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

JB Richards, D Waterworth, S O'Rahilly, MF Hivert, RJF Loos, JRB Perry, T Tanaka, NJ Timpson, RK Semple, N Soranzo, K Song, N Rocha, E Grundberg, J Dupuis, JC Florez, C Langenberg, I Prokopenko, R Saxena, R Sladek, Yuriy AulchenkoD Evans, G Waeber, J Erdmann, MS Burnett, N Sattar, J Devaney, C Willenborg, A Hingorani, JCM Witteman, P Vollenweider, B Glaser, C Hengstenberg, L Ferrucci, D Melzer, K Stark, J Deanfield, J Winogradow, M Grassl, AS Hall, JM Egan, JR Thompson, SL Ricketts, IR Konig, W Reinhard, S Grundy, HE Wichmann, P Barter, R Mahley, YA Kesaniemi, DJ Rader, MP Reilly, SE Epstein, AFR Stewart, Cornelia Duijn, H Schunkert, K Burling, P Deloukas, T Pastinen, NJ Samani, R McPherson, GD Smith, TM Frayling, NJ Wareham, JB Meigs, V Mooser, TD Spector

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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 <= 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.
Original languageUndefined/Unknown
JournalPLoS Genetics (print)
Volume5
Issue number12
DOIs
Publication statusPublished - 2009

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