A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.
Richards JB., Waterworth D., O'Rahilly S., Hivert M-F., Loos RJF., Perry JRB., Tanaka T., Timpson NJ., Semple RK., Soranzo N., Song K., Rocha N., Grundberg E., Dupuis J., Florez JC., Langenberg C., Prokopenko I., Saxena R., Sladek R., Aulchenko Y., Evans D., Waeber G., Erdmann J., Burnett M-S., Sattar N., Devaney J., Willenborg C., Hingorani A., Witteman JCM., Vollenweider P., Glaser B., Hengstenberg C., Ferrucci L., Melzer D., Stark K., Deanfield J., Winogradow J., Grassl M., Hall AS., Egan JM., Thompson JR., Ricketts SL., König IR., Reinhard W., Grundy S., Wichmann H-E., Barter P., Mahley R., Kesaniemi YA., Rader DJ., Reilly MP., Epstein SE., Stewart AFR., Van Duijn CM., Schunkert H., Burling K., Deloukas P., Pastinen T., Samani NJ., McPherson R., Davey Smith G., Frayling TM., Wareham NJ., Meigs JB., Mooser V., Spector TD., GIANT Consortium None.
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.