A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.
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- 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; Song, Kijoung; Rocha, Nuno; Grundberg, Elin; Dupuis, JosΓ©e; 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; Hingorani, Aroon; Witteman, Jaquelin C M; Vollenweider, Peter; Glaser, Beate; Hengstenberg, Christian; Ferrucci, Luigi; Melzer, David; Stark, Klaus; Deanfield, John; Winogradow, Janina; Grassl, Martina; Hall, Alistair S; Egan, Josephine M; Thompson, John R; Ricketts, Sally L; KΓΆnig, Inke R; Reinhard, Wibke; Grundy, Scott; Wichmann, H-Erich; Barter, Phil; Mahley, Robert; Kesaniemi, Y Antero; Rader, Daniel J; Reilly, Muredach P; Epstein, Stephen E; Stewart, Alexandre F R; Van Duijn, Cornelia M; Schunkert, Heribert; Burling, Keith; Deloukas, Panos; Pastinen, Tomi; Samani, Nilesh J; McPherson, Ruth; Davey Smith, George; Frayling, Timothy M; Wareham, Nicholas J; Meigs, James B; Mooser, Vincent; Spector, Tim D; GIANT Consortium
- Year
- 2009
- Journal
- PLoS genetics
- PMID
- 20011104
- DOI
- 10.1371/journal.pgen.1000768
- PMCID
- PMC2781107
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.
Overall study design.
Association between SNPs near ARL15 and adiponectin levels.(A) βLog(P-value) measures for association between single nucleotide polymorphisms (SNPs) and chromosomal position. (B) Linkage disequilibrium in GOLD heat map Haploview 4.0 color scheme, CEPH (Centre d'Γtude du Polymorphisme Humain) population. The x axis represents genomic position in Mb (A) and in kb (B). All P-values are derived from the discovery meta-analysis of CoLaus, TwinsUK, and Genetic Etiology of Metabolic Syndrome (GEMS) cohorts, except that for the lead SNP, rs4311394 (in red), which is derived from the combined P-value from the CoLaus, TwinsUK, GEMS, Framingham, InCHIANTI, Baltimore Longitudinal Study of Aging (BLSA), Avon Longitudinal Study of Parents and Children (ALSPAC), and European Prospective Investigation of Cancer-Norfolk (EPIC-Norfolk) cohorts.
Tissue distribution of ARL15 expression.mRNA levels determined by quantitative real-time PCR in a panel of human tissues.
Western blot showing ARL15 expression in insulin-responsive tissues in humans with Ξ±-tubulin as a loading control.HEK293 = untransfected HEK293 cells; ARL15 = HEK293 cells transiently expressing wild type human ARL15. SkM = skeletal muscle; WAT = white adipose tissue.
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