Objective. The aim of this study was to determine whether serum urate (SU)-associated genetic variants differ in their influence on gout risk in people taking a diuretic compared to those not taking a diuretic. Methods. This research was conducted using the UK Biobank Resource (n = 359,876). Ten SU-associated single-nucleotide polymorphisms (SNP) were tested for their association with gout according to diuretic use. Gene-diuretic interactions for gout association were tested using a genetic risk score (GRS) and individual SNP by logistic regression adjusting for relevant confounders. Results. After adjustment, use of a loop diuretic was positively associated with prevalent gout (OR 2.34, 95% CI 2.08-2.63), but thiazide diuretics were inversely associated with prevalent gout (OR 0.60, 95% CI 0.55-0.66). Compared with a lower GRS (< mean), a higher GRS (≥ mean) was positively associated with gout in those not taking diuretics (OR 2.63, 2.49-2.79), in those taking loop diuretics (OR 2.04, 95% CI 1.65-2.53), in those taking thiazide diuretics (OR 2.70, 2.26-3.23), and in those taking thiazide-like diuretics (OR 2.11, 95% CI 1.37-3.25). No nonadditive gene-diuretic interactions were observed. Conclusion. In people taking diuretics, SU-associated genetic variants contribute strongly to gout risk, with a similar effect to that observed in those not taking a diuretic. These findings suggest that the contribution of genetic variants is not restricted to people with “primary” gout, and that genetic variants can play an important role in gout susceptibility in the presence of other risk factors.
