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dc.contributor.authorRichards, J. Brenten_US
dc.contributor.authorWaterworth, Dawnen_US
dc.contributor.authorO'Rahilly, Stephenen_US
dc.contributor.authorHivert, Marie-Franceen_US
dc.contributor.authorLoos, Ruth J. F.en_US
dc.contributor.authorPerry, John R. B.en_US
dc.contributor.authorTanaka, Toshikoen_US
dc.contributor.authorTimpson, Nicholas Johnen_US
dc.contributor.authorSemple, Robert K.en_US
dc.contributor.authorSoranzo, Nicoleen_US
dc.contributor.authorSong, Kijoungen_US
dc.contributor.authorRocha, Nunoen_US
dc.contributor.authorGrundberg, Elinen_US
dc.contributor.authorDupuis, Joséeen_US
dc.contributor.authorFlorez, Jose C.en_US
dc.contributor.authorLangenberg, Claudiaen_US
dc.contributor.authorProkopenko, Ingaen_US
dc.contributor.authorSaxena, Richaen_US
dc.contributor.authorSladek, Roberten_US
dc.contributor.authorAulchenko, Yuriien_US
dc.contributor.authorEvans, Daviden_US
dc.contributor.authorWaeber, Gerarden_US
dc.contributor.authorErdmann, Jeanetteen_US
dc.contributor.authorBurnett, Mary-Susanen_US
dc.contributor.authorSattar, Naveeden_US
dc.contributor.authorDevaney, Josephen_US
dc.contributor.authorWillenborg, Christinaen_US
dc.contributor.authorHingorani, Aroonen_US
dc.contributor.authorWitteman, Jaquelin C. M.en_US
dc.contributor.authorVollenweider, Peteren_US
dc.contributor.authorGlaser, Beateen_US
dc.contributor.authorHengstenberg, Christianen_US
dc.contributor.authorFerrucci, Luigien_US
dc.contributor.authorMelzer, Daviden_US
dc.contributor.authorStark, Klausen_US
dc.contributor.authorDeanfield, Johnen_US
dc.contributor.authorWinogradow, Janinaen_US
dc.contributor.authorGrassl, Martinaen_US
dc.contributor.authorHall, Alistair S.en_US
dc.contributor.authorEgan, Josephine M.en_US
dc.contributor.authorThompson, John R.en_US
dc.contributor.authorRicketts, Sally L.en_US
dc.contributor.authorKönig, Inke R.en_US
dc.contributor.authorReinhard, Wibkeen_US
dc.contributor.authorGrundy, Scotten_US
dc.contributor.authorWichmann, H-Erichen_US
dc.contributor.authorBarter, Philen_US
dc.contributor.authorMahley, Roberten_US
dc.contributor.authorKesaniemi, Y. Anteroen_US
dc.contributor.authorRader, Daniel J.en_US
dc.contributor.authorReilly, Muredach P.en_US
dc.contributor.authorEpstein, Stephen E.en_US
dc.contributor.authorStewart, Alexandre F. R.en_US
dc.contributor.authorVan Duijn, Cornelia M.en_US
dc.contributor.authorSchunkert, Heriberten_US
dc.contributor.authorBurling, Keithen_US
dc.contributor.authorDeloukas, Panosen_US
dc.contributor.authorPastinen, Tomien_US
dc.contributor.authorSamani, Nilesh J.en_US
dc.contributor.authorMcPherson, Ruthen_US
dc.contributor.authorDavey Smith, Georgeen_US
dc.contributor.authorFrayling, Timothy M.en_US
dc.contributor.authorWareham, Nicholas J.en_US
dc.contributor.authorMeigs, James B.en_US
dc.contributor.authorMooser, Vincenten_US
dc.contributor.authorSpector, Tim D.en_US
dc.date.accessioned2012-01-11T16:09:04Z
dc.date.available2012-01-11T16:09:04Z
dc.date.issued2009-12-11en_US
dc.identifier.citationRichards, J. Brent, Dawn Waterworth, Stephen O'Rahilly, Marie-France Hivert, Ruth J. F. Loos, John R. B. Perry, Toshiko Tanaka, Nicholas John Timpson, Robert K. Semple, Nicole Soranzo, Kijoung Song, Nuno Rocha, Elin Grundberg, Josée Dupuis, Jose C. Florez, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Robert Sladek, Yurii Aulchenko, David Evans, Gerard Waeber, Jeanette Erdmann, Mary-Susan Burnett, Naveed Sattar, Joseph Devaney, Christina Willenborg, Aroon Hingorani, Jaquelin C. M. Witteman, Peter Vollenweider, Beate Glaser, Christian Hengstenberg, Luigi Ferrucci, David Melzer, Klaus Stark, John Deanfield, Janina Winogradow, Martina Grassl, Alistair S. Hall, Josephine M. Egan, John R. Thompson, Sally L. Ricketts, Inke R. König, Wibke Reinhard, Scott Grundy, H-Erich Wichmann, Phil Barter, Robert Mahley, Y. Antero Kesaniemi, Daniel J. Rader, Muredach P. Reilly, Stephen E. Epstein, Alexandre F. R. Stewart, Cornelia M. Van Duijn, Heribert Schunkert, Keith Burling, Panos Deloukas, Tomi Pastinen, Nilesh J. Samani, Ruth McPherson, George Davey Smith, Timothy M. Frayling, Nicholas J. Wareham, James B. Meigs, Vincent Mooser, Tim D. Spector. "A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels" PLoS Genetics 5(12):e1000768. (2009)en_US
dc.identifier.issn1553-7404en_US
dc.identifier.urihttp://hdl.handle.net/2144/3099
dc.description.abstractThe adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10−6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10−3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk. Author Summary Through a meta-analysis of genome-wide association studies of 14,733 individuals, we identified common base-pair variants in the genome which influence circulating adiponectin levels. Since adiponectin is an adipocyte-derived circulating protein which has been inversely associated with risk of obesity-related diseases such as type 2 diabetes (T2D) and coronary heart disease (CHD), we next sought to understand if the identified variants influencing adiponectin levels also influence risk of T2D, CHD, and several metabolic traits. In addition to confirming that variation at the ADIPOQ locus influences adiponectin levels, our analyses point to a variant in the ARL15 (ADP-ribosylation factor-like 15) locus which decreases adiponectin levels and increases risk of CHD and T2D. Further, this same variant was associated with increased fasting insulin levels and glycated hemoglobin. While the function of ARL15 is not known, we provide insight into the tissue specificity of ARL15 expression. These results thus provide novel insights into the physiology of the adiponectin pathway and obesity-related diseases.en_US
dc.description.sponsorshipWellcome Trust (080952/Z/06/Z, 078986/Z/06/Z); United Kingdom Medical Research Council Centre for Obesity and Related Metabolic Diseases; Canadian Institutes of Health Research; NIHR Cambridge Biomedical Research Centre; Cardiovascular Institute of the University of Pennsylvania; GlaxoSmithKline; Center for Applied Genomics at the Children's Hospital of Philadelphia; Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research; Cardiogenics (LSHM-CT-2006-037593); GSF National Research Centre for Environment and Health; German Federal Ministry of Education and Research and the State of Bavaria; Cancer Research United Kingdom and the Medical Research Council; British Heart Foundation (BHF) Family Heart Study Research Group; UK Medical Research Council; University of Bristol; British Heart Foundation (MRC PG/07/002); Genome Quebec; Genome Canada; National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195); Affymetrix (N02-HL-6-4278); Framingham Heart Study SNP Health Association Resource (SHARe) project; the National Institutes of Health, National Center for Research Resources; General Clinical Research Centers Program (M01-RR-01066); American Diabetes Association; sanofi-aventis; National Institues of Health and National Center for Research Resources (1S10RR163736-01A1); Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195), National Institute for Diabetes and Digestive and Kidney Diseases (R01 DK078616, NIDDK K24 DK080140, K23 DK65978) a Massachusetts General Hospital; Doris Duke Charitable Foundation; Centre de Recherche Medicale de l'Universite de Sherbrooke; European Community's Seventh Framework Programme (FP7/2007-2013, HEALTH-F2-2008-201865-GEFOS, FP7/2007-2013); ENGAGE project (HEALTH-F4-2007-201413; FP-5 GenomEUtwin Project (QLG2-CT-2002-01254); National Institute for Health Researchen_US
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsRichards et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.titleA Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levelsen_US
dc.typearticleen_US
dc.identifier.doi10.1371/journal.pgen.1000768en_US
dc.identifier.pubmedid20011104en_US
dc.identifier.pmcid2781107en_US


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