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

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.

Figure 1

ABCG2 locus (Panel A): −log10 p-values of genome-wide association analysis of uric acid for FHS and Rotterdam; (Panel B): −log10 p-values vs. physical position based on NCBI build 36.2 for SNPs (minor allele frequency >0.01) within 60Kb of ABCG2 (open diamonds) for uric acid association analysis for FHS (in blue), Rotterdam (in orange, only SNPs with p<10⁻⁷ included), and ARIC whites (in green) (only SNPs with p<10⁻⁷ included). The top associated SNP rs2231142 is plotted with solid diamonds with respective colors for the three studies, and the p-value from the meta-analysis combining the results of the three studies is plotted with a red solid diamond; (Panel C): Plot of linkage disequilibrium pattern in the ABCG2 region with all minor allele frequency >0.01 of SNPs typed in FHS. Each diamond contains a pair-wise r² value (no value means r²=1) between two SNPs, with a darker shade representing higher correlation. The relative locations of the SNPs are marked on the top panel. SNPs with p-value <10⁻⁸ in FHS are in bold font, and the r² tracks with top associated SNP are outlined by red lines. The LD plot was generated using the program Haploview; haplotype blocks are defined using the method by Gabriel et al.(48, 49)

Figure 2

Additive genetic risk score in the FHS, Rotterdam, and ARIC Studies. (A): prevalence of the genetic risk score; (B): mean serum uric acid, μmol/l; (C): prevalence of gout, %; (D) Odds ratio (OR) of gout, adjusted for age, sex, BMI, alcohol intake, antihypertensive medication, cohort in FHS and study center in ARIC. Results are presented for white ARIC participants only. Error bars present standard errors. Prevalence is period prevalence in the Rotterdam Study.

Figure 3

Interaction of Sex with SLC2A9 rs16890979 and ABCG2 rs2231142 on Uric Acid Levels and Gout Risk. Multivariable adjusted (A) difference in mean uric acid levels; (B) odds ratio of gout. Results are presented for ARIC whites, results from FHS and Rotterdam are presented in Supplementary Table 5. Error bars represent standard errors. Numbers inside/next to bars present sample size (uric acid) and number of gout cases/sample size (gout). The sex-specific R² (proportion of variance explained, [men/women]) was for rs16890979: 2.0%/8.8% [FHS], 1.4%/4.1% [Rotterdam], 1.7%/7.6% [ARIC white], 0.5%/3.4% [ARIC black]; for rs2231142: 2.1%/0.8% [FHS], 1.6%/0.5% [Rotterdam], 2.0%/0.6% [ARIC white], 0.4%/0.3% [ARIC black].