Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study
The Lancet , Volume 372 - Issue 9654 p. 1953- 1961
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<5·0×10-8) or the Rotterdam cohort (p<1·0×10-7) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Findings: 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=7·0×10-168and 2·9×10-18for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10-60and 9·8×10-4), and rs1165205 in SLC17A3 (p=3·3×10-26and 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=7·0×10-14), rs2231142 (1·74, 1·51-1·99, p=3·3×10-15), 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 μmol/L in the Framingham cohort, 269-386 μmol/L in the Rotterdam cohort, and 303-426 μmol/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). Interpretation: 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. Funding: Netherlands Organisation for Scientific Research (NWO); the National Heart, Lung, and Blood Institute.
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Dehghan, A, Köttgen, A, Yang, Q, Hwang, S.J, Kao, W.H.L, Rivadeneira Ramirez, F, … Fox, C.S. (2008). Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. The Lancet, 372(9654), 1953–1961. doi:10.1016/S0140-6736(08)61343-4