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  • 301.
    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.

  • 302.
    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.

  • 303.
    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.

  • 304. 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.

  • 305.
    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.

  • 306.
    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.

  • 307.
    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.

  • 308.
    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.

  • 309. 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.

  • 310.
    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.

  • 311.
    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.

  • 312. 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.

  • 313.
    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.

  • 314. 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.

  • 315. 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.

  • 316.
    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.

  • 317.
    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.

  • 318. 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.

  • 319. 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.

  • 320.
    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.

  • 321. 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.

  • 322. 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.

  • 323.
    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.

  • 324. 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.

  • 325.
    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.

  • 326.
    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.

  • 327. 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)
  • 328.
    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.

  • 329.
    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.

  • 330. 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.

  • 331.
    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.

  • 332.
    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.

  • 333.
    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.

  • 334. 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.

  • 335.
    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.

  • 336.
    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.

  • 337. 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.

  • 338.
    Guo, Zhongmin
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Molecular mechanisms in cervical carcinogenesis: Studies of clonality, somatic genetic alterations and human papillomavirus variants in cervical pre-invasive and invasive cancer2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Cervical cancer derives from a series of pre-invasive cervical neoplastic lesions termed CIN I-III (Cervical Intraepithelial Neoplasia) via typical multiple-step processes. In contrast to premalignant disorders in other organs, different degrees of CIN possess a distinct biological behaviour where a proportion spontaneously regress or persist, whereas some progress to invasive cancer. A meticulous examination of pathological, genetical and viological aspects of the mechanisms for this dynamic event was performed.

    Clonality and clonal lineages of CIN and invasive cancer were studied on microdissected single or multiple synchronous lesions. Independent CIN lesions were both monoclonal and polyclonal, whereas invasive cancer and adjacent CIN inevitably were monoclonal in origin. Mostly when multiple lesions were analyzed, the invasive cancer shared an identical clonality pattern with the co-existing CIN but one third of multiple CIN lesions were multifocal and their clonal origin was not identical to synchronous invasive cancer. The data suggest that CIN lesions vary in their biological behaviour although they are morphologically similar. Polyclonal CIN may represent a benign proliferation,whereas monoclonal CIN more likely progresses to an invasive stage. Multifocal origin of CIN suggests that multiple cells from the cervix undergo transformation simultaneously, implying an essential role of a "field defect" (HPV?) in cervical carcinogenesis.

    Genetic deletions (LOH) of chromosome 3p, 6p and 6q were investigated in CIN and SCC. The detection of allelic losses and the deletion mapping suggested that the alterations of 3p22-21.3, 3p21.1, HLA region on 6p and 6q16.1-21 were frequent and early genetic events in cervical cancer and imply that these chromosome regions harbour potential tumor suppressor genes important in thecervical carcinogenesis.

    HPV 16 E6 and L1 gene variations were analyzed in CIN lesions independent or synchronous with invasive cancer. Distribution of HPV in the infected cervix is more restricted to neoplastic lesions than normal epithelia. Identical HPV types and variants were detected in multiple synchronous CIN and invasive cancer, emphasizing the role of persistence of the same oncogenic HPV in the initiation of transformation events. The most common HPV 16 E6 and L1 gene variations were established. The data provide a base for further in vitro studies and for design of vaccine strategy for prevention of HPV 16 associated diseases.

  • 339.
    Gustafsson, Ann-Sofie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Abramenkovs, Andris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Suppression of DNA-dependent protein kinase sensitize cells to radiation without affecting DSB repair2014Inngår i: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 769, s. 1-10Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Efficient and correct repair of DNA double-strand break (DSB) is critical for cell survival. Defects in the DNA repair may lead to cell death, genomic instability and development of cancer. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is an essential component of the non-homologous end joining (NHEJ) which is the major DSB repair pathway in mammalian cells. In the present study, by using siRNA against DNA-PKcs in four human cell lines, we examined how low levels of DNA-PKcs affected cellular response to ionizing radiation. Decrease of DNA-PKcs levels by 80-95%, induced by siRNA treatment, lead to extreme radiosensitivity, similar to that seen in cells completely lacking DNA-PKcs and low levels of DNA-PKcs promoted cell accumulation in G2/M phase after irradiation and blocked progression of mitosis. Surprisingly, low levels of DNA-PKcs did not affect the repair capacity and the removal of 53BP1 or gamma-H2AX foci and rejoining of DSB appeared normal. This was in strong contrast to cells completely lacking DNA-PKcs and cells treated with the DNA-PKcs inhibitor NU7441, in which DSB repair were severely compromised. This suggests that there are different mechanisms by which loss of DNA-PKcs functions can sensitize cells to ionizing radiation. Further, foci of phosphorylated DNA-PKcs (T2609 and S2056) co-localized with DSB and this was independent of the amount of DNA-PKcs but foci of DNA-PKcs was only seen in siRNA-treated cells. Our study emphasizes on the critical role of DNA-PKcs for maintaining survival after radiation exposure which is uncoupled from its essential function in DSB repair. This could have implications for the development of therapeutic strategies aiming to radiosensitize tumors by affecting the DNA-PKcs function.

  • 340.
    Gustafsson, S.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Lönn, M.
    Genetic differentiation and habitat preference of flowering-time variants within Gymnadenia conopsea2003Inngår i: Heredity, nr 91, s. 284-292Artikkel i tidsskrift (Fagfellevurdert)
  • 341.
    Gustafsson, S.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Sjögren-Gulve, P.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Genetic diversity in the rare orchid, Gymnadenia odoratissima and a comparison with the more common congener, G. conopsea2002Inngår i: Conservation Genetics, Vol. 3, s. 225-234Artikkel i tidsskrift (Fagfellevurdert)
  • 342.
    Gustavsson, Peter
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Diamond-Blackfan anemia: Mapping and identification of the disease gene2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis presents the positional cloning of the gene behind Diamond-Blackfan anemia. Evidence for the involvement of ribosomal protein (RP) S19 gene mutations in Diamond-Blackfan anemia is given. This is the first example of a human disease that is directly related to a ribosomal protein.

    A chromosomal translocation in a girl with DBA was characterized, using fluorescent in situ hybridization (FISH) to metaphase chromosomes. These results suggested that the disease gene is located on chromosome 19q13. Analysis of familial cases with DBA showed significant linkage for the disease to the region defined by the translocation breakpoint. FISH analysis of metaphase chromosomes identified a cosmid spanning the translocation breakpoint. Sequence analysis of the cosmid revealed a gene encoding the ribosomal protein S19 (RPS19), which is disrupted by the translocation. Subsequent analysis of the RPS19 gene in independent DBA patients revealed mutations that segregate with the disease.

    Diamond-Blackfan anemia is a disease characterized by a congenital defect of erythropoiesis with an absence or a reduction of the erythroblasts present in bone marrow. This disorder may act as a model for our further understanding of the regulation of red blood cell production. Several different factors involved in the production of red blood cells (erythropoiesis) have been identified. However, much is yet unknown regarding the complex regulatory mechanisms of hematopoietic stem cells and the results presented in this study provide another link in the erythropoietic pathway.

  • 343.
    Gyllenstrand, N
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Institutionen för evolution, genomik och systematik. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Institutionen för evolution, genomik och systematik, Evolutionär funktionsgenomik. evolutionär funktionsgenomik.
    Seppä, P
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Institutionen för evolution, genomik och systematik. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Institutionen för evolution, genomik och systematik, Evolutionär funktionsgenomik. evolutionär funktionsgenomik.
    Conservation genetics of the wood ant, Formica lugubris, in a fragmented landscape.2003Inngår i: Mol Ecol, ISSN 0962-1083, Vol. 12, nr 11, s. 2931-40Artikkel i tidsskrift (Annet vitenskapelig)
  • 344.
    Göransson, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Readout Strategies for Biomolecular Analyses2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis describes three readout formats for molecular analyses. A common feature in all works is probing techniques that upon specific target recognition ideally results in equimolar amounts of DNA circles. These are then specifically amplified and detected using any of the techniques presented herein. The first paper presents a method that enables homogeneous digital detection and enumeration of biomolecules, represented as fluorescence-labelled DNA macromolecules. This method offers precise measurements to be performed with a wide linear dynamic range. As an application, two closely related bacterial species were selectively detected. The second paper further investigates and optimizes the properties of the technique presented in paper one. The third paper demonstrates a platform that enables simultaneous quantitative analysis of large numbers of biomolecules. The array format and decoding scheme together propose a digital strategy for decoding of biomolecules. The array and the decoding procedure were characterized and evaluated for gene copy-number measurements. The fourth paper examines a new strategy for non-optical measurements of biomolecules. Characteristics of this technique are investigated, and compared to its optical equivalent, fluorescence polarization.

  • 345.
    Götz, Alexandra
    et al.
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tyynismaa, Henna
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Euro, Liliya
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Ellonen, Pekka
    nstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Ojala, Tiina
    Department of Pediatric Cardiology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Hämäläinen, Riikka H
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tommiska, Johanna
    nstitute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland g.
    Raivio, Taneli
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Karikoski, Riitta
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tammela, Outi
    Pediatric Research Centre, Tampere University Hospital, Tampere, Finland.
    Simola, Kalle O J
    Genetics Outpatient Clinic, Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Paetau, Anders
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tyni, Tiina
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Pediatric Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Suomalainen, Anu
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy2011Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, nr 5, s. 635-642Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.

  • 346.
    Hagberg, Anette
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Expression profiling using manifold supports2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Analyses of mRNA provides a condensed view of gene structure and quantitative analysis can reveal the induction of physiological or pathological gene expression programs. This thesis describes a new method for mRNA isolation, followed by sensitive real time detection via polymerase chain reaction (PCR), in order to quantitate transcripts of interest.

    Chimeric genes that result from chromosomal translocations can be used as disease-specific markers for the malignant clone to detect minimal residual diseases. It is important to detect an expanding clone as early as possible to increase the chance of a successful treatment. Accordingly, RT-PCR (reverse transcription PCR) of such chimeric transcripts has gained interest as a means to monitor patients due to its sensitivity. Expression of BCR-ABL in bone marrow or blood can be used as a measure of minimal residual disease (MRD) in patients with chronic myeloid leukemia. The newly described method for mRNA isolation was used to analyse the tumor burden in patient samples via real time detection using PCR. The proposed method constitues a promising, reproducible, and sensitive means to quantify BCR-ABL mRNA and it is suitable to monitor MRD in leukemic patients.

    Recombinant human erythropoietin (r-HuEpo) has an important role in the treatment of anemic patients. β-globin mRNA was monitored in order to elucidate if it could serve as a new marker for monitoring the response to r-HuEpo. Because of the high cost of EPO treatment, an early indicator of whether a patient responds to the therapy would be of great value. The response pattern for mRNA was compared to the reticulocyte count, levels of hemoglobin, transferrin receptor and ferritin in healty individuals receiving r-HuEpo or in controls. Following treatment, β-globin mRNA showed a more distinct increase compared to all other laboratory measurements and is therefore promising as a marker for the response to EPO treatment.

    The fourth project was undertaken to investigate fluctuations of mRNA expression levels for cytokines important for the rejection of xenotransplants. Porcine islet xenotransplantation could potentially solve the problem of the limited supply of suitable human donors for transplanation of islets, in order to offer a curative treatment of insulin dependent diabetes mellitus (IDDM). The rejection process was studied in the pig→rat model. Earlier studies reported a Th2 associated response. However, both morphological pattern and mRNA expression profiling supported the view that rejection is primarily due to a Th1 response.

  • 347. Hagberg, Carolina E.
    et al.
    Falkevall, Annelie
    Wang, Xun
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Huusko, Jenni
    Nilsson, Ingrid
    van Meeteren, Laurens A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Samen, Erik
    Lu, Li
    Vanwildemeersch, Maarten
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Genove, Guillem
    Pietras, Kristian
    Stone-Elander, Sharon
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ylä-Herttuala, Seppo
    Lindahl, Per
    Eriksson, Ulf
    Vascular endothelial growth factor B controls endothelial fatty acid uptake2010Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 464, nr 7290, s. 917-921Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.

  • 348.
    Hagglund, Anna-Carin
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Jones, Iwan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development2017Inngår i: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 10, nr 3, s. 245-257Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and systemic forms of dysgenesis that are best exemplified by aniridia and Axenfeld-Rieger syndrome, respectively. Extensive clinical overlap in disease presentation amongst ASD syndromes creates challenges for correct diagnosis and classification. The use of animal models has therefore proved to be a robust approach for unravelling this complex genotypic and phenotypic heterogeneity. However, despite these successes, it is clear that additional genes that underlie several ASD syndromes remain unidentified. Here, we report the characterisation of a novel mouse model of ASD. Conditional deletion of Tsc1 during eye development leads to a premature upregulation of mTORC1 activity within the ciliary margin, periocular mesenchyme and lens epithelium. This aberrant mTORC1 signalling within the ciliary margin in particular leads to a reduction in the number of cells that express Pax6, Bmp4 and Msx1. Sustained mTORC1 signalling also induces a decrease in ciliary margin progenitor cell proliferation and a consequent failure of ciliary body and iris development in postnatal animals. Our study therefore identifies Tsc1 as a novel candidate ASD gene. Furthermore, the Tsc1-ablated mouse model also provides a valuable resource for future studies concerning the molecular mechanisms underlying ASD and acts as a platform for evaluating therapeutic approaches for the treatment of visual disorders.

  • 349. Hahn-Stromberg, Victoria
    et al.
    Askari, Shlear
    Befekadu, Rahel
    Matthiessen, Peter
    Karlsson, Sune
    Nilsson, Torbjörn K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Polymorphisms in the CLDN1 and CLDN7 genes are related to differentiation and tumor stage in colon carcinoma2014Inngår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, nr 7, s. 636-642Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tight junction is composed of transmembrane proteins important for maintaining cell polarity and regulating ion flow. Among these proteins are the tissue-specific claudins, proteins that have recently been suggested as tumor markers for several different types of cancer. An altered claudin expression has been observed in colon, prostatic, ovarian, and breast carcinoma. The aim of this study was to analyze the allele frequencies of three common single nucleotide polymorphisms (SNPs) in the genes for claudin 1 and claudin 7 in colon cancer (CC) patients and in a control population of healthy blood donors. Pyrosequencing was used to genotype the CLDN1 SNP rs9869263 (c.369C>T), and the CLDN7 SNPs rs4562 (c.590C>T) and rs374400 (c.606T>G) in DNA from 102 formalin fixed paraffin embedded (FFPE) colon cancer tissue, and 111 blood leukocyte DNA from blood/plasma donors. These results were correlated with clinical parameters such as TNM stage, tumor localization, tumor differentiation, complexity index, sex, and age. We found that there was a significant association between the CLDN1 genotype CC in tumor samples and a higher risk of colon cancer development (OR 3.0, p < 0.001). We also found that the CLDN7 rs4562 (c.590C>T) genotype CT had a higher risk of lymph node involvement (p = 0.031) and a lower degree of tumor differentiation (p = 0.028). In the control population, the allele frequencies were very similar to those in the HapMap cohort for CLDN7. The CLDN1 rs9869263 genotype (c.369C>T) was related to increased risk of colon cancer, and the CLDN7 rs4562 genotype (c.590C>T) was related to tumor differentiation and lymph node involvement in colon carcinoma. Further studies are warranted to ascertain their potential uses as biomarkers predicting tumor development, proliferation, and outcome in this disease.

  • 350.
    Halim, Danny
    et al.
    Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands..
    Hofstra, Robert M. W.
    Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands.;UCL Inst Child Hlth, Birth Defects Res Ctr, London, England..
    Signorile, Luca
    Erasmus Univ, Med Ctr, Dept Cell Biol, Rotterdam, Netherlands..
    Verdijk, Rob M.
    Erasmus Univ, Med Ctr, Dept Pathol, Rotterdam, Netherlands..
    van der Werf, Christine S.
    Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands..
    Sribudiani, Yunia
    Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands.;Padjadjaran State Univ, Fac Med, Dept Biochem & Mol Biol, Bandung, Indonesia..
    Brouwer, Rutger W. W.
    Erasmus Univ, Med Ctr, Erasmus Ctr Biom, Rotterdam, Netherlands..
    van IJcken, Wilfred F. J.
    Erasmus Univ, Med Ctr, Erasmus Ctr Biom, Rotterdam, Netherlands..
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala Univ, Dept Immunol Genet & Pathol, Med Genet & Genom, Uppsala, Sweden..
    Verheij, Joke B. G. M.
    Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands..
    Baumann, Clarisse
    Hop Univ Robert Debre, Clin Genet Unit, Paris, France..
    Kerner, John
    Stanford Univ, Lucile Salter Packard Childrens Hosp, Palo Alto, CA 94304 USA..
    van Bever, Yolande
    Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands..
    Galjart, Niels
    Erasmus Univ, Med Ctr, Dept Cell Biol, Rotterdam, Netherlands..
    Wijnen, Rene M. H.
    Erasmus Univ, Med Ctr, Dept Pediat Surg, Rotterdam, Netherlands..
    Tibboel, Dick
    Erasmus Univ, Med Ctr, Dept Pediat Surg, Rotterdam, Netherlands..
    Burns, Alan J.
    Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands.;UCL Inst Child Hlth, Birth Defects Res Ctr, London, England..
    Muller, Franoise
    Hop Univ Robert Debre, Biochim Prenatale, Paris, France..
    Brooks, Alice S.
    Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands..
    Alves, Maria M.
    Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands..
    ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome2016Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, nr 3, s. 571-583Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin gamma-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we screened a cohort of eleven MMIHS patients, eight sporadic and three familial cases, and performed immunohistochemistry, molecular modeling and molecular dynamics (MD) simulations, and in vitro assays. In all sporadic cases, a heterozygous missense variant in ACTG2 was identified. ACTG2 expression was detected in all intestinal layers where smooth muscle cells are present in different stages of human development. No histopathological abnormalities were found in the patients. Using molecular modeling and MD simulations, we predicted that ACTG2 variants lead to significant changes to the protein function. This was confirmed by in vitro studies, which showed that the identified variants not only impair ACTG2 polymerization, but also contribute to reduced cell contractility. Taken together, our results confirm the involvement of ACTG2 in sporadic MMIHS, and bring new insights to MMIHS pathogenesis.

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