Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.
BACKGROUND
Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout.


METHODS
Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-7)) were evaluated with gout. The results obtained in white participants were combined using meta-analysis.


RESULTS
Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7.0 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 10(-26) and 0.33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0.59 per T allele, 95% CI 0.52-0.68, p=7.0 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 10(-15)), and rs1165205 (0.85, 0.77-0.94, p=0.002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1.71, 1.06-2.77, p=0.028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study).


CONCLUSIONS
We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout.
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands.
Abbas
A
Dehghan
Anna
A
Köttgen
Qiong
Q
Yang
Shih-Jen
SJ
Hwang
Wh Linda
WL
Kao
Fernando
F
Rivadeneira
Eric
E
Boerwinkle
Daniel
D
Levy
Albert
A
Hofman
Brad C
BC
Astor
Emelia J
EJ
Benjamin
Cornelia M
CM
van Duijn
Jacqueline C
JC
Witteman
Josef
J
Coresh
Caroline S
CS
Fox
D000483:Alleles; D002905:Chromosomes, Human, 4-5 / Q000235:genetics*; D002906:Chromosomes, Human, 6-12 and X / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006073:Gout / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D006801:Humans; D033461:Hyperuricemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D012307:Risk Factors; D014527:Uric Acid / Q000097:blood*
D014527:Uric Acid