Objective To test for a urate gene-by-diuretic interaction on incident gout.
Methods The Atherosclerosis Risk in Communities Study is a prospective population-based cohort of 15 792 participants recruited from four US communities (1987–1989). Participants with hypertension and available single nucleotide polymorphism (SNP) genotype data were included. A genetic urate score (GUS) was created from common urate-associated SNPs for eight genes. Gout incidence was self-reported. Using logistic regression, the authors estimated the adjusted OR of incident gout by diuretic use, stratified by GUS median.
Results Of 3524 participants with hypertension, 33% used a diuretic and 3.1% developed gout. The highest 9-year cumulative incidence of gout was in those with GUS above the median and taking a thiazide or loop diuretic (6.3%). Compared with no thiazide or loop diuretic use, their use was associated with an OR of 0.40 (95% CI 0.14 to 1.15) among those with a GUS below the median and 2.13 (95% CI 1.23 to 3.67) for those with GUS above the median; interaction p=0.006. When investigating the genes separately, SLC22A11 and SLC2A9 showed a significant interaction, consistent with the former encoding an organic anion/dicarboxylate exchanger, which mediates diuretic transport in the kidney.
Conclusions Participants who were genetically predisposed to hyperuricaemia were susceptible to developing gout when taking thiazide or loop diuretics, an effect not evident among those without a genetic predisposition. These findings argue for a potential benefit of genotyping individuals with hypertension to assess gout risk, relative in part to diuretic use.
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Funding The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C). Mara McAdams DeMarco was supported by a T32 training grant from the National Heart, Lung, and Blood Institute grant (5T32HL007024). Alan Baer and Janet Maynard were supported by the Donald B and Dorothy Stabler Foundation. Anna Köttgen was supported by the Emmy Noether Programme of the German Research Foundation. The funding sources had no role in the analysis or interpretation.
Competing interests None.
Ethics approval Approval provided by the Johns Hopkins Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement ARIC is available for public use through the NHLBI. This research was presented as an oral presentation at the American College for Rheumatology Annual Meeting in Chicago, Illinois, USA (7 November 2011).