A urate gene-by-diuretic interaction and gout risk in participants with hypertension: results from the ARIC study

Abstract

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.

Figure 1

(A) Nine-year gout cumulative incidence by diuretic use (no diuretic use, any diuretic use, or thiazide or loop diuretic use) and median of genetic urate score (−0.31 µmol/l) in the Atherosclerosis Risk in Communities Study (ARIC) (n=3524); exact CIs. (B) Nine-year gout cumulative incidence by diuretic use and SLC22A11 (CC high risk genotype; frequency=21%) and SLC2A9 (TT high risk genotype; frequency=52%) in ARIC (n=3524); exact CIs. No participants carrying low risk alleles for SLC2A9 using either a thiazide or loop diuretics developed gout.

Figure 2

The predicted probability of developing gout over 9 years. D+, either thiazide or loop diuretic use; D−, no thiazide or loop diuretic use; G+, high genetic risk; G−, low genetic risk.