Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.
Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.
Kolz
Melanie
M
Institute of Epidemiology, Helmholtz Zentrum München, National Research Center for Environment and Health, Neuherberg, Germany.
Johnson
Toby
T
Sanna
Serena
S
Teumer
Alexander
A
Vitart
Veronique
V
Perola
Markus
M
Mangino
Massimo
M
Albrecht
Eva
E
Wallace
Chris
C
Farrall
Martin
M
Johansson
Asa
A
Nyholt
Dale R
DR
Aulchenko
Yurii
Y
Beckmann
Jacques S
JS
Bergmann
Sven
S
Bochud
Murielle
M
Brown
Morris
M
Campbell
Harry
H
Connell
John
J
Dominiczak
Anna
A
Homuth
Georg
G
Lamina
Claudia
C
McCarthy
Mark I
MI
Meitinger
Thomas
T
Mooser
Vincent
V
Munroe
Patricia
P
Nauck
Matthias
M
Peden
John
J
Prokisch
Holger
H
Salo
Perttu
P
Salomaa
Veikko
V
Samani
Nilesh J
NJ
Schlessinger
David
D
Uda
Manuela
M
Völker
Uwe
U
Waeber
Gérard
G
Waterworth
Dawn
D
Wang-Sattler
Rui
R
Wright
Alan F
AF
Adamski
Jerzy
J
Whitfield
John B
JB
Gyllensten
Ulf
U
Wilson
James F
JF
Rudan
Igor
I
Pramstaller
Peter
P
Watkins
Hugh
H
Doering
Angela
A
Wichmann
H-Erich
HE
Spector
Tim D
TD
Peltonen
Leena
L
Völzke
Henry
H
Nagaraja
Ramaiah
R
Vollenweider
Peter
P
Caulfield
Mark
M
Illig
Thomas
T
Gieger
Christian
C
D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006073:Gout / Q000209:etiology; D006801:Humans; D008297:Male; D014527:Uric Acid / Q000097:blood*
D014527:Uric Acid