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- Title
A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels.
- Authors
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; Kijoung Song; Rocha, Nuno; Grundberg, Elin; Dupuis, Josée; Florez, Jose C.; Langenberg, Claudia; Prokopenko, Inga; Saxena, Richa; Sladek, Robert; Aulchenko, Yurii
- 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 = 3.2×10-6, 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.
- Subjects
GENOMES; FAT cells; DIABETES; NUCLEOTIDES; GENETIC polymorphisms; PROTEINS
- Publication
PLoS Genetics, 2009, Vol 5, Issue 12, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1000768