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  • 301.
    Forsberg, Lars A.
    et al.
    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.
    Rasi, Chiara
    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.
    Malmqvist, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Davies, Hanna
    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.
    Pasupulati, Saichand
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pakalapati, Geeta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandgren, Johanna
    de Stahl, Teresita Diaz
    Zaghlool, Ammar
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Score, Joannah
    Cross, Nicholas C. P.
    Absher, Devin
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Lindgren, Cecilia M.
    Morris, Andrew P.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Dumanski, Jan P.
    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.
    Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, nr 6, s. 624-628Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained(1,2). Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells(3,4), but the phenotypic consequences of LOY have been elusive(5-10). From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.

  • 302.
    Forsberg, Simon K. G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Bloom, Joshua S.
    Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA.; Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA.; Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90024 USA..
    Sadhu, Meru J.
    Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA.; Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA.; Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90024 USA..
    Kruglyak, Leonid
    Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA.; Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA.; Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90024 USA..
    Carlborg, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeast2017Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, nr 4, s. 497-503Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Experiments in model organisms report abundant genetic interactions underlying biologically important traits, whereas quantitative genetics theory predicts, and data support, the notion that most genetic variance in populations is additive. Here we describe networks of capacitating genetic interactions that contribute to quantitative trait variation in a large yeast intercross population. The additive variance explained by individual loci in a network is highly dependent on the allele frequencies of the interacting loci. Modeling of phenotypes for multilocus genotype classes in the epistatic networks is often improved by accounting for the interactions. We discuss the implications of these results for attempts to dissect genetic architectures and to predict individual phenotypes and long-term responses to selection.

  • 303.
    Forsberg, Simon K. G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Carlborg, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    On the relationship between epistasis and genetic variance heterogeneity.2017Inngår i: Journal of Experimental Botany, ISSN 0022-0957, E-ISSN 1460-2431, Vol. 68, nr 20, s. 5431-5438Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epistasis and genetic variance heterogeneity are two non-additive genetic inheritance patterns that are often, but not always, related. Here we use theoretical examples and empirical results from earlier analyses of experimental data to illustrate the connection between the two. This includes an introduction to the relationship between epistatic gene action, statistical epistasis, and genetic variance heterogeneity, and a brief discussion about how genetic processes other than epistasis can also give rise to genetic variance heterogeneity.

  • 304.
    Forslund, Josefin M. E.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pfeiffer, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Stojkovič, Gorazd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wanrooij, Pauline H.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The presence of rNTPs decreases the speed of mitochondrial DNA replication2018Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, nr 3, artikkel-id e1007315Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ribonucleotides (rNMPs) are frequently incorporated during replication or repair by DNA polymerases and failure to remove them leads to instability of nuclear DNA (nDNA). Conversely, rNMPs appear to be relatively well-tolerated in mitochondnal DNA (mtDNA), although the mechanisms behind the tolerance remain unclear. We here show that the human mitochondrial DNA polymerase gamma (Pol gamma) bypasses single rNMPs with an unprecedentedly high fidelity and efficiency. In addition, Pol gamma exhibits a strikingly low frequency of rNMP incorporation, a property, which we find is independent of its exonuclease activity. However, the physiological levels of free rNTPs partially inhibit DNA synthesis by Pol gamma and render the polymerase more sensitive to imbalanced dNTP pools. The characteristics of Pol gamma reported here could have implications for forms of rntDNA depletion syndrome (MDS) that are associated with imbalanced cellular dNTP pools. Our results show that at the rNTPidNIP ratios that are expected to prevail in such disease states, Pol gamma enters a polymerasetexonuclease idling mode that leads to mtDNA replication stalling. This could ultimately lead to mtDNA depletion and, consequently, to mitochondrial disease phenotypes such as those observed in MDS.

  • 305.
    Franco, Irene
    et al.
    Karolinska Inst, Sweden.
    Johansson, Anna
    Uppsala Univ, Sweden.
    Olsson, Karl
    Karolinska Inst, Sweden.
    Vrtacnik, Peter
    Karolinska Inst, Sweden.
    Lundin, Par
    Karolinska Inst, Sweden; Stockholm Univ, Sweden.
    Helgadottir, Hafdis T.
    Karolinska Inst, Sweden.
    Larsson, Malin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Revechon, Gwladys
    Karolinska Inst, Sweden.
    Bosia, Carla
    IIGM, Italy; Politecn Torino, Italy.
    Pagnani, Andrea
    IIGM, Italy; Politecn Torino, Italy.
    Provero, Paolo
    Mol Biotechnol Ctr, Italy; Ist Sci San Raffaele, Italy.
    Gustafsson, Thomas
    Karolinska Inst, Sweden.
    Fischer, Helene
    Karolinska Inst, Sweden.
    Eriksson, Maria
    Karolinska Inst, Sweden.
    Somatic mutagenesis in satellite cells associates with human skeletal muscle aging2018Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikkel-id 800Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

  • 306. Franco, Irene
    et al.
    Johansson, Anna
    Olsson, Karl
    Vrtačnik, Peter
    Lundin, Pär
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Helgadottir, Hafdis T.
    Larsson, Malin
    Revêchon, Gwladys
    Bosia, Carla
    Pagnani, Andrea
    Provero, Paolo
    Gustafsson, Thomas
    Fischer, Helene
    Eriksson, Maria
    Somatic mutagenesis in satellite cells associates with human skeletal muscle aging2018Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikkel-id 800Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

  • 307.
    Franks, Paul W.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Merino, Jordi
    Gene-lifestyle interplay in type 2 diabetes2018Inngår i: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 50, s. 35-40Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Type 2 diabetes (T2D) is widespread, affecting the health of hundreds of millions worldwide. The disease results from the complex interplay of lifestyle factors acting on a backdrop of inherited DNA risk variants. Detecting and understanding biomarkers, whether genotypes or other downstream biological features that dictate a person's phenotypic response to different lifestyle exposures, may have tremendous utility in the prevention of T2D. Here, we explore (i) evidence of how human genetic adaptation to diverse local environments might interact with lifestyle factors in T2D, (ii) the key challenges facing the research area of gene x lifestyle interactions in T2D, and (iii) the solutions that might be pursued in future studies. Overall, many preliminary examples of such interactions exist, but none is sufficient to have a major impact on clinical decision making. Future studies, integrating genetics and other biological markers into regulatory networks, are likely to be necessary to facilitate the integration of genomics into lifestyle medicine in T2D.

  • 308.
    Franks, Paul W.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, United Kingdom; Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA.
    Timpson, Nicholas J.
    Genotype-Based Recall Studies in Complex Cardiometabolic Traits2018Inngår i: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 11, nr 8, artikkel-id e001947Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In genotype-based recall (GBR) studies, people (or their biological samples) who carry genotypes of special interest for a given hypothesis test are recalled from a larger cohort (or biobank) for more detailed investigations. There are several GBR study designs that offer a range of powerful options to elucidate (1) genotype-phenotype associations (by increasing the efficiency of genetic association studies, thereby allowing bespoke phenotyping in relatively small cohorts), (2) the effects of environmental exposures (within the Mendelian randomization framework), and (3) gene-treatment interactions (within the setting of GBR interventional trials). In this review, we overview the literature on GBR studies as applied to cardiometabolic health outcomes. We also review the GBR approaches used to date and outline new methods and study designs that might enhance the utility of GBR-focused studies. Specifically, we highlight how GBR methods have the potential to augment randomized controlled trials, providing an alternative application for the now increasingly accepted Mendelian randomization methods usually applied to large-scale population-based data sets. Further to this, we consider how functional and basic science approaches alongside GBR designs offer intellectually intriguing and potentially powerful ways to explore the implications of alterations to specific (and potentially druggable) biological pathways.

  • 309. Fransson, Susanne
    et al.
    Hansson, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Univ Gothenburg, Sahlgrenska Acad, Dept Pathol, SE-40530 Gothenburg, Sweden.
    Ruuth, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Djos, Anna
    Berbegall, Ana
    Javanmardi, Niloufar
    Abrahamsson, Jonas
    Palmer, Ruth H.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Univ Gothenburg, Sahlgrenska Acad, Dept Med Chem & Cell Biol, SE-40530 Gothenburg, Sweden.
    Noguera, Rosa
    Hallberg, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Univ Gothenburg, Sahlgrenska Acad, Dept Med Chem & Cell Biol, SE-40530 Gothenburg, Sweden.
    Kogner, Per
    Martinsson, Tommy
    Intragenic Anaplastic Lymphoma Kinase (ALK) Rearrangements: Translocations as a Novel Mechanism of ALK Activation in Neuroblastoma Tumors2015Inngår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, nr 2, s. 99-109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anaplastic lymphoma kinase (ALK) has been demonstrated to be deregulated in sporadic as well as in familiar cases of neuroblastoma (NB). Whereas ALK-fusion proteins are common in lymphoma and lung cancer, there are few reports of ALK rearrangements in NB indicating that ALK mainly exerts its oncogenic capacity via activating mutations and/or overexpression in this tumor type. In this study, 332 NB tumors and 13 cell lines were screened by high resolution single nucleotide polymorphism microarray. Gain of 2p was detected in 23% (60/332) of primary tumors and 46% (6/13) of cell lines, while breakpoints at the ALK locus were detected in four primary tumors and two cell lines. These were further analyzed by next generation sequencing and a targeted enrichment approach. Samples with both ALK and MYCN amplification displayed complex genomic rearrangements with multiple breakpoints within the amplicon. None of the translocations characterized in primary NB tumors are likely to result in a chimeric protein. However, immunohistochemical analysis reveals high levels of phosphorylated ALK in these samples despite lack of initial exons, possibly due to alternative transcription initiation sites. Both ALK proteins predicted to arise from such alterations and from the abnormal ALK exon 4-11 deletion observed in the CLB-BAR cell line show strong activation of downstream targets STAT3 and extracellular signal-regulated kinase (ERK) when expressed in PC12 cells. Taken together, our data indicate a novel, although rare, mechanism of ALK activation with implications for NB tumorigenesis. 

  • 310.
    Fransén, Karin
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Franzén, Petra
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Magnuson, Anders
    Örebro University Hospital, Örebro, Sweden.
    Elmabsout, Ali
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Nyhlin, Nils
    Region Örebro län.
    Wickbom, Anna
    Örebro University Hospital, Örebro, Sweden.
    Curman, Bengt
    Örebro University Hospital, Örebro, Sweden.
    Törkvist, Leif
    Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, Mauro
    Karolinska University Hospital, Stockholm, Sweden.
    Bohr, Johan
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län.
    Tysk, Curt
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län.
    Sirsjö, Allan
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för läkarutbildning. Region Örebro län.
    Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's disease2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 8, s. e72739-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.

  • 311.
    Franzén, Åsa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Regulatory Effects of TGF-β Superfamily Members on Normal and Neoplastic Thyroid Epithelial Cells2002Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Thyroid growth and function is partly regulated by growth factors binding to receptors on the cell surface. In the present thesis, the transforming growth factor-β (TGF-β) superfamily members have been studied for their role in regulation of growth and differentiation of both normal and neoplastic thyroid epithelial cells.

    TGF-β1 is a negative regulator of thyrocyte growth and function. However, the importance of other TGF-β superfamily members has not been fully investigated. TGF-β1, activin A, bone morphogenetic protein (BMP)-7 and their receptors were found to be expressed in porcine thyrocytes. In addition to TGF-β1, activin A was also found to be a negative regulator of thyroid growth and function, and both stimulated phosphorylation and nuclear translocation of Smad proteins. Furthermore, TGF-β1 and epidermal growth factor (EGF) demonstrated a synergistic negative effect on thyrocyte differentiation. Simultaneous addition of the two factors resulted in a loss of the transepithelial resistance and expression of the epithelial marker E-cadherin. This was followed by a transient expression of N-cadherin.

    Despite the extremely malignant character of anaplastic thyroid carcinoma (ATC) tumor cells, established cell lines are still responsive to TGF-β1. A majority of the cell lines were also found to be growth inhibited by BMP-7. BMP-7 induced cell cycle arrest of the ATC cell line HTh 74 in a dose- and cell density-dependent manner. This was associated with upregulation of p21CIP1 and p27KIP1, decreased cyclin-dependent kinase (Cdk) activity and hypophosphorylation of the retinoblastoma protein (pRb). TGF-β1, and to some extent also BMP-7, induced the expression of N-cadherin and matrix metalloproteinase (MMP)-2 and -9. Stimulation of HTh 74 cells with TGF-β1 increased the migration through a reconstituted basement membrane indicating an increased invasive phenotype of the cells.

    Taken together, these data show that TGF-β superfamily members not only affect growth and function of normal thyroid follicle cells but may also, in combination with EGF, play a role in cell dedifferentiation. This study additionally suggests that the TGF-β superfamily members may be important for the invasive properties of ATC cells.

  • 312.
    fredga, K
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi. CONSERVATION BIOLOGY AND GENETICS.
    Chromosome races of Sorex araneus in Norway. Description of two new races.2003Inngår i: Mammalia, Vol. 67, s. 179-185Artikkel i tidsskrift (Fagfellevurdert)
  • 313.
    Fredrikson, Mats
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Annas, Peter
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Hettema, John M.
    Different genetic factors underlie fear conditioning and episodic memory2015Inngår i: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 25, nr 4, s. 155-162Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ObjectiveFear conditioning seems to account for the acquisition of post-traumatic stress disorder, whereas conscious recall of events in aftermath of trauma reflects episodic memory. Studies show that both fear conditioning and episodic memory are heritable, but no study has evaluated whether they reflect common or separate genetic factors. To this end, we studied episodic memory and fear conditioning in 173 healthy twin pairs using visual stimuli predicting unconditioned electric shocks.MethodsFear conditioning acquisition and extinction was determined using conditioned visual stimuli predicting unconditioned mild electric shocks, whereas electrodermal activity served as the fear learning index. Episodic memory was evaluated using cued recall of pictorial stimuli unrelated to conditioning. We used multivariate structural equation modeling to jointly analyze memory performance and acquisition as well as extinction of fear conditioning.ResultsBest-fit twin models estimated moderate genetic loadings for conditioning and memory measures, with no genetic covariation between them.ConclusionIndividual differences in fear conditioning and episodic memory reflect distinct genetically influenced processes, suggesting that the genetic risk for learning-induced anxiety disorders includes at least two memory-related genetic factors. These findings are consistent with the facts that the two separate learning forms are distant in their evolutionary development, involve different brain mechanisms, and support that genetically independent memory systems are pivotal in the development and maintenance of syndromes related to fear learning.

  • 314.
    Fredriksson, Mona
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Using Minisequencing Technology for Analysing Genetic Variation in DNA and RNA2005Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In this thesis, the four-color fluorescence tag-microarray minisequencing system pioneered by our group was further developed and applied for analysing genetic variation in human DNA and RNA. A SNP marker panel representing different chromosomal regions was established and used for identification of informative SNP markers for monitoring chimerism after stem cell transplantation (SCT). The success of SCT was monitored by measuring the allelic ratios of informative SNPs in follow-up samples from nine patients with leukaemia. The results agreed with data obtained using microsatellite markers. Further the same SNP marker panel was used for evaluation of two whole genome amplification methods, primer extension preamplification (PEP) and multiple displacement amplification (MDA) in comparison with genomic DNA with respect to SNP genotyping success and accuracy in tag-array minisequencing. Identical results were obtained from MDA products and genomic DNA.

    The tag-microarray minisequencing system was also established for multiplexed quantification of imbalanced expression of SNP alleles. Two endothelial cell lines and a panel of ten coding SNPs in five genes were used as model system. Six heterozygous SNPs were genotyped in RNA (cDNA) from the cell lines. Comparison of the relative amounts of the SNPs alleles in cDNA to heterozygote SNPs in genomic DNA displayed four SNPs with significant imbalanced expression between the SNP alleles. Finally, the tag-array minisequencing system was modified for detection of splice variants in mRNA from five leukaemia cell lines. A panel of 20 cancer-related genes with 74 alternatively splice variants was screened. Over half of the splice variants were detected in the cell lines, and similar alternative splicing patterns were observed in each cell line. The results were verified by size analysis of the PCR product subjected to the minisequencing primer extension reaction. The data from both methods agreed well, evidencing for a high sensitivity of our system.

  • 315.
    Fredriksson, Simon
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Proximity Ligation: Transforming protein analysis into nucleic acid detection through proximity-dependent ligation of DNA sequence tagged protein-binders2002Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    A novel technology for protein detection, proximity ligation, has been developed along with improved methods for in situ synthesis of DNA microarrays. Proximity ligation enables a specific and quantitative transformation of proteins present in a sample into nucleic acid sequences. As pairs of so-called proximity probes bind the individual target protein molecules at distinct sites, these reagents are brought in close proximity. The probes consist of a protein specific binding part coupled to an oligonucleotide with either a free 3’- or 5’-end capable of hybridizing to a common connector oligonucleotide. When the probes are in proximity, promoted by target binding, then the DNA strands can be joined by enzymatic ligation. The nucleic acid sequence that is formed can then be amplified and quantitatively detected in a real-time monitored polymerase chain reaction. This convenient assay is simple to perform and allows highly sensitive protein detection. Parallel analysis of multiple proteins by DNA microarray technology is anticipated for proximity ligation and enabled by the information carrying ability of nucleic acids to define the individual proteins. Assays detecting cytokines using SELEX aptamers or antibodies, monoclonal and polyclonal, are presented in the thesis.

    Microarrays synthesized in situ using photolithographic methods generate impure products due to damaged molecules and interrupted synthesis. Through a molecular inversion mechanism presented here, these impurities may be removed. At the end of synthesis, full-length oligonucleotides receive a functional group that can then be made to react with the solid support forming an arched structure. The 3’-ends of the oligonucleotides are then cleaved, removing the impurities from the support and allowing the liberated 3’-hydroxyl to prime polymerase extension reactions from the inverted oligonucleotides. The effect of having pure oligonucleotides probes compared to ones contaminated with shorter variants was investigated in allele specific hybridization reactions. Pure probes were shown to have greater ability to discriminate between matched and singly mismatched targets at optimal hybridization temperatures.

  • 316.
    Frumerie, Clara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Functional characterization of a phage integrase and its possible use in gene therapy2005Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Bacteriophage P2 infecting Escherichia coli can integrate into the bacterial chromosome by site-specific recombination, which is catalyzed by the P2 Int recombinase. The recombination event takes place between the phage attachment site, attP, and the bacterial attachment site, attB. Once integrated into the host chromosome the P2 prophage is very stable since an additional phage protein, Cox, is required for excision. For both integration and excision, the host-encoded protein IHF is also required.

    In this thesis, I have made a functional characterization of the P2 integrase and investigated its future potential as a tool for gene therapy. The P2 integrase was found to have cooperative interactions upon DNA binding with its accessory proteins, IHF and Cox. An N-terminal truncated Int protein retained these cooperative interactions, although it was disrupted in arm-binding. Moreover, the Int protein was found to form stable dimers in the absence of DNA, and the C-terminus and amino acid E197 was found to be important for dimerization. Dimerization was found to be essential for recombination, but dimerization deficient mutant proteins were able to bind as well as the wt protein to attP.

    The P2 Int was found to mediate recombination with a human sequence at a low frequency. It was also found that the insertion of HMG-recognition boxes can substitute for the requirement of IHF for recombination in an eukaryotic cell extract and that the integrase protein is localized in the cell nucleus. Taken together, these results indicate that the P2 integrase could be of potential use in gene therapy.

  • 317. Frykholm, Carina
    et al.
    Klar, Joakim
    Arnesson, Hanna
    Rehnman, Anna-Carin
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Specialpedagogiska institutionen.
    Lodahl, Marianne
    Weden, Ulla
    Dahl, Niklas
    Tranebjaerg, Lisbeth
    Rendtorff, Nanna D.
    Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation2015Inngår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 563, nr 1, s. 10-16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Linkage to an interval overlapping the DFNA10 locus on chromosome 6q22-23 was found through genome wide linkage analysis in a seven-generation Swedish family segregating postlingual, autosomal dominant nonsyndromic sensorineural hearing impairment. A novel heterozygous frame-shift mutation (c.579_580insTACC, p.(Asp194Tyrfs*52)) in EYA4 was identified that truncates the so-called variable region of the protein. The mutation is predicted to result in haploinsufficiency of the EYA4 product. No evidence for dilated cardiomyopathy was found in the family, contrasting to a previous family with a deletion resulting in a similar truncation in the variable region. A highly variable age of onset was seen in the mutation carriers. For assessment of the aetiology of this variability, clinical and audiometric data analyses were performed. The affected family members all had similar cross-sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DENA10 family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy.

  • 318.
    Frykholm, Carina
    et al.
    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.
    Klar, Joakim
    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.
    Arnesson, Hanna
    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.
    Rehnman, Anna-Carin
    Lodahl, Marianne
    Weden, Ulla
    Dahl, Niklas
    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.
    Tranebjaerg, Lisbeth
    Rendtorff, Nanna D.
    Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation2015Inngår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 563, nr 1, s. 10-16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Linkage to an interval overlapping the DFNA10 locus on chromosome 6q22-23 was found through genome wide linkage analysis in a seven-generation Swedish family segregating postlingual, autosomal dominant nonsyndromic sensorineural hearing impairment. A novel heterozygous frame-shift mutation (c.579_580insTACC, p.(Asp194Tyrfs*52)) in EYA4 was identified that truncates the so-called variable region of the protein. The mutation is predicted to result in haploinsufficiency of the EYA4 product. No evidence for dilated cardiomyopathy was found in the family, contrasting to a previous family with a deletion resulting in a similar truncation in the variable region. A highly variable age of onset was seen in the mutation carriers. For assessment of the aetiology of this variability, clinical and audiometric data analyses were performed. The affected family members all had similar cross-sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DENA10 family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy.

  • 319.
    Frånberg, Mattias
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Karolinska Institutet, Sweden; Karolinska Universitetsjukhuset, Sweden.
    Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk2017Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, nr 3, s. 403-415Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

  • 320.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Molecular Studies of Diamond-Blackfan Anemia and Congenital Nail Dysplasia2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The aim of this thesis is to investigate the effect of genetic mutations on the pathophysiology of two human disorders: Diamond-Blackfan Anemia (DBA) and isolated congenital nail dysplasia.

    The first part of this thesis (Paper I-III) investigates the mechanism associated with DBA. DBA is a rare bone marrow failure syndrome characterized by the absence or decrease of erythroid precursor cells. The disease is further associated with growth retardation, malformations, predisposition to malignant disease and heterozygous mutations in ribosomal protein (RP) genes. The second part of this thesis (Paper IV) investigates the genetic basis of isolated autosomal recessive nail dysplasia characterized by pachyonychia and onycholysis of both finger- and toenails. It further dissects the molecular mechanisms regulating nail development.

    In the first study, we investigated the previously reported RPS19/PIM-1 interaction by generating a combined Rps19/Pim-1 knockout mouse model. We found that allelic Rps19 insufficiency and Pim-1 deficiency have a cooperative effect on murine hematopoiesis resulting in increased myeloid cellularity associated with cell cycle alterations and reduced apoptosis. In the second study, we analyzed primary fibroblasts from DBA patients with truncating mutations in RPS19 or RPS24 and observed a marked delay in cellular growth associated with specific cell cycle defects. In the third study, we discovered that recombinant RPS19 binds its own mRNA and that the binding is altered when two DBA-associated RPS19 mutations are introduced. In the fourth study, we identified mutations in the WNT signaling receptor Frizzled 6 (FZD6). We observed that the nonsense mutant fails to interact with the first downstream effector Dishevelled. Fzd6 mutant mice displayed claw malformations and we detected a transient Fzd6 expression in the distal digits at the embryonic time point for nail development.

    In summary, this thesis elucidates several mechanisms in the etiology of DBA and congenital nail dysplasia and mechanisms regulating nail development.

  • 321.
    Fröjmark, Anne-Sophie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Thuveson, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Cooperative effect of ribosomal protein s19 and Pim-1 kinase on murine c-Myc expression and myeloid/erythroid cellularity2010Inngår i: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 88, nr 1, s. 39-46Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diamond Blackfan anemia (DBA) is a bone marrow failure syndrome associated with heterozygous mutations in the ribosomal protein S19 (RPS19) gene in a subgroup of patients. One of the interacting partners with RPS19 is the oncoprotein PIM-1 kinase. We intercrossed Rps19+/- and Pim-1-/- mice strains to study the effect from the disruption of both genes. The double mutant (Rps19+/-Pim-1-/-) mice display normal growth with increased peripheral white- and red blood cell counts when compared to the w.t. mice (Rps19+/+Pim-1+/+). Molecular analysis of bone marrow cells in Rps19+/-Pim-1-/- mice revealed up-regulated levels of c-Myc and the anti-apoptotic factors Bcl2, BclXL and Mcl-1. This is associated with a reduction of the apoptotic factors Bak and Caspase 3 as well as the cell cycle regulator p21. Our findings suggest that combined Rps19 insufficiency and Pim-1 deficiency promote murine myeloid cell growth through a deregulation of c-Myc and a simultaneous up-regulation of anti-apoptotic Bcl proteins.

  • 322. Fuchsberger, Christian
    et al.
    Flannick, Jason
    Teslovich, Tanya M.
    Mahajan, Anubha
    Agarwala, Vineeta
    Gaulton, Kyle J.
    Ma, Clement
    Fontanillas, Pierre
    Moutsianas, Loukas
    McCarthy, Davis J.
    Rivas, Manuel A.
    Perry, John R. B.
    Sim, Xueling
    Blackwell, Thomas W.
    Robertson, Neil R.
    Rayner, N. William
    Cingolani, Pablo
    Locke, Adam E.
    Tajes, Juan Fernandez
    Highland, Heather M.
    Dupuis, Josee
    Chines, Peter S.
    Lindgren, Cecilia M.
    Hartl, Christopher
    Jackson, Anne U.
    Chen, Han
    Huyghe, Jeroen R.
    van de Bunt, Martijn
    Pearson, Richard D.
    Kumar, Ashish
    Mueller-Nurasyid, Martina
    Grarup, Niels
    Stringham, Heather M.
    Gamazon, Eric R.
    Lee, Jaehoon
    Chen, Yuhui
    Scott, Robert A.
    Below, Jennifer E.
    Chen, Peng
    Huang, Jinyan
    Go, Min Jin
    Stitzel, Michael L.
    Pasko, Dorota
    Parker, Stephen C. J.
    Varga, Tibor V.
    Green, Todd
    Beer, Nicola L.
    Day-Williams, Aaron G.
    Ferreira, Teresa
    Fingerlin, Tasha
    Horikoshi, Momoko
    Hu, Cheng
    Huh, Iksoo
    Ikram, Mohammad Kamran
    Kim, Bong-Jo
    Kim, Yongkang
    Kim, Young Jin
    Kwon, Min-Seok
    Lee, Juyoung
    Lee, Selyeong
    Lin, Keng-Han
    Maxwell, Taylor J.
    Nagai, Yoshihiko
    Wang, Xu
    Welch, Ryan P.
    Yoon, Joon
    Zhang, Weihua
    Barzilai, Nir
    Voight, Benjamin F.
    Han, Bok-Ghee
    Jenkinson, Christopher P.
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Manning, Alisa
    Ng, Maggie C. Y.
    Palmer, Nicholette D.
    Balkau, Beverley
    Stancakova, Alena
    Abboud, Hanna E.
    Boeing, Heiner
    Giedraitis, Vilmantas
    Prabhakaran, Dorairaj
    Gottesman, Omri
    Scott, James
    Carey, Jason
    Kwan, Phoenix
    Grant, George
    Smith, Joshua D.
    Neale, Benjamin M.
    Purcell, Shaun
    Butterworth, Adam S.
    Howson, Joanna M. M.
    Lee, Heung Man
    Lu, Yingchang
    Kwak, Soo-Heon
    Zhao, Wei
    Danesh, John
    Lam, Vincent K. L.
    Park, Kyong Soo
    Saleheen, Danish
    So, Wing Yee
    Tam, Claudia H. T.
    Afzal, Uzma
    Aguilar, David
    Arya, Rector
    Aung, Tin
    Chan, Edmund
    Navarro, Carmen
    Cheng, Ching-Yu
    Palli, Domenico
    Correa, Adolfo
    Curran, Joanne E.
    Rybin, Denis
    Farook, Vidya S.
    Fowler, Sharon P.
    Freedman, Barry I.
    Griswold, Michael
    Hale, Daniel Esten
    Hicks, Pamela J.
    Khor, Chiea-Chuen
    Kumar, Satish
    Lehne, Benjamin
    Thuillier, Dorothee
    Lim, Wei Yen
    Liu, Jianjun
    van der Schouw, Yvonne T.
    Loh, Marie
    Musani, Solomon K.
    Puppala, Sobha
    Scott, William R.
    Yengo, Loic
    Tan, Sian-Tsung
    Taylor, Herman A., Jr.
    Thameem, Farook
    Wilson, Gregory, Sr.
    Wong, Tien Yin
    Njolstad, Pal Rasmus
    Levy, Jonathan C.
    Mangino, Massimo
    Bonnycastle, Lori L.
    Schwarzmayr, Thomas
    Fadista, Joao
    Surdulescu, Gabriela L.
    Herder, Christian
    Groves, Christopher J.
    Wieland, Thomas
    Bork-Jensen, Jette
    Brandslund, Ivan
    Christensen, Cramer
    Koistinen, Heikki A.
    Doney, Alex S. F.
    Kinnunen, Leena
    Esko, Tonu
    Farmer, Andrew J.
    Hakaste, Liisa
    Hodgkiss, Dylan
    Kravic, Jasmina
    Lyssenko, Valeriya
    Hollensted, Mette
    Jorgensen, Marit E.
    Jorgensen, Torben
    Ladenvall, Claes
    Justesen, Johanne Marie
    Karajamaki, Annemari
    Kriebel, Jennifer
    Rathmann, Wolfgang
    Lannfelt, Lars
    Lauritzen, Torsten
    Narisu, Narisu
    Linneberg, Allan
    Melander, Olle
    Milani, Lili
    Neville, Matt
    Orho-Melander, Marju
    Qi, Lu
    Qi, Qibin
    Roden, Michael
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Swift, Amy
    Rosengren, Anders H.
    Stirrups, Kathleen
    Wood, Andrew R.
    Mihailov, Evelin
    Blancher, Christine
    Carneiro, Mauricio O.
    Maguire, Jared
    Poplin, Ryan
    Shakir, Khalid
    Fennell, Timothy
    DePristo, Mark
    de Angelis, Martin Hrabe
    Deloukas, Panos
    Gjesing, Anette P.
    Jun, Goo
    Nilsson, Peter
    Murphy, Jacquelyn
    Onofrio, Robert
    Thorand, Barbara
    Hansen, Torben
    Meisinger, Christa
    Hu, Frank B.
    Isomaa, Bo
    Karpe, Fredrik
    Liang, Liming
    Peters, Annette
    Huth, Cornelia
    O'Rahilly, Stephen P.
    Palmer, Colin N. A.
    Pedersen, Oluf
    Rauramaa, Rainer
    Tuomilehto, Jaakko
    Salomaa, Veikko
    Watanabe, Richard M.
    Syvanen, Ann-Christine
    Bergman, Richard N.
    Bharadwaj, Dwaipayan
    Bottinger, Erwin P.
    Cho, Yoon Shin
    Chandak, Giriraj R.
    Chan, Juliana C. N.
    Chia, Kee Seng
    Daly, Mark J.
    Ebrahim, Shah B.
    Langenberg, Claudia
    Elliott, Paul
    Jablonski, Kathleen A.
    Lehman, Donna M.
    Jia, Weiping
    Ma, Ronald C. W.
    Pollin, Toni I.
    Sandhu, Manjinder
    Tandon, Nikhil
    Froguel, Philippe
    Barroso, Ines
    Teo, Yik Ying
    Zeggini, Eleftheria
    Loos, Ruth J. F.
    Small, Kerrin S.
    Ried, Janina S.
    DeFronzo, Ralph A.
    Grallert, Harald
    Glaser, Benjamin
    Metspalu, Andres
    Wareham, Nicholas J.
    Walker, Mark
    Banks, Eric
    Gieger, Christian
    Ingelsson, Erik
    Im, Hae Kyung
    Illig, Thomas
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
    Buck, Gemma
    Trakalo, Joseph
    Buck, David
    Prokopenko, Inga
    Magi, Reedik
    Lind, Lars
    Farjoun, Yossi
    Owen, Katharine R.
    Gloyn, Anna L.
    Strauch, Konstantin
    Tuomi, Tiinamaija
    Kooner, Jaspal Singh
    Lee, Jong-Young
    Park, Taesung
    Donnelly, Peter
    Morris, Andrew D.
    Hattersley, Andrew T.
    Bowden, Donald W.
    Collins, Francis S.
    Atzmon, Gil
    Chambers, John C.
    Spector, Timothy D.
    Laakso, Markku
    Strom, Tim M.
    Bell, Graeme I.
    Blangero, John
    Duggirala, Ravindranath
    Tai, E. Shyong
    McVean, Gilean
    Hanis, Craig L.
    Wilson, James G.
    Seielstad, Mark
    Frayling, Timothy M.
    Meigs, James B.
    Cox, Nancy J.
    Sladek, Rob
    Lander, Eric S.
    Gabriel, Stacey
    Burtt, Noel P.
    Mohlke, Karen L.
    Meitinger, Thomas
    Groop, Leif
    Abecasis, Goncalo
    Florez, Jose C.
    Scott, Laura J.
    Morris, Andrew P.
    Kang, Hyun Min
    Boehnke, Michael
    Altshuler, David
    McCarthy, Mark I.
    The genetic architecture of type 2 diabetes2016Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 536, nr 7614, s. 41-47Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

  • 323.
    Gao, Ling
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    p53 Alterations in Human Skin: A Molecular Study Based on Morphology2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Mutation of the p53 gene appears to be an early event in skin cancer development. The present study is based on morphology and represents a cellular and genetic investigation of p53 alterations in normal human skin and basal cell cancer.

    Using double immunofluorescent labelling, we have demonstrated an increase in thymine dimers and p53 protein expression in the same keratinocytes following ultraviolet radiation. Large inter-individual differences in the kinetics of thymine dimer repair and subsequent epidermal p53 response were evident in both sunscreen-protected and non-protected skin. The formation of thymine dimers and the epidermal p53 response were partially blocked by topical sunscreen. We have optimized a method to analyze the p53 gene in single cells from frozen tissue sections. In chronically sun-exposed skin there exist clusters of p53 immunoreactive keratinocytes (p53 clones) in addition to scattered p53 immunoreactive cells. Laser assisted microdissection was used to retrieve single keratinocytes from immunostained tissue sections, single cells were amplified and the p53 gene was sequenced. We have shown that p53 mutations are prevalent in normal skin. Furthermore, we detected an epidermal p53 clone which had prevailed despite two months of total protection from ultraviolet light. Loss of heterozygosity in the PTCH and p53 loci as well as in the sequenced p53 gene was determined in basal cell cancer from sporadic cases and in patients with Gorlin syndrome. Allelic loss in the PTCH region was prominent in both sporadic and hereditary tumors, while loss of heterozygosity in the p53 locus was rare in both groups. p53 mutations found in the hereditary tumors differed from the typical mutations found in sporadic cases. In addition, we found genetically linked subclones with partially different p53 and/or PTCH genotypes in individual tumors. Our data show that both genes are important in the development of basal cell cancer.

  • 324.
    Garousi, Javad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindbo, Sarah
    Nilvebrant, Johan
    Åstrand, Mikael
    Buijs, Jos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Honarvar, Hadis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Hober, Sophia
    ADAPT, a novel scaffold protein-based probe for radionuclide imaging of molecular targets that are expressed in disseminated cancers2015Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, nr 20, s. 4364-4371Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small engineered scaffold proteins have attracted attention as probes for radionuclide-based molecular imaging. One class of these imaging probes, termed ABD-Derived Affinity ProTeins (ADAPT), have been created using the albumin-binding domain (ABD) of streptococcal protein G as a stable protein scaffold. In this study, we report the development of a clinical lead probe termed ADAPT6 that binds HER2, an oncoprotein overexpressed in many breast cancers that serves as a theranostic biomarker for several approved targeting therapies. Surface-exposed amino acids of ABD were randomized to create a combinatorial library enabling selection of high affinity binders to various proteins. Further, ABD was engineered to rapidly purify ADAPT6, eradicate its binding to albumin and enable rapid blood clearance. Incorporation of a unique cysteine allowed site-specific conjugation to a maleimido derivative of a DOTA chelator, enabling radionuclide labeling, 111In for SPECT imaging and 68Ga for PET imaging. Pharmacological studies in mice demonstrated that the fully engineered molecule 111In/68Ga-DOTA-(HE)3-ADAPT6 was specifically bound and taken up by HER2-expressing tumors, with a high tumor-to-normal tissue ratio in xenograft models of human cancer. Unbound tracer underwent rapid renal clearance followed by high renal reabsorption. HER2-expressing xenografts were visualized by gamma-camera or PET by one hour post-infusion. PET experiments demonstrated feasibility for discrimination of xenografts with high or low HER2 expression. Our results offer a preclinical proof of concept for the use of ADAPT probes for non-invasive in vivo imaging.

  • 325. Garzón, J.
    et al.
    Rodríguez, R.
    Kong, Ziqing
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Rodríguez-Acebes, S.
    Méndez, J.
    Moreno, S.
    García-Higuera, I.
    Shortage of dNTPs underlies altered replication dynamics and DNA breakage in the absence of the APC/C cofactor Cdh12017Inngår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 36, nr 42, s. 5808-5818Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The APC/C-Cdh1 ubiquitin-ligase complex targets cell cycle regulators for proteosomal degradation and helps prevent tumor development and accumulation of chromosomal aberrations. Replication stress has been proposed to be the main driver of genomic instability in the absence of Cdh1, but the real contribution of APC/C-Cdh1 to efficient replication, especially in normal cells, remains unclear. Here we show that, in primary MEFs, acute depletion or permanent ablation of Cdh1 slowed down replication fork movement and increased origin activity. Partial inhibition of origin firing does not accelerate replication forks, suggesting that fork progression is intrinsically limited in the absence of Cdh1. Moreover, exogenous supply of nucleotide precursors, or ectopic overexpression of RRM2, the regulatory subunit of Ribonucleotide Reductase, restore replication efficiency, indicating that dNTP availability could be impaired upon Cdh1 loss. Indeed, we found reduced dNTP levels in Cdh1-deficient MEFs. Importantly, DNA breakage is also significantly alleviated by increasing intracellular dNTP pools, strongly suggesting that genomic instability is the result of aberrant replication. These observations highlight the relevance of APC/C-Cdh1 activity during G1 to ensure an adequate supply of dNTPs to the replisome, prevent replication stress and the resulting chromosomal breaks and, ultimately, suppress tumorigenesis.

  • 326.
    Gaulton, Kyle J.
    et al.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Stanford Univ, Dept Genet, Stanford, CA 94305 USA..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Lee, Yeji
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Raimondo, Anne
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Maegi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Reschen, Michael E.
    Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Locke, Adam
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Rayner, N. William
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Hinxton, England..
    Robertson, Neil
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Scott, Robert A.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England..
    Prokopenko, Inga
    Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England..
    Scott, Laura J.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Green, Todd
    Broad Inst Harvard & MIT, Cambridge, MA USA..
    Sparso, Thomas
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Thuillier, Dorothee
    European Genom Inst Diabet, Lille Inst Biol, Lille, France..
    Yengo, Loic
    European Genom Inst Diabet, Lille Inst Biol, Lille, France..
    Grallert, Harald
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Wahl, Simone
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Franberg, Mattias
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Numer Anal & Comp Sci, S-10691 Stockholm, Sweden..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden..
    Kestler, Hans
    Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany.;Univ Ulm, Med Syst Biol, D-89069 Ulm, Germany..
    Chheda, Himanshu
    Finnish Inst Mol Med, Helsinki, Finland..
    Eisele, Lewin
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany..
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Steinthorsdottir, Valgerdur
    deCODE Genet Amgen Inc, Reykjavik, Iceland..
    Thorleifsson, Gudmar
    deCODE Genet Amgen Inc, Reykjavik, Iceland..
    Qi, Lu
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA.;Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA..
    Karssen, Lennart C.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    van Leeuwen, Elisabeth M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Willems, Sara M.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England.;Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Li, Man
    Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA..
    Chen, Han
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Fuchsberger, Christian
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Kwan, Phoenix
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Ma, Clement
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Linderman, Michael
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Thomsen, Soren K.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Rundle, Jana K.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Beer, Nicola L.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    van de Bunt, Martijn
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Chalisey, Anil
    Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England..
    Kang, Hyun Min
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Voight, Benjamin F.
    Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA..
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Almgren, Peter
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    Baldassarre, Damiano
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy..
    Balkau, Beverley
    Ctr Rech Epidemiol & Sante Populat CESP, INSERM, U1018, Villejuif, France.;Univ Paris 11, UMRS 1018, Villejuif, France..
    Benediktsson, Rafn
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Reykjavik, Iceland..
    Blueher, Matthias
    Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany.;Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Boeing, Heiner
    German Inst Human Nutr, Potsdam, Germany..
    Bonnycastle, Lori L.
    NHGRI, US NIH, Bethesda, MD 20892 USA..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Burtt, Noel P.
    Broad Inst Harvard & MIT, Cambridge, MA USA..
    Carey, Jason
    Broad Inst Harvard & MIT, Cambridge, MA USA..
    Charpentier, Guillaume
    Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France..
    Chines, Peter S.
    NHGRI, US NIH, Bethesda, MD 20892 USA..
    Cornelis, Marilyn C.
    Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA..
    Couper, David J.
    Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA..
    Crenshaw, Andrew T.
    Broad Inst Harvard & MIT, Cambridge, MA USA..
    van Dam, Rob M.
    Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore..
    Doney, Alex S. F.
    Univ Dundee, Ninewells Hosp, Biomed Res Inst, Ctr Diabet Res, Dundee, Scotland.;Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland..
    Dorkhan, Mozhgan
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Novo Nordisk Scandinavia, Malmo, Sweden..
    Edkins, Sarah
    Wellcome Trust Sanger Inst, Hinxton, England..
    Eriksson, Johan G.
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.;Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA..
    Eury, Elodie
    CNRS, UMR 8199, Inst Biol, Lille, France.;Univ Lille 2, Inst Pasteur, Lille, France..
    Fadista, Joao
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    Flannick, Jason
    Broad Inst Harvard & MIT, Cambridge, MA USA..
    Fontanillas, Pierre
    Broad Inst Harvard & MIT, Cambridge, MA USA..
    Fox, Caroline
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Franks, Paul W.
    Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden.;Lund Univ, Dept Clin Sci, Malmo, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden..
    Gieger, Christian
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Gigante, Bruna
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden..
    Gottesman, Omri
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Grant, George B.
    Broad Inst Harvard & MIT, Cambridge, MA USA..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Groves, Christopher J.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hassinen, Maija
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Have, Christian T.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Herder, Christian
    Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;Partner Site Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany..
    Holmen, Oddgeir L.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway..
    Hreidarsson, Astradur B.
    Landspitali Univ Hosp, Reykjavik, Iceland..
    Humphries, Steve E.
    UCL, Inst Cardiovasc Sci, British Heart Fdn BHF Labs, Cardiovasc Genet, London, England..
    Hunter, David J.
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Jonsson, Anna
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    Jorgensen, Marit E.
    Steno Diabet Ctr, DK-2820 Gentofte, Denmark..
    Jorgensen, Torben
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark..
    Kao, Wen-Hong L.
    Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA..
    Kerrison, Nicola D.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Klopp, Norman
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany..
    Kong, Augustine
    deCODE Genet Amgen Inc, Reykjavik, Iceland..
    Kovacs, Peter
    Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany.;Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Kraft, Peter
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA..
    Kravic, Jasmina
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    Langford, Cordelia
    Wellcome Trust Sanger Inst, Hinxton, England..
    Leander, Karin
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden..
    Liang, Liming
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Lichtner, Peter
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Broad Inst Harvard & MIT, Cambridge, MA USA..
    Lindholm, Eero
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    Linneberg, Allan
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Rigshosp, Copenhagen Univ Hosp, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Liu, Ching-Ti
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Lobbens, Stephane
    CNRS, UMR 8199, Inst Biol, Lille, France.;Univ Lille 2, Inst Pasteur, Lille, France..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England..
    Lyssenko, Valeriya
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden.;Steno Diabet Ctr, DK-2820 Gentofte, Denmark..
    Mannisto, Satu
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    McLeod, Olga
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden..
    Meyer, Julia
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Mirza, Ghazala
    Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Guys & St Thomas Hosp, Genom Core Facil, Biomed Res Ctr, London, England..
    Muehleisen, Thomas W.
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany.;Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany.;Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany.;Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Navarro, Carmen
    Inst Murciano Invest Biosanitaria Virgen de la Ar, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain.;CIBERESP, Madrid, Spain.;Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain..
    Noethen, Markus M.
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany..
    Oskolkov, Nikolay N.
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    Owen, Katharine R.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England..
    Palli, Domenico
    Canc Res & Prevent Inst ISPO, Florence, Italy..
    Pechlivanis, Sonali
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany..
    Peltonen, Leena
    Wellcome Trust Sanger Inst, Hinxton, England.;Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Perry, John R. B.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England..
    Platou, Carl G. P.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway.;Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway..
    Roden, Michael
    Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;Partner Site Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany.;Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany..
    Ruderfer, Douglas
    Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA..
    Rybin, Denis
    Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA..
    van der Schouw, Yvonne T.
    Univ Med Ctr Utrecht, Utrecht, Netherlands..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden..
    Sigurdsson, Gunnar
    Landspitali Univ Hosp, Reykjavik, Iceland.;Iceland Heart Assoc, Kopavogur, Iceland..
    Stancakova, Alena
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Steinbach, Gerald
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Ulm, Dept Clin Chem & Cent Lab, D-89069 Ulm, Germany..
    Storm, Petter
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    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, Neuherberg, Germany..
    Stringham, Heather M.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Sun, Qi
    Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA..
    Thorand, Barbara
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Tikkanen, Emmi
    Stanford Univ, Dept Genet, Stanford, CA 94305 USA.;Finnish Inst Mol Med, Helsinki, Finland.;Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland..
    Tonjes, Anke
    Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany.;Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Trakalo, Joseph
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Tremoli, Elena
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy..
    Tuomi, Tiinamaija
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Finnish Inst Mol Med, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland.;Univ Helsinki, Res Program Diabet & Obes, Helsinki, Finland..
    Wennauer, Roman
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands..
    Wiltshire, Steven
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Wood, Andrew R.
    Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England.;Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Hinxton, England..
    Dunham, Ian
    Wellcome Trust Sanger Inst, Hinxton, England.;European Mol Biol Lab, EBI, Hinxton, England..
    Birney, Ewan
    Wellcome Trust Sanger Inst, Hinxton, England.;European Mol Biol Lab, EBI, Hinxton, England..
    Pasquali, Lorenzo
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England.;Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England.;Germans Trias & Pujol Univ Hosp & Res Inst, Div Endocrinol, Badalona, Spain.;Josep Carreras Leukaemia Res Inst, Badalona, Spain.;CIBERDEM, Barcelona, Spain..
    Ferrer, Jorge
    Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England.;Inst Invest Biomed August Pi & Sunyer, Ctr Esther Koplowitz, Barcelona, Spain..
    Loos, Ruth J. F.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
    Florez, Jose C.
    Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Pankow, James S.
    Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    van Duijn, Cornelia
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands.;Netherlands Consortium Hlth Ageing, Netherlands Genom Initiat, Rotterdam, Netherlands.;Ctr Med Syst Biol, Rotterdam, Netherlands..
    Sijbrands, Eric
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands..
    Meigs, James B.
    Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA..
    Hu, Frank B.
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA..
    Thorsteinsdottir, Unnur
    deCODE Genet Amgen Inc, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Stefansson, Kari
    deCODE Genet Amgen Inc, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Lakka, Timo A.
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland..
    Stumvoll, Michael
    Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany.;Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Keinanen-Kiukaanniemi, Sirkka M.
    Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland.;Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland..
    Korpi-Hyovalti, Eeva
    South Ostrobothnia Cent Hosp, Seinajoki, Finland..
    Saaristo, Timo E.
    Finnish Diabet Assoc, Tampere, Finland.;Pirkanmaa Dist Hosp, Tampere, Finland..
    Saltevo, Juha
    Cent Finland Cent Hosp, Dept Med, Jyvasklya, Finland..
    Kuusisto, Johanna
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Laakso, Markku
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia..
    Erbel, Raimund
    Univ Duisdurg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany..
    Joecke, Karl-Heinz
    Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland..
    Moebus, Susanne
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany..
    Ripatti, Samuli
    Stanford Univ, Dept Genet, Stanford, CA 94305 USA.;Wellcome Trust Sanger Inst, Hinxton, England.;Finnish Inst Mol Med, Helsinki, Finland.;Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland.;Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Boehm, Bernhard O.
    Univ Med Ctr Ulm, Dept Internal Med, Div Endocrinol & Diabet, Ulm, Germany.;Univ London Imperial Coll Sci Technol & Med, Lee Kong Chian Sch Med, London SW7 2AZ, England.;Nanyang Technol Univ, Singapore 639798, Singapore..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA..
    Collins, Francis S.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;NHGRI, US NIH, Bethesda, MD 20892 USA..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Koistinen, Heikki
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Dept Med, Div Endocrinol, Helsinki, Finland.;Minerva Fdn, Helsinki, Finland..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Hosp Univ La Paz, Inst Invest Sanitaria, Madrid, Spain.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia..
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway..
    Njolstad, Inger
    Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway..
    Deloukas, Panagiotis
    Wellcome Trust Sanger Inst, Hinxton, England.;Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Donnelly, Peter J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Dept Stat, Oxford OX1 3TG, England..
    Frayling, Timothy M.
    Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England.;Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England..
    Hattersley, Andrew T.
    Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden..
    Illig, Thomas
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany..
    Peters, Annette
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res, Neuherberg, Germany.;Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Cauchi, Stephane
    European Genom Inst Diabet, Lille Inst Biol, Lille, France..
    Sladek, Rob
    Ctr Hosp Univ Montreal, Ctr Rech, Montreal Diabet Res Ctr, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Froguel, Philippe
    Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England.;CNRS, UMR 8199, Inst Biol, Lille, France.;Univ Lille 2, Inst Pasteur, Lille, France..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Morris, Andrew D.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Palmer, Collin N. A.
    Univ Dundee, Ninewells Hosp, Biomed Res Inst, Ctr Diabet Res, Dundee, Scotland.;Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland..
    Kathiresan, Sekar
    Broad Inst Harvard & MIT, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Melander, Olle
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    Nilsson, Peter M.
    Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    Groop, Leif C.
    Finnish Inst Mol Med, Helsinki, Finland.;Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Cambridge, Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Cambridge, England.;Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England..
    O'Callaghan, Christopher A.
    Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England..
    Gloyn, Anna L.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England..
    Altshuler, David
    Broad Inst Harvard & MIT, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA.;Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA. Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Teslovich, Tanya M.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England..
    Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci2015Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, nr 12, s. 1415-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

  • 327. Gaulton, Kyle J.
    et al.
    Ferreira, Teresa
    Lee, Yeji
    Raimondo, Anne
    Maegi, Reedik
    Reschen, Michael E.
    Mahajan, Anubha
    Locke, Adam
    Rayner, N. William
    Robertson, Neil
    Scott, Robert A.
    Prokopenko, Inga
    Scott, Laura J.
    Green, Todd
    Sparso, Thomas
    Thuillier, Dorothee
    Yengo, Loic
    Grallert, Harald
    Wahl, Simone
    Franberg, Mattias
    Strawbridge, Rona J.
    Kestler, Hans
    Chheda, Himanshu
    Eisele, Lewin
    Gustafsson, Stefan
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Qi, Lu
    Karssen, Lennart C.
    van Leeuwen, Elisabeth M.
    Willems, Sara M.
    Li, Man
    Chen, Han
    Fuchsberger, Christian
    Kwan, Phoenix
    Ma, Clement
    Linderman, Michael
    Lu, Yingchang
    Thomsen, Soren K.
    Rundle, Jana K.
    Beer, Nicola L.
    van de Bunt, Martijn
    Chalisey, Anil
    Kang, Hyun Min
    Voight, Benjamin F.
    Abecasis, Goncalo R.
    Almgren, Peter
    Baldassarre, Damiano
    Balkau, Beverley
    Benediktsson, Rafn
    Blueher, Matthias
    Boeing, Heiner
    Bonnycastle, Lori L.
    Bottinger, Erwin P.
    Burtt, Noel P.
    Carey, Jason
    Charpentier, Guillaume
    Chines, Peter S.
    Cornelis, Marilyn C.
    Couper, David J.
    Crenshaw, Andrew T.
    van Dam, Rob M.
    Doney, Alex S. F.
    Dorkhan, Mozhgan
    Edkins, Sarah
    Eriksson, Johan G.
    Esko, Tonu
    Eury, Elodie
    Fadista, Joao
    Flannick, Jason
    Fontanillas, Pierre
    Fox, Caroline
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA; Lund University Diabetes Centre, Department of Clinical Science Malmö, Scania University Hospital, Lund University, Malmö, Sweden; Department of Clinical Sciences, Lund University, Malmö, Sweden..
    Gertow, Karl
    Gieger, Christian
    Gigante, Bruna
    Gottesman, Omri
    Grant, George B.
    Grarup, Niels
    Groves, Christopher J.
    Hassinen, Maija
    Have, Christian T.
    Herder, Christian
    Holmen, Oddgeir L.
    Hreidarsson, Astradur B.
    Humphries, Steve E.
    Hunter, David J.
    Jackson, Anne U.
    Jonsson, Anna
    Jorgensen, Marit E.
    Jorgensen, Torben
    Kao, Wen-Hong L.
    Kerrison, Nicola D.
    Kinnunen, Leena
    Klopp, Norman
    Kong, Augustine
    Kovacs, Peter
    Kraft, Peter
    Kravic, Jasmina
    Langford, Cordelia
    Leander, Karin
    Liang, Liming
    Lichtner, Peter
    Lindgren, Cecilia M.
    Lindholm, Eero
    Linneberg, Allan
    Liu, Ching-Ti
    Lobbens, Stephane
    Luan, Jian'an
    Lyssenko, Valeriya
    Mannisto, Satu
    McLeod, Olga
    Meyer, Julia
    Mihailov, Evelin
    Mirza, Ghazala
    Muehleisen, Thomas W.
    Mueller-Nurasyid, Martina
    Navarro, Carmen
    Noethen, Markus M.
    Oskolkov, Nikolay N.
    Owen, Katharine R.
    Palli, Domenico
    Pechlivanis, Sonali
    Peltonen, Leena
    Perry, John R. B.
    Platou, Carl G. P.
    Roden, Michael
    Ruderfer, Douglas
    Rybin, Denis
    van der Schouw, Yvonne T.
    Sennblad, Bengt
    Sigurdsson, Gunnar
    Stancakova, Alena
    Steinbach, Gerald
    Storm, Petter
    Strauch, Konstantin
    Stringham, Heather M.
    Sun, Qi
    Thorand, Barbara
    Tikkanen, Emmi
    Tonjes, Anke
    Trakalo, Joseph
    Tremoli, Elena
    Tuomi, Tiinamaija
    Wennauer, Roman
    Wiltshire, Steven
    Wood, Andrew R.
    Zeggini, Eleftheria
    Dunham, Ian
    Birney, Ewan
    Pasquali, Lorenzo
    Ferrer, Jorge
    Loos, Ruth J. F.
    Dupuis, Josee
    Florez, Jose C.
    Boerwinkle, Eric
    Pankow, James S.
    van Duijn, Cornelia
    Sijbrands, Eric
    Meigs, James B.
    Hu, Frank B.
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Lakka, Timo A.
    Rauramaa, Rainer
    Stumvoll, Michael
    Pedersen, Nancy L.
    Lind, Lars
    Keinanen-Kiukaanniemi, Sirkka M.
    Korpi-Hyovalti, Eeva
    Saaristo, Timo E.
    Saltevo, Juha
    Kuusisto, Johanna
    Laakso, Markku
    Metspalu, Andres
    Erbel, Raimund
    Joecke, Karl-Heinz
    Moebus, Susanne
    Ripatti, Samuli
    Salomaa, Veikko
    Ingelsson, Erik
    Boehm, Bernhard O.
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Koistinen, Heikki
    Tuomilehto, Jaakko
    Hveem, Kristian
    Njolstad, Inger
    Deloukas, Panagiotis
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    de Faire, Ulf
    Hamsten, Anders
    Illig, Thomas
    Peters, Annette
    Cauchi, Stephane
    Sladek, Rob
    Froguel, Philippe
    Hansen, Torben
    Pedersen, Oluf
    Morris, Andrew D.
    Palmer, Collin N. A.
    Kathiresan, Sekar
    Melander, Olle
    Nilsson, Peter M.
    Groop, Leif C.
    Barroso, Ines
    Langenberg, Claudia
    Wareham, Nicholas J.
    O'Callaghan, Christopher A.
    Gloyn, Anna L.
    Altshuler, David
    Boehnke, Michael
    Teslovich, Tanya M.
    McCarthy, Mark I.
    Morris, Andrew P.
    Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci2015Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, nr 12, s. 1415-1425Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

  • 328. Gaulton, Kyle J.
    et al.
    Ferreira, Teresa
    Lee, Yeji
    Raimondo, Anne
    Maegi, Reedik
    Reschen, Michael E.
    Mahajan, Anubha
    Locke, Adam
    Rayner, N. William
    Robertson, Neil
    Scott, Robert A.
    Prokopenko, Inga
    Scott, Laura J.
    Green, Todd
    Sparso, Thomas
    Thuillier, Dorothee
    Yengo, Loic
    Grallert, Harald
    Wahl, Simone
    Frånberg, Mattias
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Strawbridge, Rona J.
    Kestler, Hans
    Chheda, Himanshu
    Eisele, Lewin
    Gustafsson, Stefan
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Qi, Lu
    Karssen, Lennart C.
    van Leeuwen, Elisabeth M.
    Willems, Sara M.
    Li, Man
    Chen, Han
    Fuchsberger, Christian
    Kwan, Phoenix
    Ma, Clement
    Linderman, Michael
    Lu, Yingchang
    Thomsen, Soren K.
    Rundle, Jana K.
    Beer, Nicola L.
    van de Bunt, Martijn
    Chalisey, Anil
    Kang, Hyun Min
    Voight, Benjamin F.
    Abecasis, Goncalo R.
    Almgren, Peter
    Baldassarre, Damiano
    Balkau, Beverley
    Benediktsson, Rafn
    Blueher, Matthias
    Boeing, Heiner
    Bonnycastle, Lori L.
    Bottinger, Erwin P.
    Burtt, Noel P.
    Carey, Jason
    Charpentier, Guillaume
    Chines, Peter S.
    Cornelis, Marilyn C.
    Couper, David J.
    Crenshaw, Andrew T.
    van Dam, Rob M.
    Doney, Alex S. F.
    Dorkhan, Mozhgan
    Edkins, Sarah
    Eriksson, Johan G.
    Esko, Tonu
    Eury, Elodie
    Fadista, Joao
    Flannick, Jason
    Fontanillas, Pierre
    Fox, Caroline
    Franks, Paul W.
    Gertow, Karl
    Gieger, Christian
    Gigante, Bruna
    Gottesman, Omri
    Grant, George B.
    Grarup, Niels
    Groves, Christopher J.
    Hassinen, Maija
    Have, Christian T.
    Herder, Christian
    Holmen, Oddgeir L.
    Hreidarsson, Astradur B.
    Humphries, Steve E.
    Hunter, David J.
    Jackson, Anne U.
    Jonsson, Anna
    Jorgensen, Marit E.
    Jorgensen, Torben
    Kao, Wen-Hong L.
    Kerrison, Nicola D.
    Kinnunen, Leena
    Klopp, Norman
    Kong, Augustine
    Kovacs, Peter
    Kraft, Peter
    Kravic, Jasmina
    Langford, Cordelia
    Leander, Karin
    Liang, Liming
    Lichtner, Peter
    Lindgren, Cecilia M.
    Lindholm, Eero
    Linneberg, Allan
    Liu, Ching-Ti
    Lobbens, Stephane
    Luan, Jian'an
    Lyssenko, Valeriya
    Mannisto, Satu
    McLeod, Olga
    Meyer, Julia
    Mihailov, Evelin
    Mirza, Ghazala
    Muehleisen, Thomas W.
    Mueller-Nurasyid, Martina
    Navarro, Carmen
    Noethen, Markus M.
    Oskolkov, Nikolay N.
    Owen, Katharine R.
    Palli, Domenico
    Pechlivanis, Sonali
    Peltonen, Leena
    Perry, John R. B.
    Platou, Carl G. P.
    Roden, Michael
    Ruderfer, Douglas
    Rybin, Denis
    van der Schouw, Yvonne T.
    Sennblad, Bengt
    Sigurdsson, Gunnar
    Stancakova, Alena
    Steinbach, Gerald
    Storm, Petter
    Strauch, Konstantin
    Stringham, Heather M.
    Sun, Qi
    Thorand, Barbara
    Tikkanen, Emmi
    Tonjes, Anke
    Trakalo, Joseph
    Tremoli, Elena
    Tuomi, Tiinamaija
    Wennauer, Roman
    Wiltshire, Steven
    Wood, Andrew R.
    Zeggini, Eleftheria
    Dunham, Ian
    Birney, Ewan
    Pasquali, Lorenzo
    Ferrer, Jorge
    Loos, Ruth J. F.
    Dupuis, Josee
    Florez, Jose C.
    Boerwinkle, Eric
    Pankow, James S.
    van Duijn, Cornelia
    Sijbrands, Eric
    Meigs, James B.
    Hu, Frank B.
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Lakka, Timo A.
    Rauramaa, Rainer
    Stumvoll, Michael
    Pedersen, Nancy L.
    Lind, Lars
    Keinanen-Kiukaanniemi, Sirkka M.
    Korpi-Hyovalti, Eeva
    Saaristo, Timo E.
    Saltevo, Juha
    Kuusisto, Johanna
    Laakso, Markku
    Metspalu, Andres
    Erbel, Raimund
    Joecke, Karl-Heinz
    Moebus, Susanne
    Ripatti, Samuli
    Salomaa, Veikko
    Ingelsson, Erik
    Boehm, Bernhard O.
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Koistinen, Heikki
    Tuomilehto, Jaakko
    Hveem, Kristian
    Njolstad, Inger
    Deloukas, Panagiotis
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    de Faire, Ulf
    Hamsten, Anders
    Illig, Thomas
    Peters, Annette
    Cauchi, Stephane
    Sladek, Rob
    Froguel, Philippe
    Hansen, Torben
    Pedersen, Oluf
    Morris, Andrew D.
    Palmer, Collin N. A.
    Kathiresan, Sekar
    Melander, Olle
    Nilsson, Peter M.
    Groop, Leif C.
    Barroso, Ines
    Langenberg, Claudia
    Wareham, Nicholas J.
    O'Callaghan, Christopher A.
    Gloyn, Anna L.
    Altshuler, David
    Boehnke, Michael
    Teslovich, Tanya M.
    McCarthy, Mark I.
    Morris, Andrew P.
    Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci2015Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, nr 12, s. 1415-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

  • 329.
    Gawel, Danuta R.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Identification of genes and regulators that are shared across T cell associated diseases2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Genome-wide association studies (GWASs) of hundreds of diseases and millions of patients have led to the identification of genes that are associated with more than one disease. The aims of this PhD thesis were to a) identify a group of genes important in multiple diseases (shared disease genes), b) identify shared up-stream disease regulators, and c) determine how the same genes can be involved in the pathogenesis of different diseases. These aims have been tested on CD4+ T cells because they express the T helper cell differentiation pathway, which was the most enriched pathway in analyses of all disease associated genes identified with GWASs.

    Combining information about known gene-gene interactions from the protein-protein interaction (PPI) network with gene expression changes in multiple T cell associated diseases led to the identification of a group of highly interconnected genes that were miss-expressed in many of those diseases – hereafter called ‘shared disease genes’. Those genes were further enriched for inflammatory, metabolic and proliferative pathways, genetic variants identified by all GWASs, as well as mutations in cancer studies and known diagnostic and therapeutic targets. Taken together, these findings supported the relevance of the shared disease genes.

    Identification of the shared upstream disease regulators was addressed in the second project of this PhD thesis. The underlying hypothesis assumed that the determination of the shared upstream disease regulators is possible through a network model showing in which order genes activate each other. For that reason a transcription factor–gene regulatory network (TF-GRN) was created. The TF-GRN was based on the time-series gene expression profiling of the T helper cell type 1 (Th1), and T helper cell type 2 (Th2) differentiation from Native T-cells. Transcription factors (TFs) whose expression changed early during polarization and had many downstream predicted targets (hubs) that were enriched for disease associated single nucleotide polymorphisms (SNPs) were prioritised as the putative early disease regulators. These analyses identified three transcription factors: GATA3, MAF and MYB. Their predicted targets were validated by ChIP-Seq and siRNA mediated knockdown in primary human T-cells. CD4+ T cells isolated from seasonal allergic rhinitis (SAR) and multiple sclerosis (MS) patients in their non-symptomatic stages were analysed in order to demonstrate predictive potential of those three TFs. We found that those three TFs were differentially expressed in symptom-free stages of the two diseases, while their TF-GRN{predicted targets were differentially expressed during symptomatic disease stages. Moreover, using RNA-Seq data we identified a disease associated SNP that correlated with differential splicing of GATA3.

    A limitation of the above study is that it concentrated on TFs as main regulators in cells, excluding other potential regulators such as microRNAs. To this end, a microRNA{gene regulatory network (mGRN) of human CD4+ T cell differentiation was constructed. Within this network, we defined regulatory clusters (groups of microRNAs that are regulating groups of mRNAs). One regulatory cluster was differentially expressed in all of the tested diseases, and was highly enriched for GWAS SNPs. Although the microRNA processing machinery was dynamically upregulated during early T-cell activation, the majority of microRNA modules showed specialisation in later time-points.

    In summary this PhD thesis shows the relevance of shared genes and up-stream disease regulators. Putative mechanisms of why shared genes can be involved in pathogenesis of different diseases have also been demonstrated: a) differential gene expression in different diseases; b) alternative transcription factor splicing variants may affect different downstream gene target group; and c) SNPs might cause alternative splicing.

  • 330.
    Genshaft, Alex S.
    et al.
    MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;MIT, Dept Chem, Cambridge, MA 02139 USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Ragon Inst Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA..
    Li, Shuqiang
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    Gallant, Caroline J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Darmanis, Spyros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sci Life Lab, Uppsala, Sweden.;Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.;Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA.;Howard Hughes Med Inst, Stanford, CA USA..
    Prakadan, Sanjay M.
    MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;MIT, Dept Chem, Cambridge, MA 02139 USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Ragon Inst Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA..
    Ziegler, Carly G. K.
    MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Ragon Inst Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Harvard Univ, Div Hlth Sci & Technol, Cambridge, MA 02138 USA.;MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA..
    Lundberg, Martin
    Olink Prote, Uppsala, Sweden..
    Fredriksson, Simon
    Olink Prote, Uppsala, Sweden..
    Hong, Joyce
    MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA..
    Regev, Aviv
    Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Dept Biol, Boston, MA 02142 USA.;MIT, Koch Inst, Boston, MA 02142 USA.;Howard Hughes Med Inst, Chevy Chase, MD 20815 USA..
    Livak, Kenneth J.
    Fluidigm Corp, San Francisco, CA 94080 USA..
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Shalek, Alex K.
    MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;MIT, Dept Chem, Cambridge, MA 02139 USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Ragon Inst Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Harvard Univ, Div Hlth Sci & Technol, Cambridge, MA 02138 USA.;MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA..
    Multiplexed, targeted profiling of single-cell proteomes and transcriptomes in a single reaction2016Inngår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 17, artikkel-id 188Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We present a scalable, integrated strategy for coupled protein and RNA detection from single cells. Our approach leverages the DNA polymerase activity of reverse transcriptase to simultaneously perform proximity extension assays and complementary DNA synthesis in the same reaction. Using the Fluidigm C1 (TM) system, we profile the transcriptomic and proteomic response of a human breast adenocarcinoma cell line to a chemical perturbation, benchmarking against in situ hybridizations and immunofluorescence staining, as well as recombinant proteins, ERCC Spike-Ins, and population lysate dilutions. Through supervised and unsupervised analyses, we demonstrate synergies enabled by simultaneous measurement of single-cell protein and RNA abundances. Collectively, our generalizable approach highlights the potential for molecular metadata to inform highly-multiplexed single-cell analyses.

  • 331. George, Julie
    et al.
    Lim, Jing Shan
    Jang, Se Jin
    Cun, Yupeng
    Ozretic, Luka
    Kong, Gu
    Leenders, Frauke
    Lu, Xin
    Fernandez-Cuesta, Lynnette
    Bosco, Graziella
    Mueller, Christian
    Dahmen, Ilona
    Jahchan, Nadine S.
    Park, Kwon-Sik
    Yang, Dian
    Karnezis, Anthony N.
    Vaka, Dedeepya
    Torres, Angela
    Wang, Maia Segura
    Korbel, Jan O.
    Menon, Roopika
    Chun, Sung-Min
    Kim, Deokhoon
    Wilkerson, Matt
    Hayes, Neil
    Engelmann, David
    Puetzer, Brigitte
    Bos, Marc
    Michels, Sebastian
    Vlasic, Ignacija
    Seidel, Danila
    Pinther, Berit
    Schaub, Philipp
    Becker, Christian
    Altmueller, Janine
    Yokota, Jun
    Kohno, Takashi
    Iwakawa, Reika
    Tsuta, Koji
    Noguchi, Masayuki
    Muley, Thomas
    Hoffmann, Hans
    Schnabel, Philipp A.
    Petersen, Iver
    Chen, Yuan
    Soltermann, Alex
    Tischler, Verena
    Choi, Chang-min
    Kim, Yong-Hee
    Massion, Pierre P.
    Zou, Yong
    Jovanovic, Dragana
    Kontic, Milica
    Wright, Gavin M.
    Russell, Prudence A.
    Solomon, Benjamin
    Koch, Ina
    Lindner, Michael
    Muscarella, Lucia A.
    la Torre, Annamaria
    Field, John K.
    Jakopovic, Marko
    Knezevic, Jelena
    Castanos-Velez, Esmeralda
    Roz, Luca
    Pastorino, Ugo
    Brustugun, Odd-Terje
    Lund-Iversen, Marius
    Thunnissen, Erik
    Koehler, Jens
    Schuler, Martin
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sandelin, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Sanchez-Cespedes, Montserrat
    Salvesen, Helga B.
    Achter, Viktor
    Lang, Ulrich
    Bogus, Magdalena
    Schneider, Peter M.
    Zander, Thomas
    Ansen, Sascha
    Hallek, Michael
    Wolf, Juergen
    Vingron, Martin
    Yatabe, Yasushi
    Travis, William D.
    Nuernberg, Peter
    Reinhardt, Christian
    Perner, Sven
    Heukamp, Lukas
    Buettner, Reinhard
    Haas, Stefan A.
    Brambilla, Elisabeth
    Peifer, Martin
    Sage, Julien
    Thomas, Roman K.
    Comprehensive genomic profiles of small cell lung cancer2015Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 524, nr 7563, s. 47-U73Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.

  • 332. Georgiadis, Panagiotis
    et al.
    Liampa, Irene
    Hebels, Dennie G
    Krauskopf, Julian
    Chatziioannou, Aristotelis
    Valavanis, Ioannis
    de Kok, Theo M C M
    Kleinjans, Jos C S
    Bergdahl, Ingvar A
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin. Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Spaeth, Florentin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Palli, Domenico
    Vermeulen, R C H
    Vlaanderen, J
    Chadeau-Hyam, Marc
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis2017Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, artikkel-id 728Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance.

    RESULTS: We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p.

    CONCLUSIONS: Our findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential.

  • 333.
    Georgii-Hemming, Patrik
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Life, death ant the role of IGF-I in human multiple myeloma1998Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Multiple myeloma (MM) is a clonal expansion of malignant cells with a plasmablast- plasma cell morphology in the bone marrow. It is a fatal disease with a median survival of 2-3 years after start of conventional therapy. The aim of the thesis was to study the regulation of growth and survival of MM cell lines and primary, cells to identify potential targets for therapy. The results of the thesis show that MM cells express IGF-I (insulin-like growth factor-I) receptors and IGF-I. Furthermore, IGF-I was shown to stimulate growth and survival of MM cells. When IGF-IR signaling is inhibited by anti-IGF-IR antibodies in MM cells they are growth inhibited and may also undergo apoptosis. The somatostatin analogue octreotide has been demonstrated to interfere with the action of IGF-I. The results of the thesis show that MM cells express sst2, sst3 and sst5 which bind octreotide with a moderate or high affinity. Moreover, octreotide inhibits the growth of all investigated MM clones. In a few cases growth inhibition was also accompanied by the induction of apoptosis.

    Resistance to apoptosis may be important for cell survival and drug resistance in MM clones. Studies in the thesis demonstrated that interferon (IFN)-α and IFN-γ augment the sensitivity to Fas-induced apoptosis in MM cells independently of their growth inhibitory effect. The sensitivity to apoptosis was also increased by inhibition of IGF-IR signaling. Incubation of MM cells with anti-IGF-IR antibodies increased the sensitivity of the cells to apoptosis induced by Fas ligation and the glucocorticoid dexamethasone.

    It can be concluded that the IGF-IR may be a potential target for therapy in MM. Furthermore, increasing the sensitivity of MM cells to apoptosis by treatment with IFNs or drugs that interfere with the action of IGF-I may increase the sensitivity of the tumor cells to cytotoxic drugs.

  • 334. Giddaluru, Sudheer
    et al.
    Espeseth, Thomas
    Salami, Alireza
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Aging Research Center, Karolinska Institutet and Stockholm University, 11330 Stockholm, Sweden.
    Westlye, Lars T
    Lundquist, Anders
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Christoforou, Andrea
    Cichon, Sven
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Steen, Vidar M
    Reinvang, Ivar
    Nilsson, Lars Göran
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). ARC, Karolinska Institutet, Stockholm, Sweden.
    Le Hellard, Stéphanie
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Genetics of structural connectivity and information processing in the brain2016Inngår i: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, nr 9, s. 4643-4661Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10(-08)). Suggestive associations (Meta P value <1 × 10(-06)) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10(-08)). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10(-07)). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10(-08)), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10(-07)) and the multimodal analysis (Fisher P value = 1 × 10(-07)). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.

  • 335. Giedraitis, V
    et al.
    Hedlund, M
    Skoglund, Lena
    Uppsala universitet.
    Blom, E
    Ingvast, S
    Brundin, R
    Lannfelt, L
    Glaser, A
    New Alzheimer's disease locus on chromosome 8.2006Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 43, nr 12Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes.

    OBJECTIVE: To map susceptibility regions for Alzheimer's disease.

    METHODS: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of < or =65 years. Mutations in known early-onset Alzheimer's disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the epsilon4 allele was observed.

    RESULTS: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multimarker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region.

    CONCLUSION: On the basis of our data, we propose the existence of a dominantly acting Alzheimer's disease susceptibility locus on chromosome 8.

  • 336.
    Gladh, Hanna
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Folestad, Erika Bergsten
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Muhl, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Ehnman, Monika
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Tannenberg, Philip
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Karolinska Univ Hosp, Div Vasc Surg, Dept Surg Sci, Stockholm, Sweden..
    Lawrence, Anna-Lisa
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Univ Michigan, Sch Med, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI USA..
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Mice Lacking Platelet-Derived Growth Factor D Display a Mild Vascular Phenotype2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 3, artikkel-id e0152276Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Platelet-derived growth factor D (PDGF-D) is the most recently discovered member of the PDGF family. PDGF-D signals through PDGF receptor beta, but its biological role remains largely unknown. In contrast to other members of the PDGF family of growth factors, which have been extensively investigated using different knockout approaches in mice, PDGF-D has until now not been characterized by gene inactivation in mice. Here, we present the phenotype of a constitutive Pdgfd knockout mouse model (Pdgfd(-/-)), carrying a LacZ reporter used to visualize Pdgfd promoter activity. Inactivation of the Pdgfd gene resulted in a mild phenotype in C57BL/6 mice, and the offspring was viable, fertile and generally in good health. We show that Pdgfd reporter gene activity was consistently localized to vascular structures in both postnatal and adult tissues. The expression was predominantly arterial, often localizing to vascular bifurcations. Endothelial cells appeared to be the dominating source for Pdgfd, but reporter gene activity was occasionally also found in sub-populations of mural cells. Tissue-specific analyses of vascular structures revealed that NG2-expressing pericytes of the cardiac vasculature were disorganized in Pdgfd(-/-) mice. Furthermore, Pdgfd(-/-) mice also had a slightly elevated blood pressure. In summary, the vascular expression pattern together with morphological changes in NG2-expressing cells, and the increase in blood pressure, support a function for PDGF-D in regulating systemic arterial blood pressure, and suggests a role in maintaining vascular homeostasis.

  • 337. Goh, Gerald
    et al.
    Scholl, Ute
    Healy, James
    Choi, Murim
    Prasad, Manju L
    Nelson-Williams, Carol
    Kuntsman, John W
    Korah, Reju
    Suttorp, Anna-Carinna
    Dietrich, Dimo
    Haase, Mathias
    Willenberg, Holger S
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Åkerström, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Carling, Tobias
    Lifton, Richard P
    Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, nr 6, s. 613-617Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adrenal tumors autonomously producing cortisol cause Cushing's syndrome1, 2, 3, 4. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin)5, 6 or GNAS (Gαs)7, 8. Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Further sequencing identified this mutation in 13 of 63 tumors (35% of adenomas with overt Cushing's syndrome). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A9, 10. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation11, 12, 13, 14, 15, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.

  • 338.
    Goraya, Mohsan Ullah
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Qureshi, Zafar ul Ahsan
    Abbas, Muhammad
    Ashraf, Muhammad
    Munir, Muhammad
    Isolation of buffalo poxvirus from clinical case and variations in the genetics of the B5R gene over fifty passages2015Inngår i: Virus genes, ISSN 0920-8569, E-ISSN 1572-994X, Vol. 51, nr 1, s. 45-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Outbreaks of buffalopox affect udder and teats, which may ultimately lead to mastitis in dairy buffalo and can significantly compromise the production. In this study, we report isolation of buffalo poxvirus and sequence analysis of the B5R gene collected from the buffalo clinically suspected to be poxvirus infected. The virus was isolated on BHK-21 cell line and was passaged for 50 times, B5R gene was amplified and sequenced using gene-specific primers, and analyzed at both nucleotide and amino acid levels. Phylogenetically, the isolate can be classified close to the previously reported Pakistani and Indian isolates with certain level of differential clustering patterns. Three significant putative mutations (I2K, N64D, and K111E) were observed in the B5R protein. The K111E was common with previous human isolate from Karachi, Pakistan in 2005. These mutations differed from pox-viruses reported from the neighboring countries. Some deletion mutations were observed which were recovered in upcoming passages. The K111E mutation suggests potential to cause zoonotic infection in human all over the country.

  • 339.
    Goropashnaya, Anna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Phylogeographic Structure and Genetic Variation in Formica Ants2003Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The aim of this thesis is to study phylogeny, species-wide phylogeography and genetic diversity in Formica ants across Eurasia in connection with the history of biotic responses to Quaternary environmental changes.

    The mitochondrial DNA phylogeny of Palaearctic Formica species supported the subgeneric grouping based on morphological similarity. The exception was that F. uralensis formed a separate phylogenetic group. The mitochondrial DNA phylogeny of the F. rufa group showed the division into three major phylogenetic groups: one with the species F. polyctena and F. rufa, one with F. aquilonia, F. lugubris and F. paralugubris, and the third one with F. pratensis.

    West-east phylogeographic divisions were found in F. pratensis suggesting post-glacial colonization of western Europe and a wide area from Sweden to the Baikal Lake from separate forest refugia. In contrast, no phylogeographic divisions were detected in either F. lugubris or F. exsecta. Contraction of the distribution range to a single refugial area during the late Pleistocene and the following population expansion could offer a general explanation for the lack of phylogeographic structure across most of Eurasia in these species.

    Sympatrically distributed and ecologically similar species F. uralensis and F. candida showed clear difference in the phylogeographic structure that reflected difference in their vicariant history. Whereas no phylogeographic divisions were detected in F. uralensis across Europe, F. candida showed a well-supported phylogeographic division between the western, the central and the southern group.

    In socially polymorphic F. cinerea, the overall level of intrapopulation microsatellite diversity was relatively high and differentiation among populations was low, indicating recent historical connections. The lack of correspondence between genetic affinities and geographic locations of studied populations did not provide any evidence for differentiating between alternative hypotheses concerning the directions and sources of postglacial colonization of Fennoscandia.

  • 340. Graham, RR
    et al.
    Kozyrev (första författare shared), Sergey
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Baechler, EC
    Linga Reddy, MV Prasad
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Plenge, RM
    Bauer, JW
    Ortmann, WA
    Koeuth, T
    Escribano, MF
    Collaborative Groups,
    Pons-Estel, B
    Petri, M
    Daly, M
    Gregersen, PK
    Marti­n, J
    Altshuler, D
    Behrens, TW
    Alarcon-Riquelme, Marta
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.2006Inngår i: Nat Genet, ISSN 1061-4036, Vol. 38, nr 5, s. 550-555Artikkel i tidsskrift (Fagfellevurdert)
  • 341.
    Gray, J. D.
    et al.
    Rockefeller Univ, NY 10021 USA.
    Rubin, T. G.
    Albert Einstein Coll Med, NY 10467 USA.
    Kogan, J. F.
    Rockefeller Univ, NY 10021 USA.
    Marrocco, J.
    Rockefeller Univ, NY 10021 USA.
    Weidmann, J.
    Linköpings universitet.
    Lindkvist, S.
    Linköpings universitet.
    Lee, F. S.
    Weill Cornell Med Coll, NY USA.
    Schmidt, E. F.
    Rockefeller Univ, NY 10021 USA.
    McEwen, B. S.
    Rockefeller Univ, NY 10021 USA.
    Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice2018Inngår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, nr 4, s. 904-913Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene-environment interactions on the translational profile of these cells.

  • 342.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Division of Gene Technology, Royal Institute of Technology, Solna, Sweden/ Royal Institute Technology, Sweden; National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Hasmats, Johanna
    Royal Institute Technology, Sweden.
    Kupershmidt, Ilya
    Royal Institute Technology, Sweden; NextBio, CA USA.
    Edsgard, Daniel
    Royal Institute Technology, Sweden.
    de Petris, Luigi
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Lewensohn, Rolf
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Blackhall, Fiona
    Christie Hospital, England; University of Manchester, England.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Besse, Benjamin
    University of Paris 11, France.
    Lindgren, Andrea
    Linköpings universitet, Institutionen för medicin och hälsa. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Lungmedicinska kliniken US. Linköpings universitet, Medicinska fakulteten.
    Branden, Eva
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Koyi, Hirsh
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lundeberg, Joakim
    Royal Institute Technology, Sweden.
    Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities2016Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, nr 2, s. 366-373Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy. (C)2015 AACR.

  • 343. Grinberg, Marianna
    et al.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Brunnström, Hans R R
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Edlund, Karolina
    Hengstler, Jan G
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Branden, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Ståhle, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Jirström, Karin
    Tracy, Derek K
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Rahnenführer, Jörg
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Reaching the limits of prognostication in non-small cell lung cancer: an optimized biomarker panel fails to outperform clinical parameters.2017Inngår i: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 30, nr 7, s. 964-977Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Numerous protein biomarkers have been analyzed to improve prognostication in non-small cell lung cancer, but have not yet demonstrated sufficient value to be introduced into clinical practice. Here, we aimed to develop and validate a prognostic model for surgically resected non-small cell lung cancer. A biomarker panel was selected based on (1) prognostic association in published literature, (2) prognostic association in gene expression data sets, (3) availability of reliable antibodies, and (4) representation of diverse biological processes. The five selected proteins (MKI67, EZH2, SLC2A1, CADM1, and NKX2-1 alias TTF1) were analyzed by immunohistochemistry on tissue microarrays including tissue from 326 non-small cell lung cancer patients. One score was obtained for each tumor and each protein. The scores were combined, with or without the inclusion of clinical parameters, and the best prognostic model was defined according to the corresponding concordance index (C-index). The best-performing model was subsequently validated in an independent cohort consisting of tissue from 345 non-small cell lung cancer patients. The model based only on protein expression did not perform better compared to clinicopathological parameters, whereas combining protein expression with clinicopathological data resulted in a slightly better prognostic performance (C-index: all non-small cell lung cancer 0.63 vs 0.64; adenocarcinoma: 0.66 vs 0.70, squamous cell carcinoma: 0.57 vs 0.56). However, this modest effect did not translate into a significantly improved accuracy of survival prediction. The combination of a prognostic biomarker panel with clinicopathological parameters did not improve survival prediction in non-small cell lung cancer, questioning the potential of immunohistochemistry-based assessment of protein biomarkers for prognostication in clinical practice.Modern Pathology advance online publication, 10 March 2017; doi:10.1038/modpathol.2017.14.

  • 344.
    Grundberg, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Genotyping and Mutation Detection In Situ: Development and application of single-molecule techniques2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The human body is composed of trillions of cells closely working together to maintain a functional organism. Every cell is unique in molecular composition and can acquire genetic variations that might cause it to turn pathological. It is essential to develop improved tools to better understand the development of normal and disease tissue, ideally enabling single-cell expression studies in preserved context of complex tissue with single-nucleotide resolution. This thesis presents the development and application of a new in situ method for localized detection and genotyping of individual transcripts directly in cells and tissues. The described technique utilizes padlock probes and target-primed rolling circle amplification and is highly suitable for sensitive in situ analysis.

    First, a new strategy for directed cleavage of single stranded DNA was investigated, e.g. nucleic acid targets with extended 3´ ends, for successful initiation of rolling circle amplification. The presented cleavage strategy is simple and applicable for subsequent enzymatic reactions, e.g. ligation and polymerization. Specific cleavage of long target overhangs was demonstrated in synthetic oligonucleotides and in genomic DNA and the detection efficiency was substantially increased.

    For multiplex detection and genotyping of individual transcripts in single cells, a new in situ method was developed. The technique showed a satisfactorily detection efficiency and was later applied as a general mutation analysis tool for detection of KRAS point mutations in complex tumor tissue sections, e.g. formalin-fixed, paraffin-embedded tumor tissues and cytologic tumor imprints. Mutation status was assessed in patient samples by in situ padlock probe detection and results were confirmed by DNA-sequencing.  Finally, the method was adapted for simultaneous detection of individual mRNA molecules and endogenous protein modifications in single cells using padlock probes and in situ PLA. This assay will be useful for gene expression analysis and exploration of new drugs with vague effector sites.

    To our knowledge, no other technique exists today that offers in situ transcript detection with single-nucleotide resolution in heterogeneous tissues. The method will especially be suitable for discrimination of highly similar transcripts, e.g. splice variants, SNPs and point mutations, within gene expression studies and for cancer diagnostics.

  • 345.
    Grundberg, Ida
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Imgenberg-Kreuz, Juliana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Kiflemariam, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Diagnostic mutation testing in situ in routine FFPE tissue sections for treatment prediction in clinical oncologyManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Activating mutations in the KRAS gene are present in different cancer types and are strongly associated with resistance to epidermal growth factor receptor (EGFR) inhibitor therapy. Hence there is a requirement for sensitive KRAS mutation analysis to determine the most suitable treatment for the patients. Also, little is known about the impact of tumor heterogeneity with regard to KRAS mutation status in different sub-clones during tumorigenesis, and if this is important for treatment response and prognosis. To improve the diagnostic accuracy, we developed an RNA-based genotyping assay that targets KRAS-mutations in codon 12 and 13 in situ on tissue samples by the use of multiple mutation specific padlock probes and rolling-circle amplification. Thus, the distribution of wild-type (green rolling-circle products) and mutated (red rolling-circle products) KRAS alleles can be determined for single cancer cells in different parts of a heterogeneous tumor without the use of microdissection. We demonstrate reliable detection of KRAS point mutations on cytologic tumor imprints as well as on fresh frozen and formalin-fixed paraffin-embedded tissue sections from colorectal and lung cancer. This in situ method offers single cell mutation detection for diagnostics and holds great promise as a tool to investigate the role of oncogenic mutations in complex tumor tissues.

  • 346.
    Gu, Xiaolian
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Boldrup, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, Philip J
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, Paris, France.
    Nylander, Elisabet
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Loizou, Christos
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Olofsson, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Norberg-Spaak, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Gärskog, Ola
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Epigenetic regulation of OAS2 shows disease-specific DNA methylation profiles at individual CpG sites2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 32579Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epigenetic modifications are essential regulators of biological processes. Decreased DNA methylation of OAS2 (2'-5'-Oligoadenylate Synthetase 2), encoding an antiviral protein, has been seen in psoriasis. To provide further insight into the epigenetic regulation of OAS2, we performed pyrosequencing to detect OAS2 DNA methylation status at 11 promoter and first exon located CpG sites in psoriasis (n = 12) and two common subtypes of squamous cell carcinoma (SCC) of the head and neck: tongue (n = 12) and tonsillar (n = 11). Compared to corresponding controls, a general hypomethylation was seen in psoriasis. In tongue and tonsillar SCC, hypomethylation was found at only two CpG sites, the same two sites that were least demethylated in psoriasis. Despite differences in the specific residues targeted for methylation/demethylation, OAS2 expression was upregulated in all conditions and correlations between methylation and expression were seen in psoriasis and tongue SCC. Distinctive methylation status at four successively located CpG sites within a genomic area of 63 bp reveals a delicately integrated epigenetic program and indicates that detailed analysis of individual CpGs provides additional information into the mechanisms of epigenetic regulation in specific disease states. Methylation analyses as clinical biomarkers need to be tailored according to disease-specific sites.

  • 347. Guilbaud, C
    et al.
    Peyrard, M
    Fransson, I
    Clifton, S W
    Roe, B A
    Carter, N P
    Dumanski, J P
    Characterization of the mouse beta-prime adaptin gene; cDNA sequence, genomic structure, and chromosomal localization.1997Inngår i: Mammalian Genome, ISSN 0938-8990, E-ISSN 1432-1777, Vol. 8, nr 9, s. 651-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adaptins are important subunits of heterotetrameric complexes called adaptors, which participate in the clathrin-coated, vesicle-mediated endocytosis and intracellular receptor transport. The gene family of adaptins is divided into three classes, alpha, beta, and gamma, with further subdivision into beta- and beta-prime components. Two beta-prime adaptins, the rat AP105a and the human BAM22, have previously been characterized. The BAM22 gene is located on human Chromosome (Chr) 22q12 and can be considered a candidate meningioma tumor suppressor gene. We report here the characterization of the mouse ortholog of the BAM22 gene, and we suggest the name adtb1 for the mouse gene. Like the BAM22 gene, the adtb1 transcript is highly and ubiquitously expressed. We provide 3885-bp cDNA sequence, which entirely covers the open reading frame of the adtb1, capable of encoding a protein of 943 amino acids. The adtb1 protein is highly conserved (>96% identity) when compared with AP105a and BAM22 proteins. We also report the genomic organization of adtb1, which is similar to the BAM22 gene. The adtb1 gene has been assigned to mouse Chr 11, band 11A2, which confirms the synteny between human Chr 22q12 and mouse Chr 11.

  • 348.
    Gullberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Proximity Ligation as a Universal Protein Detection Tool2003Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Among the great challenges in biology are the precise quantification of specific sets of proteins and analyses of their patterns of interaction on a much larger scale than is possible today.

    This thesis presents a novel protein detection technique - proximity ligation - and reports the development and application of a nucleic acid amplification technique, RCA. Proximity ligation converts information about the presence or co-localization of specific proteins to unique sets of nucleic acid sequences. For detection of target proteins or protein complexes the coincident binding by pairs or triplets of specific protein-binding reagents are required. Oligonucleotide-extensions attached to those binding reagents are joined by a DNA ligase and subsequently analyzed by standard molecular genetic techniques. The technique is shown to sensitively detect an assortment of proteins using different types of binders converted to proximity probes, including SELEX aptamers and mono- and polyclonal antibodies. I discuss factors important for using the technique to analyze many proteins simultaneously.

    Quantification of target molecules requires precise amplification and detection. I show how rolling circle amplification, RCA, can be used for precise quantification of circular templates using modified molecular beacons with real-time detection. The combination of proximity-probe templated circularization and RCA results in a sensitive method with high selectivity, capable of visualizing individual immobilized proteins. This technique is used for localized detection of a set of individual proteins and protein complexes at sub-cellular resolution.

  • 349.
    Gunnarsson, Rebeqa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    New insights into the pathobiology of chronic lymphocytic leukemia2011Inngår i: Journal of Hematopathology, ISSN 1868-9256, Vol. 4, nr 3, s. 149-163Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a varying clinical outcome; however, the pathogenic mechanisms involved in disease development have remained largely unknown. In recent years, novel biomarkers, such as certain recurrent genomic alterations and the immunoglobulin heavy variable gene mutational status, have significantly improved the subdivision of the disease along with the prognostic assessment of individual patients. Advanced molecular studies have also revealed important genetic/epigenetic events and potential susceptibility loci for CLL, as well as implicating antigens in CLL development. Furthermore, the presence of monoclonal B cell lymphocytosis (MBL) has been demonstrated to precede CLL and appears to be a pre-leukemic condition. In this review, we will not only focus on recent developments made in the fields of genetics and immunogenetics in CLL, but also provide a brief overview of MBL, since we believe that advancements in these areas will have a major impact on our understanding of CLL pathobiology.

  • 350. Guo, Ying
    et al.
    Gu, Xiaorong
    Sheng, Zheya
    Wang, Yanqiang
    Luo, Chenglong
    Liu, Ranran
    Qu, Hao
    Shu, Dingming
    Wen, Jie
    Crooijmans, Richard P M A
    Carlborg, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Zhao, Yiqiang
    Hu, Xiaoxiang
    Li, Ning
    A Complex Structural Variation on Chromosome 27 Leads to the Ectopic Expression of HOXB8 and the Muffs and Beard Phenotype in Chickens2016Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, nr 6, artikkel-id e1006071Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Muffs and beard (Mb) is a phenotype in chickens where groups of elongated feathers gather from both sides of the face (muffs) and below the beak (beard). It is an autosomal, incomplete dominant phenotype encoded by the Muffs and beard (Mb) locus. Here we use genome-wide association (GWA) analysis, linkage analysis, Identity-by-Descent (IBD) mapping, array-CGH, genome re-sequencing and expression analysis to show that the Mb allele causing the Mb phenotype is a derived allele where a complex structural variation (SV) on GGA27 leads to an altered expression of the gene HOXB8. This Mb allele was shown to be completely associated with the Mb phenotype in nine other independent Mb chicken breeds. The Mb allele differs from the wild-type mb allele by three duplications, one in tandem and two that are translocated to that of the tandem repeat around 1.70 Mb on GGA27. The duplications contain total seven annotated genes and their expression was tested during distinct stages of Mb morphogenesis. A continuous high ectopic expression of HOXB8 was found in the facial skin of Mb chickens, strongly suggesting that HOXB8 directs this regional feather-development. In conclusion, our results provide an interesting example of how genomic structural rearrangements alter the regulation of genes leading to novel phenotypes. Further, it again illustrates the value of utilizing derived phenotypes in domestic animals to dissect the genetic basis of developmental traits, herein providing novel insights into the likely role of HOXB8 in feather development and differentiation.

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