Elsevier

The Lancet

Volume 372, Issue 9654, 6–12 December 2008, Pages 1953-1961
The Lancet

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

https://doi.org/10.1016/S0140-6736(08)61343-4Get rights and content

Summary

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.

Introduction

Gout is one of the most common forms of arthritis,1, 2 affecting more than 700 000 adults in the UK2 and nearly 3 million adults in USA,3 and accounting for almost 4 million outpatient visits every year,4 with a substantial economic burden.5 Epidemiological studies from different countries suggest that prevalence and incidence of gout are increasing.6 Gout is characterised by joint pain, inflammation, and painful tophi, and can lead to joint destruction and disability, if untreated.7

Uric acid is the end product of purine metabolism, and its concentration is mainly controlled by endogenous metabolism (synthesis and cell turnover), and the rate of excretion and reabsorption in the kidney.1 Human beings lack uricase, the enzyme responsible for converting uric acid into its soluble and excretable form. Renal excretion of urate accounts for most hyperuricaemia and gout.8 Thus, understanding the molecular mechanisms of urate transport in the kidney has potential research and clinical implications.

Known risk factors for gout include hyperuricaemia, obesity, hypertension, use of diuretic drugs, and alcohol consumption.9 Despite much research in renal urate transport, the mechanisms that determine serum uric acid concentration, by contributing to either secretion or reabsorption of urate in the proximal renal tubules, have not been fully elucidated.10 We have previously shown that heritability of serum uric acid concentration is 63%,11 suggesting that genetic variation might contribute to determining uric acid concentration through regulation of uric acid synthesis, excretion, or reabsorption.

Several recent genome-wide association studies identified substantial associations between single nucleotide polymorphisms (SNPs) in the solute carrier family 2 (facilitative glucose transporter), member 9 gene (SLC2A9) and uric acid concentration and gout.12, 13, 14, 15, 16 SLC2A9 had not previously been implicated in uric acid metabolism, emphasising the power of genome-wide association studies to identify unknown physiological mechanisms contributing to disease. Phenotype and genotype results were obtained by the genome-wide association study initiatives of the Framingham cohort and the Rotterdam cohort, and then replicated in a third population-based study, the Atherosclerosis Risk in Communities (ARIC) study. These are large population-based studies set up to investigate cardiovascular diseases and their risk factors, ageing, neurological diseases, locomotion, and eye diseases.

Our aim was to identify genetic loci associated with uric acid concentration with genome-wide association studies in two populations (11 847 participants), and subsequently replicate these loci in a third population-based study (14 867 participants). Finally, the SNPs that associated with uric acid were tested for association with gout.

Section snippets

Participants

The Framingham cohort study started in 1948, when 5209 participants underwent examinations every two years to identify cardiovascular diseases and their risk factors.17, 18 In 1971, 5124 participants were enrolled into the Framingham Offspring Study. Offspring were examined roughly every 4 years.19, 20 In 2002, the third generation—ie, the children of the offspring cohort—was recruited (n=4095).21 Almost all participants in the Framingham cohort are self-identified white individuals (of

Results

Table 1 shows the characteristics of 26 714 participants. SNPs genotyped in all three studies met quality control standards (webtable 1). Three loci had SNPs that reached genome-wide significance in the Framingham cohort. For each locus, the most significant SNPs were rs16890979 (a missense SNP in SLC2A9), rs2231142 (a missense SNP in ABCG2), and rs1165205 (intron 1 of SLC17A3) (table 2). Similarly, two loci showed genome-wide significance in the Rotterdam cohort: rs6449213 (intron 4 of SLC2A9)

Discussion

We identified two new loci, ABCG2 and SLC17A3, that show association with uric acid concentration and risk of gout. A missense SNP in ABCG2 (rs2231142; Q141K) was associated with uric acid concentration and gout in both white and black individuals and may be a causal candidate variant. Furthermore, we confirmed the previously reported association of variation in SLC2A9 with uric acid and gout in white individuals, and extended the findings to black individuals. Also, we described sex-specific

References (47)

  • RC Lawrence et al.

    Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II

    Arthritis Rheum

    (2008)
  • E Krishnan et al.

    Gout in ambulatory care settings in the United States

    J Rheumatol

    (2008)
  • EQ Wu et al.

    Disease-related and all-cause health care costs of elderly patients with gout

    J Manag Care Pharm

    (2008)
  • E Roddy et al.

    The changing epidemiology of gout

    Nat Clin Pract Rheumatol

    (2007)
  • JS Sundy et al.

    Uricase and other novel agents for the management of patients with treatment-failure gout

    Curr Rheumatol Rep

    (2007)
  • A Taniguchi et al.

    Control of renal uric acid excretion and gout

    Curr Opin Rheumatol

    (2008)
  • KG Saag et al.

    Epidemiology, risk factors, and lifestyle modifications for gout

    Arthritis Res Ther

    (2006)
  • SA Eraly et al.

    Multiple organic anion transporters contribute to net renal excretion of uric acid

    Physiol Genomics

    (2008)
  • S Li et al.

    The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts

    PLoS Genet

    (2007)
  • A Doring et al.

    SLC2A9 influences uric acid concentrations with pronounced sex-specific effects

    Nat Genet

    (2008)
  • V Vitart et al.

    SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout

    Nat Genet

    (2008)
  • K Stark et al.

    Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study

    PLoS ONE

    (2008)
  • TR Dawber et al.

    An approach to longitudinal studies in a community: the Framingham Study

    Ann N Y Acad Sci

    (1963)
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    These authors contributed equally

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