Serum Urate-Associated Genetic Variants Strongly Contribute to Gout Risk Regardless of Diuretic Use

Serum urate-associated genetic variants strongly contribute to gout risk regardless of diuretic use, according to research results published in Journal of Rheumatology. Based on study data, the researchers indicated the importance of the role of genetic variants in gout susceptibility in the presence of other risk factors.

Using data from the United Kingdom Biobank, researchers sought to determine whether serum urate-associated genetic variants differed in terms of their influence on the risk for gout in participants receiving diuretic medications compared with those not receiving diuretics.

Genome-wide genotype data were available for 359,876 study participants, of whom 29,711 (8.3%) received diuretics. Among these participants, 3728 (12.5%) received a loop diuretic, 23,623 (78.9%) received a thiazide diuretic, and 2001 (6.7%) received a thiazide-like diuretic. In total, 2.0% of participants had gout. Patients with gout who took any type of diuretic were generally older, with a higher body mass index and a higher prevalence of comorbidities, including hypertension. In particular, loop diuretic use was associated with a higher prevalence of renal and heart failure.

Researchers identified gout in 1.9% of nondiuretic users, 12.4% of loop diuretic users, 2.6% of thiazide diuretic users, and 5.1% of thiazide-like diuretic users. In an unadjusted model, participants in the loop diuretic group had the highest odds ratio (OR) for gout (7.46; 95% CI, 6.74-8.25); this association persisted in a fully adjusted model (OR, 2.34; 95% CI, 2.08-2.63). The unadjusted model also identified a positive association between gout and thiazide diuretic use (OR, 1.41; 95% CI, 1.30-1.53); however, the fully adjusted model demonstrated an inverse association with gout (OR, 0.60; 95% CI, 0.55-0.66). Among participants receiving a thiazide-like diuretic, the unadjusted model showed an increased OR for gout (2.83; 95% CI, 2.32-3.46); however, after adjusting for confounders, no gout association was observed (1.05; 95% CI, 0.85-1.29).

All participants, including those with gout, demonstrated a mean genetic risk score of 1.15±0.26. Across the entire study population, 48.9% of participants had a higher (≥mean) genetic risk score, although patients with gout had a significantly higher genetic risk score compared with those without gout (mean, 1.30±0.26 vs 1.15±0.26; P <1×10^-300). Compared with participants with a lower (<mean) genetic risk score, the unadjusted OR for gout was 2.48 (95% CI, 2.36-2.61) among participants who had a higher genetic risk score. This association persisted after adjusting for age, sex, body mass index, hypertension, and renal or heart failure.

Mean genetic risk scores were higher among patients with gout compared with those without gout for all diuretic users. Compared with participants with a lower genetic risk score, gout prevalence was higher in patients with a higher genetic risk score among nondiuretic, loop diuretic, thiazide diuretic, and thiazide-like diuretic users. Compared with participants with a lower genetic risk score, nondiuretic users demonstrated that a higher genetic risk score was positively associated with gout (OR, 2.63; 95% CI, 2.49-2.79; P =8.74×10-²⁴⁰).

For nondiuretic users, an association with gout was observed for all 10 serum urate-associated single nucleotide polymorphisms. Specifically, an association with gout was observed for ABCG2 (rs2231142) and SLC2A9 (rs12498742) for loop diuretic users, the same 2 single nucleotide polymorphisms and GCKR (rs1260326), SLC17A3 (rs1165151), and SLC22A11 (rs2078267) for thiazide diuretic users, and ABCG2 (rs2231142) for thiazide-like diuretic users. Similar ORs for gout association were found among diuretic and nondiuretic users, but they did not reach experiment-wide significance.

Finally, investigators conducted a sensitivity analysis where the genetic risk score was modeled using the previously described effect sizes for gout. The mean genetic risk score for all participants was 0.78±0.18. Patients with gout had a significantly higher genetic risk score compared with those without gout (0.88±0.19 vs 0.78±0.18; P <1×10^-300), with a higher mean genetic risk score among patients with gout compared with those without gout across diuretic user groups.

Study limitations included a potential lack of generalizability across ethnic and racial groups, the exclusion of patients with early-onset gout and adults aged >70 years from the study cohort, and the use of self-report to collect comorbidity and medication use data.

“In [participants receiving] diuretics, serum urate-associated genetic variants contribute strongly to gout risk, with a similar effect to that observed in those not taking a diuretic,” the researchers concluded. “This suggests that the contribution of genetic variants is not restricted to [patients] with ‘primary’ gout and can play an important role in gout susceptibility in the presence of other risk factors.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Narang RK, Gamble G, Phipps-Green AJ, et al. Do serum urate-associated genetic variants influence gout risk in people on diuretics? Analysis of the UK Biobank [published online February 1, 2020]. J Rheumatol. doi:10.3899/jrheum.191005