A genome-wide association study reveals variants in ARL15 that influence adiponectin levels

Richards, J.B. et al. (2009) A genome-wide association study reveals variants in ARL15 that influence adiponectin levels. PLoS Genetics, 5(12), e1000768. (doi: 10.1371/journal.pgen.1000768)

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 = 3.2×10⁻³, 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sattar, Professor Naveed
• Authors: Richards, J.B., Waterworth, D., O'Rahilly, S., Hivert, M.-F., Loos, R.J.F., Perry, J.R.B., Tanaka, T., Timpson, N.J., Semple, R.K., Soranzo, N., Song, K., Rocha, N., Grundberg, E., Dupuis, J., Florez, J.C., 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, J.C.M., Vollenweider, P., Glaser, B., Hengstenberg, C., Ferrucci, L., Melzer, D., Stark, K., Deanfield, J., Winogradow, J., Grassl, M., Hall, A.S., Egan, J.M., Thompson, J.R., Ricketts, S.L., König, I.R., Reinhard, W., Grundy, S., Wichmann, H.-E., Barter, P., Mahley, R., Kesaniemi, Y.A., Rader, D.J., Reilly, M.P., Epstein, S.E., Stewart, A.F.R., Van Duijn, C.M., Schunkert, H., Burling, K., Deloukas, P., Pastinen, T., Samani, N.J., McPherson, R., Davey Smith, G., Frayling, T.M., Wareham, N.J., Meigs, J.B., Mooser, V., and Spector, T.D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: PLoS Genetics
• Publisher: Public Library of Science
• ISSN: 1553-7390
• ISSN (Online): 1553-7404
• Published Online: 11 December 2009
• Copyright Holders: Copyright © 2009 The Authors
• First Published: First published in PLoS Genetics 5(12):e1000768
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher