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Richards, J. Brent; Waterworth, Dawn; O'Rahilly, Stephen; Hivert, Marie-France; Loos, Ruth J. F.; Perry, John R. B.; Tanaka, Toshiko; Timpson, Nicholas John; Semple, Robert K.; Soranzo, Nicole; Song, Kijoung; Rocha, Nuno; Grundberg, Elin; Dupuis, Josee; Florez, Jose C.; Langenberg, Claudia; Prokopenko, Inga; Saxena, Richa; Sladek, Robert; Aulchenko, Yurii; Evans, David; Waeber, Gerard; Erdmann, Jeanette; Burnett, Mary-Susan; Sattar, Naveed; Devaney, Joseph; Willenborg, Christina; Hingorani, Aroon; Witteman, Jaquelin C. M.; Vollenweider, Peter; Glaser, Beate; Hengstenberg, Christian; Ferrucci, Luigi; Melzer, David; Stark, Klaus; Deanfield, John; Winogradow, Janina; Grassl, Martina; Hall, Alistair S.; Egan, Josephine M.; Thompson, John R.; Ricketts, Sally L.; Koenig, Inke R.; Reinhard, Wibke; Grundy, Scott; Wichmann, Heinz-Erich; Barter, Phil; Mahley, Robert; Kesaniemi, Y. Antero; Rader, Daniel J.; Reilly, Muredach P.; Epstein, Stephen E.; Stewart, Alexandre F. R.; Van Duijn, Cornelia M.; Schunkert, Heribert; Burling, Keith; Deloukas, Panos; Pastinen, Tomi; Samani, Nilesh J.; McPherson, Ruth; Smith, George Davey; Frayling, Timothy M.; Wareham, Nicholas J.; Meigs, James B.; Mooser, Vincent; Spector, Tim D.; Consortium, GIANT (December 2009): A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels.
In: PLOS Genetics 5(12), e1000768
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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 <= 5x10(-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 = 9.2x10(-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 = 2.9x10(-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 = 8.5610 26, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-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.