A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.
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.
Richards
J Brent
JB
Departments of Medicine, Human Genetics, and Epidemiology and Biostatistics, Jewish General Hospital, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca
Waterworth
Dawn
D
O'Rahilly
Stephen
S
Hivert
Marie-France
MF
Loos
Ruth J F
RJ
Perry
John R B
JR
Tanaka
Toshiko
T
Timpson
Nicholas John
NJ
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Robert K
RK
Soranzo
Nicole
N
Song
Kijoung
K
Rocha
Nuno
N
Grundberg
Elin
E
Dupuis
Josée
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Florez
Jose C
JC
Langenberg
Claudia
C
Prokopenko
Inga
I
Saxena
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Sladek
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Aulchenko
Yurii
Y
Evans
David
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Waeber
Gerard
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Jeanette
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Burnett
Mary-Susan
MS
Sattar
Naveed
N
Devaney
Joseph
J
Willenborg
Christina
C
Hingorani
Aroon
A
Witteman
Jaquelin C M
JC
Vollenweider
Peter
P
Glaser
Beate
B
Hengstenberg
Christian
C
Ferrucci
Luigi
L
Melzer
David
D
Stark
Klaus
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Deanfield
John
J
Winogradow
Janina
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Grassl
Martina
M
Hall
Alistair S
AS
Egan
Josephine M
JM
Thompson
John R
JR
Ricketts
Sally L
SL
König
Inke R
IR
Reinhard
Wibke
W
Grundy
Scott
S
Wichmann
H-Erich
HE
Barter
Phil
P
Mahley
Robert
R
Kesaniemi
Y Antero
YA
Rader
Daniel J
DJ
Reilly
Muredach P
MP
Epstein
Stephen E
SE
Stewart
Alexandre F R
AF
Van Duijn
Cornelia M
CM
Schunkert
Heribert
H
Burling
Keith
K
Deloukas
Panos
P
Pastinen
Tomi
T
Samani
Nilesh J
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McPherson
Ruth
R
Davey Smith
George
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D052242:Adiponectin / Q000097:blood* / Q000235:genetics / Q000502:physiology; D003327:Coronary Disease / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
D052242:Adiponectin