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
Affiliations
- 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
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.