweden..
    Holmgren, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden..
    Hultdin, Johan
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Johansson, Bengt
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden..
    Näslund, Ulf
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden..
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Söderberg, Stefan
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden..
    Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement2018Inngår i: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 138, nr 6, s. 590-599Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights.

    Methods: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study.

    Results: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease.

    Conclusions: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

  • 38. Locke, Adam E
    et al.
    Kahali, Bratati
    Berndt, Sonja I
    Justice, Anne E
    Pers, Tune H
    Day, Felix R
    Powell, Corey
    Vedantam, Sailaja
    Buchkovich, Martin L
    Yang, Jian
    Croteau-Chonka, Damien C
    Esko, Tonu
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ferreira, Teresa
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kutalik, Zoltán
    Luan, Jian'an
    Mägi, Reedik
    Randall, Joshua C
    Winkler, Thomas W
    Wood, Andrew R
    Workalemahu, Tsegaselassie
    Faul, Jessica D
    Smith, Jennifer A
    Hua Zhao, Jing
    Zhao, Wei
    Chen, Jin
    Fehrmann, Rudolf
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karjalainen, Juha
    Schmidt, Ellen M
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bolton, Jennifer L
    Bragg-Gresham, Jennifer L
    Buyske, Steven
    Demirkan, Ayse
    Deng, Guohong
    Ehret, Georg B
    Feenstra, Bjarke
    Feitosa, Mary F
    Fischer, Krista
    Goel, Anuj
    Gong, Jian
    Jackson, Anne U
    Kanoni, Stavroula
    Kleber, Marcus E
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Medland, Sarah E
    Nalls, Michael A
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Peters, Marjolein J
    Prokopenko, Inga
    Shungin, Dmitry
    Stančáková, Alena
    Strawbridge, Rona J
    Ju Sung, Yun
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van Setten, Jessica
    Van Vliet-Ostaptchouk, Jana V
    Wang, Zhaoming
    Yengo, Loïc
    Zhang, Weihua
    Isaacs, Aaron
    Albrecht, Eva
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Arscott, Gillian M
    Attwood, Antony P
    Bandinelli, Stefania
    Barrett, Amy
    Bas, Isabelita N
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Blagieva, Roza
    Blüher, Matthias
    Böhringer, Stefan
    Bonnycastle, Lori L
    Böttcher, Yvonne
    Boyd, Heather A
    Bruinenberg, Marcel
    Caspersen, Ida H
    Ida Chen, Yii-Der
    Clarke, Robert
    Warwick Daw, E
    de Craen, Anton J M
    Delgado, Graciela
    Dimitriou, Maria
    Doney, Alex S F
    Eklund, Niina
    Estrada, Karol
    Eury, Elodie
    Folkersen, Lasse
    Fraser, Ross M
    Garcia, Melissa E
    Geller, Frank
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gigante, Bruna
    Go, Alan S
    Golay, Alain
    Goodall, Alison H
    Gordon, Scott D
    Gorski, Mathias
    Grabe, Hans-Jörgen
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grönberg, Henrik
    Groves, Christopher J
    Gusto, Gaëlle
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    Hallmans, Goran
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L
    Helmer, Quinta
    Hengstenberg, Christian
    Holmen, Oddgeir
    Hottenga, Jouke-Jan
    James, Alan L
    Jeff, Janina M
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Kinnunen, Leena
    Koenig, Wolfgang
    Koskenvuo, Markku
    Kratzer, Wolfgang
    Laitinen, Jaana
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R
    Lichtner, Peter
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindström, Jaana
    Sin Lo, Ken
    Lobbens, Stéphane
    Lorbeer, Roberto
    Lu, Yingchang
    Mach, François
    Magnusson, Patrik K E
    Mahajan, Anubha
    McArdle, Wendy L
    McLachlan, Stela
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L
    Morken, Mario A
    Mulas, Antonella
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Musk, Arthur W
    Nagaraja, Ramaiah
    Nöthen, Markus M
    Nolte, Ilja M
    Pilz, Stefan
    Rayner, Nigel W
    Renstrom, Frida
    Rettig, Rainer
    Ried, Janina S
    Ripke, Stephan
    Robertson, Neil R
    Rose, Lynda M
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R
    Scott, William R
    Seufferlein, Thomas
    Shi, Jianxin
    Vernon Smith, Albert
    Smolonska, Joanna
    Stanton, Alice V
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen
    Stringham, Heather M
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Swertz, Morris A
    Swift, Amy J
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tan, Sian-Tsung
    Tayo, Bamidele O
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tyrer, Jonathan P
    Uh, Hae-Won
    Vandenput, Liesbeth
    Verhulst, Frank C
    Vermeulen, Sita H
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Warren, Helen R
    Waterworth, Dawn
    Weedon, Michael N
    Wilkens, Lynne R
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Wright, Alan F
    Zhang, Qunyuan
    Brennan, Eoin P
    Choi, Murim
    Dastani, Zari
    Drong, Alexander W
    Eriksson, Per
    Franco-Cereceda, Anders
    Gådin, Jesper R
    Gharavi, Ali G
    Goddard, Michael E
    Handsaker, Robert E
    Huang, Jinyan
    Karpe, Fredrik
    Kathiresan, Sekar
    Keildson, Sarah
    Kiryluk, Krzysztof
    Kubo, Michiaki
    Lee, Jong-Young
    Liang, Liming
    Lifton, Richard P
    Ma, Baoshan
    McCarroll, Steven A
    McKnight, Amy J
    Min, Josine L
    Moffatt, Miriam F
    Montgomery, Grant W
    Murabito, Joanne M
    Nicholson, George
    Nyholt, Dale R
    Okada, Yukinori
    Perry, John R B
    Dorajoo, Rajkumar
    Reinmaa, Eva
    Salem, Rany M
    Sandholm, Niina
    Scott, Robert A
    Stolk, Lisette
    Takahashi, Atsushi
    Tanaka, Toshihiro
    Van't Hooft, Ferdinand M
    Vinkhuyzen, Anna A E
    Westra, Harm-Jan
    Zheng, Wei
    Zondervan, Krina T
    Heath, Andrew C
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Blangero, John
    Bovet, Pascal
    Campbell, Harry
    Caulfield, Mark J
    Cesana, Giancarlo
    Chakravarti, Aravinda
    Chasman, Daniel I
    Chines, Peter S
    Collins, Francis S
    Crawford, Dana C
    Adrienne Cupples, L
    Cusi, Daniele
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M
    Dominiczak, Anna F
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G
    Farrall, Martin
    Felix, Stephan B
    Ferrannini, Ele
    Ferrières, Jean
    Ford, Ian
    Forouhi, Nita G
    Forrester, Terrence
    Franco, Oscar H
    Gansevoort, Ron T
    Gejman, Pablo V
    Gieger, Christian
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hall, Alistair S
    Harris, Tamara B
    Hattersley, Andrew T
    Hicks, Andrew A
    Hindorff, Lucia A
    Hingorani, Aroon D
    Hofman, Albert
    Homuth, Georg
    Kees Hovingh, G
    Humphries, Steve E
    Hunt, Steven C
    Hyppönen, Elina
    Illig, Thomas
    Jacobs, Kevin B
    Jarvelin, Marjo-Riitta
    Jöckel, Karl-Heinz
    Johansen, Berit
    Jousilahti, Pekka
    Wouter Jukema, J
    Jula, Antti M
    Kaprio, Jaakko
    Kastelein, John J P
    Keinanen-Kiukaanniemi, Sirkka M
    Kiemeney, Lambertus A
    Knekt, Paul
    Kooner, Jaspal S
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lyssenko, Valeriya
    Männistö, Satu
    Marette, André
    Matise, Tara C
    McKenzie, Colin A
    McKnight, Barbara
    Moll, Frans L
    Morris, Andrew D
    Morris, Andrew P
    Murray, Jeffrey C
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Madden, Pamela A F
    Pasterkamp, Gerard
    Peden, John F
    Peters, Annette
    Postma, Dirkje S
    Pramstaller, Peter P
    Price, Jackie F
    Qi, Lu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ridker, Paul M
    Rioux, John D
    Ritchie, Marylyn D
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schunkert, Heribert
    Schwarz, Peter E H
    Sever, Peter
    Shuldiner, Alan R
    Sinisalo, Juha
    Stolk, Ronald P
    Strauch, Konstantin
    Tönjes, Anke
    Trégouët, David-Alexandre
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Völker, Uwe
    Waeber, Gérard
    Willemsen, Gonneke
    Witteman, Jacqueline C
    Zillikens, M Carola
    Adair, Linda S
    Amouyel, Philippe
    Asselbergs, Folkert W
    Assimes, Themistocles L
    Bochud, Murielle
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bornstein, Stefan R
    Bottinger, Erwin P
    Bouchard, Claude
    Cauchi, Stéphane
    Chambers, John C
    Chanock, Stephen J
    Cooper, Richard S
    de Bakker, Paul I W
    Dedoussis, George
    Ferrucci, Luigi
    Franks, Paul W
    Froguel, Philippe
    Groop, Leif C
    Haiman, Christopher A
    Hamsten, Anders
    Hui, Jennie
    Hunter, David J
    Hveem, Kristian
    Kaplan, Robert C
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G
    März, Winfried
    Melbye, Mads
    Metspalu, Andres
    Moebus, Susanne
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Rivadeneira, Fernando
    Saaristo, Timo E
    Saleheen, Danish
    Sattar, Naveed
    Schadt, Eric E
    Schlessinger, David
    Eline Slagboom, P
    Snieder, Harold
    Spector, Tim D
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    van der Harst, Pim
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J
    Watkins, Hugh
    Weir, David R
    Wichmann, H-Erich
    Wilson, James F
    Zanen, Pieter
    Borecki, Ingrid B
    Deloukas, Panos
    Fox, Caroline S
    Heid, Iris M
    O'Connell, Jeffrey R
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Abecasis, Gonçalo R
    Franke, Lude
    Frayling, Timothy M
    McCarthy, Mark I
    Visscher, Peter M
    Scherag, André
    Willer, Cristen J
    Boehnke, Michael
    Mohlke, Karen L
    Lindgren, Cecilia M
    Beckmann, Jacques S
    Barroso, Inês
    North, Kari E
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hirschhorn, Joel N
    Loos, Ruth J F
    Speliotes, Elizabeth K
    Genetic studies of body mass index yield new insights for obesity biology2015Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, nr 7538, s. 197-206Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

  • 39. Loth, Daan W
    et al.
    Artigas, María Soler
    Gharib, Sina A
    Wain, Louise V
    Franceschini, Nora
    Koch, Beate
    Pottinger, Tess D
    Smith, Albert Vernon
    Duan, Qing
    Oldmeadow, Chris
    Lee, Mi Kyeong
    Strachan, David P
    James, Alan L
    Huffman, Jennifer E
    Vitart, Veronique
    Ramasamy, Adaikalavan
    Wareham, Nicholas J
    Kaprio, Jaakko
    Wang, Xin-Qun
    Trochet, Holly
    Kähönen, Mika
    Flexeder, Claudia
    Albrecht, Eva
    Lopez, Lorna M
    de Jong, Kim
    Thyagarajan, Bharat
    Alves, Alexessander Couto
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Omenaas, Ernst
    Joshi, Peter K
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Viñuela, Ana
    Launer, Lenore J
    Loehr, Laura R
    Fornage, Myriam
    Li, Guo
    Wilk, Jemma B
    Tang, Wenbo
    Manichaikul, Ani
    Lahousse, Lies
    Harris, Tamara B
    North, Kari E
    Rudnicka, Alicja R
    Hui, Jennie
    Gu, Xiangjun
    Lumley, Thomas
    Wright, Alan F
    Hastie, Nicholas D
    Campbell, Susan
    Kumar, Rajesh
    Pin, Isabelle
    Scott, Robert A
    Pietiläinen, Kirsi H
    Surakka, Ida
    Liu, Yongmei
    Holliday, Elizabeth G
    Schulz, Holger
    Heinrich, Joachim
    Davies, Gail
    Vonk, Judith M
    Wojczynski, Mary
    Pouta, Anneli
    Johansson, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Wild, Sarah H
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rivadeneira, Fernando
    Völzke, Henry
    Hysi, Pirro G
    Eiriksdottir, Gudny
    Morrison, Alanna C
    Rotter, Jerome I
    Gao, Wei
    Postma, Dirkje S
    White, Wendy B
    Rich, Stephen S
    Hofman, Albert
    Aspelund, Thor
    Couper, David
    Smith, Lewis J
    Psaty, Bruce M
    Lohman, Kurt
    Burchard, Esteban G
    Uitterlinden, André G
    Garcia, Melissa
    Joubert, Bonnie R
    McArdle, Wendy L
    Musk, A Bill
    Hansel, Nadia
    Heckbert, Susan R
    Zgaga, Lina
    van Meurs, Joyce B J
    Navarro, Pau
    Rudan, Igor
    Oh, Yeon-Mok
    Redline, Susan
    Jarvis, Deborah L
    Zhao, Jing Hua
    Rantanen, Taina
    O'Connor, George T
    Ripatti, Samuli
    Scott, Rodney J
    Karrasch, Stefan
    Grallert, Harald
    Gaddis, Nathan C
    Starr, John M
    Wijmenga, Cisca
    Minster, Ryan L
    Lederer, David J
    Pekkanen, Juha
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Campbell, Harry
    Morris, Andrew P
    Gläser, Sven
    Hammond, Christopher J
    Burkart, Kristin M
    Beilby, John
    Kritchevsky, Stephen B
    Gudnason, Vilmundur
    Hancock, Dana B
    Williams, O Dale
    Polasek, Ozren
    Zemunik, Tatijana
    Kolcic, Ivana
    Petrini, Marcy F
    Wjst, Matthias
    Kim, Woo Jin
    Porteous, David J
    Scotland, Generation
    Smith, Blair H
    Viljanen, Anne
    Heliövaara, Markku
    Attia, John R
    Sayers, Ian
    Hampel, Regina
    Gieger, Christian
    Deary, Ian J
    Boezen, H Marike
    Newman, Anne
    Jarvelin, Marjo-Riitta
    Wilson, James F
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Stricker, Bruno H
    Teumer, Alexander
    Spector, Timothy D
    Melén, Erik
    Peters, Marjolein J
    Lange, Leslie A
    Barr, R Graham
    Bracke, Ken R
    Verhamme, Fien M
    Sung, Joohon
    Hiemstra, Pieter S
    Cassano, Patricia A
    Sood, Akshay
    Hayward, Caroline
    Dupuis, Josée
    Hall, Ian P
    Brusselle, Guy G
    Tobin, Martin D
    London, Stephanie J
    Genome-wide association analysis identifies six new loci associated with forced vital capacity2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, s. 669-677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

  • 40.
    Megquier, Katherine
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Tonomura, Noriko
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Noh, Hyun Ji
    Broad Institute.
    Turner-Maier, Jason
    Broad Institute.
    Swofford, Ross
    Broad Institute.
    Koltookian, Michele
    Broad Institute.
    Biagi, Tara
    Fryc, Sarah
    Arendt, Maja Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Häggström, Jens
    Barber, Lisa
    Tufts Cummings School of Veterinary Medicine.
    Burgess, Kristine
    Tufts Cummings School of Veterinary Medicine.
    Thomas, Rachael
    NCSU.
    Breen, Matthew
    NCSU.
    Modiano, Jaime
    University of Minnesota.
    Elvers, Ingegerd
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Azuma, Chieko
    University of Massachusetts Medical School.
    Karlsson, Elinor
    Broad Institute.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Genome-wide meta-analysis identifies inherited variation contributing to overall risk and age of onset in canine angiosarcomaManuskript (preprint) (Annet vitenskapelig)
  • 41.
    Mitchell, Adam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Wolk, Alicja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Type 2 Diabetes in Relation to Hip Bone Density, Area, and Bone Turnover in Swedish Men and Women: A Cross-Sectional Study2018Inngår i: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 103, nr 5, s. 501-511Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Men and women with type 2 diabetes mellitus (T2DM) have higher risk of hip fracture, but the mechanisms are not fully understood. We aimed to investigate how T2DM, glucose, and insulin were associated with femoral bone mineral density (BMD), bone mineral area (BMA), and bone turnover markers. We used two cross-sectional cohorts: the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 452, mean age 82 years) and the Swedish Mammography Cohort Clinical (SMCC, n = 4713, mean age 68 years). We identified men and women with normal fasting glucose (NFG), impaired fasting plasma glucose (IFG), and T2DM. BMD and BMA at the total hip and femoral shaft were measured using dual energy X-ray absorptiometry (DXA). Bone turnover markers; CrossLaps and osteocalcin were measured in women. Linear regression models were applied. Men and women showed a progressively higher BMD following the clinical cutoffs of fasting glucose from NFG to IFG to T2DM. In contrast, there was a progressively lower BMA. Men and women with T2DM, compared to those with NFG, had lower BMA at the total hip (- 1.7%; 95% CI - 3.2, - 0.2 and - 1.0%; 95% CI - 1.6, - 0.4) and the femoral shaft (- 2.0%; 95% CI - 3.5, - 0.4 and - 0.6%; 95% CI - 1.2, - 0.01), respectively. T2DM was associated with lower concentrations of CrossLaps (- 8.1%; 95% CI - 12.7, - 3.6) and osteocalcin (- 15.2%; 95% CI - 19.0, - 11.2). These cross-sectional results indicate that those with T2DM have smaller bone area and lower bone turnover, which could increase the risk of hip fracture.

  • 42.
    Mubanga, Mwenya
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Egenvall, Agneta
    Department of Clinical Sciences, Division of Ruminant Medicine and Veterinary Epidemiology, Swedish University of Agricultural Sciences.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Magnusson, Patrik K
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA..
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dog ownership and Cardiovascular Risk Factors: a nationwide prospective register-based cohort study2019Inngår i: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 9, artikkel-id e023447Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective To study the association between dog ownership and cardiovascular risk factors.

    Design A nationwide register–based cohort study and a cross-sectional study in a subset.

    Setting A cohort of 2 026 865 participants was identified from the Register of the Total Population and linked to national registers for information on dog ownership, prescribed medication, hospital admissions, education level, income and country of birth. Participants were followed from 1 October, 2006, to the end of the study on 31 December, 2012, assessing medication for a cardiovascular risk factor, emigration and death. Cross-sectional associations were further assessed in 10 110 individuals from the TwinGene study with additional adjustment for professional level, employment status, Charlson comorbidity index, disability and tobacco use.

    Participants All Swedish residents aged 45–80 years on 1 October, 2006.

    Main outcome measures Initiation of medication for hypertension, dyslipidaemia and diabetes mellitus.

    Results After adjustment for confounders, the results indicated slightly higher likelihood of initiating antihypertensive (HR, 1.02; 95% CI, 1.01 to 1.03) and lipid-lowering treatment (HR, 1.02; 95% CI, 1.01 to 1.04) in dog owners than in non-owners, particularly among those aged 45–60 years and in those owning mixed breed or companion/toy breed dogs. No association of dog ownership with initiation of treatment for diabetes was found in the overall analysis (HR, 0.98; 95% CI, 0.95 to 1.01). Sensitivity analyses in the TwinGene cohort indicated confounding of the association between dog ownership and prevalent treatment for hypertension, dyslipidaemia and diabetes mellitus, respectively, from factors not available in the national cohort, such as employment status and non cardiovascularchronic disease status.

    Conclusions In this large cohort study, dog ownership was associated with a minimally higher risk of initiation of treatment for hypertension and dyslipidaemia implying that the previously reported lower risk of cardiovascular mortality among dog owners in this cohort is not explained by reduced hypertension and dyslipidaemia. These observations may suffer from residual confounding despite access to multiple important covariates, and future studies may add valuable information.

  • 43.
    Mubanga, Mwenya
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Nowak, Christoph
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Egenvall, Agneta
    Department of Clinical Sciences, Division of Ruminant Medicine and Veterinary Epidemiology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Magnusson, Patrik K
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Dog ownership and the risk of cardiovascular disease and death: a nationwide cohort study2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, nr 1, artikkel-id 15821Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dogs may be beneficial in reducing cardiovascular risk in their owners by providing social support and motivation for physical activity. We aimed to investigate the association of dog ownership with incident cardiovascular disease (CVD) and death in a register-based prospective nation-wide cohort (n = 3,432,153) with up to 12 years of follow-up. Self-reported health and lifestyle habits were available for 34,202 participants in the Swedish Twin Register. Time-to-event analyses with time-updated covariates were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). In single- and multiple-person households, dog ownership (13.1%) was associated with lower risk of death, HR 0.67 (95% CI, 0.65-0.69) and 0.89 (0.87-0.91), respectively; and CVD death, HR 0.64 (0.59-0.70), and 0.85 (0.81-0.90), respectively. In single-person households, dog ownership was inversely associated with cardiovascular outcomes (HR composite CVD 0.92, 95% CI, 0.89-0.94). Ownership of hunting breed dogs was associated with lowest risk of CVD. Further analysis in the Twin Register could not replicate the reduced risk of CVD or death but also gave no indication of confounding by disability, comorbidities or lifestyle factors. In conclusion, dog ownership appears to be associated with lower risk of CVD in single-person households and lower mortality in the general population.

  • 44.
    Nowak, C.
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden.
    Carlsson, A. C.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden.
    Östgren, C. J.
    Linkoping Univ, Linkoping, Sweden.
    Nyström, F. H.
    Linkoping Univ, Linkoping, Sweden.
    Alam, M.
    Dalarna Univ, Falun, Sweden.
    Feldreich, T. R.
    Dalarna Univ, Falun, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Roig, J. J. Carrero
    Karolinska Inst, Solna, Sweden.
    Leppert, Jerzy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Hedberg, Pär O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Cordeiro, A. C.
    Dante Pazzanese Inst Cardiol, Sao Paulo, Brazil.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, E.
    Stanford Univ, Sch Med, Stanford, CA 94305 USA.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Arnlöv, J.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden;Dalarna Univ, Falun, Sweden.
    Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes2018Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, s. S65-S65Artikkel i tidsskrift (Annet vitenskapelig)
  • 45.
    Nowak, Christoph
    et al.
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden.
    Carlsson, Axel C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden.
    Östgren, Carl Johan
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Nyström, Fredrik H.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Alam, Moudud
    Dalarna Univ, Sch Technol & Business Studies Stat, Falun, Sweden.
    Feldreich, Tobias
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Carrero, Juan-Jesus
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Leppert, Jerzy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Hedberg, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Henriksen, Egil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Cordeiro, Antonio C.
    Dante Pazzanese Inst Cardiol, Dept Hypertens & Nephrol, Sao Paulo, Brazil.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ärnlöv, Johan
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden;Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes2018Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, nr 8, s. 1748-1757Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims/hypothesis Multiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes. Methods We combined data from six prospective epidemiological studies of 30-77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample. Results Of 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (+/- SD) of 6.4 +/- 2.3 years. We replicated associations (< 5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit alpha (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample. Conclusions/interpretation We identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.

  • 46.
    Nowak, Christoph
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Hetty, Susanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Castillejo-Lopez, Casimiro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ganna, Andrea
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Cook, Naomi L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Broeckling, Corey D.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA.
    Prenni, Jessica E.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA.
    Shen, Xia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ärnlöv, Johan
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Glucose challenge metabolomics implicates medium-chain acylcarnitines in insulin resistance2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 8691Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insulin resistance (IR) predisposes to type 2 diabetes and cardiovascular disease but its causes are incompletely understood. Metabolic challenges like the oral glucose tolerance test (OGTT) can reveal pathogenic mechanisms. We aimed to discover associations of IR with metabolite trajectories during OGTT. In 470 non-diabetic men (age 70.6 +/- 0.6 years), plasma samples obtained at 0, 30 and 120 minutes during an OGTT were analyzed by untargeted liquid chromatography-mass spectrometry metabolomics. IR was assessed with the hyperinsulinemic-euglycemic clamp method. We applied age-adjusted linear regression to identify metabolites whose concentration change was related to IR. Nine trajectories, including monounsaturated fatty acids, lysophosphatidylethanolamines and a bile acid, were significantly associated with IR, with the strongest associations observed for medium-chain acylcarnitines C10 and C12, and no associations with L-carnitine or C2-, C8-, C14- or C16-carnitine. Concentrations of C10-and C12-carnitine decreased during OGTT with a blunted decline in participants with worse insulin resistance. Associations persisted after adjustment for obesity, fasting insulin and fasting glucose. In mouse 3T3-L1 adipocytes exposed to different acylcarnitines, we observed blunted insulin-stimulated glucose uptake after treatment with C10-or C12-carnitine. In conclusion, our results identify medium-chain acylcarnitines as possible contributors to IR.

  • 47.
    Nowak, Christoph
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Use of type 2 diabetes risk scores in clinical practice: a call for action2015Inngår i: LANCET DIABETES & ENDOCRINOLOGY, ISSN 2213-8587, Vol. 3, nr 3, s. 166-167Artikkel i tidsskrift (Annet vitenskapelig)
  • 48.
    Nowak, Christoph
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ganna, Andrea
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA.;Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
    Brandmaier, Stefan
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany..
    Tukiainen, Taru
    Univ Helsinki, FIMM, Helsinki, Finland..
    Broeckling, Corey D.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA..
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
    Prenni, Jessica E.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA..
    Wang-Sattler, Rui
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany..
    Peters, Annette
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany.;Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany..
    Meitinger, Thomas
    Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Gieger, Christian
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany..
    Ripatti, Samuli
    Univ Helsinki, FIMM, Helsinki, Finland.;Univ Helsinki, Fac Med, Publ Hlth, Helsinki, Finland.;Wellcome Trust Sanger Inst, Hinxton, England..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study2016Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, nr 10, artikkel-id e1006379Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

  • 49.
    Nowak, Christoph
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sundstrom, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Type 2 diabetes, glycaemic traits and cardiovascular disease: a Mendelian Randomization studyManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Type 2 diabetes (T2D) and its hallmarks insulin resistance, impaired insulin secretion, and hyperglycaemia affect over 400 million persons worldwide and are associated with raised cardiovascular risk, but their causal role has been difficult to dissect due to overlap between risk factors. We used Mendelian randomization analysis, which utilises genetic polymorphisms associated with a risk factor, to assess causal effects of T2D, insulin resistance, insulin secretion, and fasting glucose on mortality, ischaemic stroke, and coronary artery disease (CAD) risk in 120,091 adults in the UK Biobank and in the CARDIoGRAMplusC4D consortium (63,746 cases of CAD and 130,681 controls). We found evidence for a causal effect of T2D on raised CAD risk (odds ratio (OR) per doubling in the odds of T2D, 1.07, 95% confidence interval (CI) 1.05 – 1.09, P = 1.2 x 10-9) and for a causal effect of impaired insulin secretion on the risk of CAD (OR per SD-unit decrease, 1.14, 95% CI 1.06 – 1.22, P = 0.002). The genetic score for insulin resistance was associated with increased coronary artery disease risk; however, sensitivity analysis indicated that the instrument might not be appropriate to use for robust causal inference testing. Our results support previous reports of a causal role of T2D and impaired insulin secretion in coronary artery disease and point to a complex relationship between variants affecting insulin resistance and cardiovascular outcomes.

  • 50.
    Nowak, Christoph
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Sundstrom, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ganna, Andrea
    Massachusetts General Hospital, Harvard Medical School and Broad Institute, Boston, Massachusetts.
    Shen, Xia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm , Sweden.
    Broeckling, Corey D.
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA.
    Prenni, Jessica
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA.
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. School of Health and Social Studies, Dalarna University, Falun, Sweden.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
    Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivityManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Impaired insulin sensitivity (IS) is a major risk factor for cardiovascular disease and type 2 diabetes. Metabolomic profiling during an oral glucose tolerance test (OGTT) can reveal early pathogenic alterations in healthy individuals. Our aim was to identify IS biomarkers and gain new pathophysiologic insights by applying untargeted metabolomics to repeated OGTT plasma samples in association with a hyperinsulinemic-euglycemic clamp assessment. We studied 192 metabolites identified by non-targeted liquid chromatography/mass spectrometry in plasma samples taken at 0, 30, and 120 min during an OGTT in 470 non-diabetic 71-yr-old men. Insulin sensitivity was associated with 35 metabolites at one or more time points in multivariable-adjusted linear regression. The trajectories of nine metabolites during the OGTT were related to IS, six of which (oleic and palmitoleic acid, decanoyl- and dodecanoylcarnitine, deoxycholate-glycine and hexose) showed no associations with IS in the baseline fasting state. The strongest effects were detected for medium-chain acylcarnitines, which increased between 30-120 min in insulin-resistant individuals compared to those with normal IS. In this large community sample, we identified novel associations between clamp-measured IS and metabolite profiles that became apparent only after an oral glucose challenge. Associations of differential medium-chain acylcarnitine and monounsaturated fatty acid trajectories with IS provide new insights into the pathogenesis of insulin resistance.

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