Journal Article

A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

Epstein, Stephen E., Meigs, James B., Sladek, Robert, Evans, David, Mahley, Robert, Waeber, Gerard, Pastinen, Tomi, Ricketts, Sally L., Semple, Robert K., Devaney, Joseph, Erdmann, Jeanette, Winogradow, Janina, Thompson, John R., Hengstenberg, Christian, McPherson, Ruth, O'Rahilly, Stephen, Loos, Ruth J. F., Deanfield, John, Tanaka, Toshiko, Deloukas, Panos, Song, Kijoung, Grassl, Martina, Schunkert, Heribert, Wareham, Nicholas J., Rader, Daniel J., Grundy, Scott, Vollenweider, Peter, Florez, Jose C., Witteman, Jaquelin C. M., Kesaniemi, Y. Antero, Reinhard, Wibke, Soranzo, Nicole, Burling, Keith, Burnett, Mary-Susan, Hall, Alistair S., Samani, Nilesh J., Glaser, Beate, Hivert, Marie-France, Langenberg, Claudia, Aulchenko, Yurii, Reilly, Muredach P., Melzer, David, Davey Smith, George, Perry, John R. B., Stewart, Alexandre F. R., Frayling, Timothy M., Ferrucci, Luigi, König, Inke R., Mooser, Vincent, Richards, J. Brent, Prokopenko, Inga, Sattar, Naveed, Spector, Tim D., Saxena, Richa, Grundberg, Elin, Waterworth, Dawn, Stark, Klaus, Timpson, Nicholas John, Van Duijn, Cornelia M., Wichmann, H-Erich, Will

2009

Overview

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< or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =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 = 8.5x10(-6), 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adiponectin - blood / Adiponectin - genetics / Adiponectin - physiology / Biomedical research / Cardiovascular disease / Cardiovascular Disorders/Congenital Heart Disease / Coronary Disease - genetics / Councils / Diabetes / Diabetes and Endocrinology/Obesity / Diabetes and Endocrinology/Type 2 Diabetes / Diabetes Mellitus, Type 2 - genetics / Female / Gene expression / Genetic Predisposition to Disease / Genetics and Genomics/Genetics of Disease / Genome-Wide Association Study / Genomes / Grants / Heart / Humans / Influence / Male / Medical research / Metabolic disorders / Polymorphism, Single Nucleotide / Proteins / Recruitment