|dc.identifier.citation||Richards, 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.description.abstract||The 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.
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.sponsorship||Wellcome 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 Research||en_US