PLoS Genetics (Dec 2009)

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

  • J Brent Richards,
  • Dawn Waterworth,
  • Stephen O'Rahilly,
  • Marie-France Hivert,
  • Ruth J F Loos,
  • John R B Perry,
  • Toshiko Tanaka,
  • Nicholas John Timpson,
  • Robert K Semple,
  • Nicole Soranzo,
  • Kijoung Song,
  • Nuno Rocha,
  • Elin Grundberg,
  • Josée Dupuis,
  • Jose C Florez,
  • Claudia Langenberg,
  • Inga Prokopenko,
  • Richa Saxena,
  • Robert Sladek,
  • Yurii Aulchenko,
  • David Evans,
  • Gerard Waeber,
  • Jeanette Erdmann,
  • Mary-Susan Burnett,
  • Naveed Sattar,
  • Joseph Devaney,
  • Christina Willenborg,
  • Aroon Hingorani,
  • Jaquelin C M Witteman,
  • Peter Vollenweider,
  • Beate Glaser,
  • Christian Hengstenberg,
  • Luigi Ferrucci,
  • David Melzer,
  • Klaus Stark,
  • John Deanfield,
  • Janina Winogradow,
  • Martina Grassl,
  • Alistair S Hall,
  • Josephine M Egan,
  • John R Thompson,
  • Sally L Ricketts,
  • Inke R König,
  • Wibke Reinhard,
  • Scott Grundy,
  • H-Erich Wichmann,
  • Phil Barter,
  • Robert Mahley,
  • Y Antero Kesaniemi,
  • Daniel J Rader,
  • Muredach P Reilly,
  • Stephen E Epstein,
  • Alexandre F R Stewart,
  • Cornelia M Van Duijn,
  • Heribert Schunkert,
  • Keith Burling,
  • Panos Deloukas,
  • Tomi Pastinen,
  • Nilesh J Samani,
  • Ruth McPherson,
  • George Davey Smith,
  • Timothy M Frayling,
  • Nicholas J Wareham,
  • James B Meigs,
  • Vincent Mooser,
  • Tim D Spector,
  • GIANT Consortium

DOI
https://doi.org/10.1371/journal.pgen.1000768
Journal volume & issue
Vol. 5, no. 12
p. e1000768

Abstract

Read online

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.