Association of Three Genetic Loci With Uric Acid Concentration and Risk of Gout: A Genome-Wide Association Study

Lancet. 2008 Dec 6;372(9654):1953-61. doi: 10.1016/S0140-6736(08)61343-4. Epub 2008 Oct 1.

Abstract

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.

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 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).

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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Chromosomes, Human, 4-5 / genetics*
  • Chromosomes, Human, 6-12 and X / genetics*
  • Cohort Studies
  • Female
  • Genetics, Population
  • Genome, Human / genetics*
  • Genome-Wide Association Study
  • Genotype
  • Gout / epidemiology
  • Gout / etiology*
  • Gout / genetics
  • Humans
  • Hyperuricemia / complications
  • Hyperuricemia / genetics*
  • Hyperuricemia / metabolism
  • Male
  • Middle Aged
  • Netherlands
  • Polymorphism, Single Nucleotide / genetics*
  • Prevalence
  • Risk Factors
  • Uric Acid / blood*

Substances

  • Uric Acid