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

By A. Dehghan, A. Köttgen, Qiong Yang, Shih-Jen Hwang, W. Kao, F. Rivadeneira, Eric Boerwinkle, Daniel Levy, Albert Hofman, B. Astor and 5 more. The Lancet, 2008

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Background Hyperuricemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes related to serum uric acid (UA) and gout. Methods Genome-wide association studies (GWAS) were conducted for serum UA in the Framingham Heart Study (FHS; n=7699) and the Rotterdam Study (RS; n=4148). Genome-wide significant SNPs were replicated among white (n=11024) and black (n=3843) Atherosclerosis Risk in Communities (ARIC) Study participants. The association of these SNPs was evaluated with gout; results in whites were combined using meta-analysis. Results Three loci in FHS and two in the RS showed genome-wide significance with UA. Top SNPs in each locus were: missense SNP rs16890979 in SLC2A9 (p=7.0×10−168 [whites]; 2.9×10−18 [blacks]), missense SNP rs2231142 in ABCG2 (p=2.5×10−60 [whites]; 9.8×10−4 [blacks]), and rs1165205 in SLC17A3 (p=3.3×10−26 [whites]; 0.33 [blacks]). All SNPs showed direction-consistent association with gout in whites: rs16890979 (OR 0.58 per T allele, 95% CI 0.53–0.63, p=1.2×10−31), rs2231142 (OR=1.74 per T allele, 1.51–1.99, p=3.3×10−15), and rs1165205 (OR=0.85 per T allele, 0.77–0.94, p=0.002). In ARIC blacks, rs2231142 showed a direction-consistent association with gout (OR=1.71, 1.06–2.77, p=0.028). An additive genetic risk score (0–6) comprised of high risk alleles at the three loci showed graded associations in each study across scores with UA (from 272–351 μmol/l [FHS], 269–386 μmol/l [RS], and 303–426 μmol/l [ARIC whites]) and gout (prevalence 2–13% [FHS], 2–8% [RS], 1–18% [ARIC whites]). Conclusions We identified three genetic loci (two novel including a candidate functional variant Q141K in ABCG2) related to UA and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk gradient for gout.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Nephrology

View Paper: https://www.semanticscholar.org/paper/52334cf25392383837b7e462018e55831d4497a2

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Citations in the corpus

The Rotterdam Study: 2010 objectives and design update (2007, neutral): “gout [54].”
Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout (2009, methodology): “Adjustment for sex explained the largest part of this difference, with the genetic effect in men significantly stronger than in women (4), which is in agreement with higher rates of renal ABCG2 expression in men compared with women (10).”
Gout. Epidemiology of gout (2010, background): “Th e association between polymorphisms in SLC2A9 and both high SUA levels and risk of gout was confi rmed in a genome-wide association study of three large cohorts [44].”
Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations (2009, background): “88) with the missense mutation rs16890979 previously described [11].”
Genotype Imputation (2009, background): “Dehghan (26) Lancet 2008/10 MACH Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study”
The SLC2 (GLUT) Family of Membrane Transporters (2013, positive): “These studies found that SLC2A9 was the major locus, explaining up to 3.5% of serum uric acid level variations (Li et al., 2007) (Caulfield et al., 2008; Dehghan et al., 2008; Doring et al., 2008; Vitart et al., 2008; Wallace et al., 2008).”