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