Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study

Abbas Dehghan, Anna Köttgen, Qiong Yang, Shih Jen Hwang, WH Linda Kao, Fernando Rivadeneira, Eric Boerwinkle, Daniel Levy, Albert Hofman, Brad C. Astor, Emelia J. Benjamin, Cornelia M. van Duijn, Jacqueline C. Witteman, Josef Coresh, Caroline S. Fox

Research output: Contribution to journalArticlepeer-review

499 Scopus citations


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=7·0×10-168 and 2·9×10-18 for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10-60 and 9·8×10-4), and rs1165205 in SLC17A3 (p=3·3×10-26 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=7·0×10-14), 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.

Original languageEnglish (US)
Pages (from-to)1953-1961
Number of pages9
JournalThe Lancet
Issue number9654
StatePublished - 2008

ASJC Scopus subject areas

  • General Medicine


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