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

作者：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

来源：PLoS Genetics, 2009, 5(12): e1000768.

DOI：10.1371/journal.pgen.1000768

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.

• 出版日期2009-12
• 单位河北医科大学