LAUSR

Objective: Increase in serum urate concentration and development of gout are common side effects of thiazide diuretics. The aim of this study was to recognize genetic associations of hydrochlorothiazide (HCTZ) -induced change in serum urate concentration. Design and method: We conducted a genome-wide association study on HCTZ-induced change in serum urate in 214 Finnish men from the Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study. GENRES is a double-blind, placebo-controlled cross-over study with four different antihypertensive monotherapies, including HCTZ 25 mg/day, used each for 4 weeks. The treatment periods were separated by 4-week placebo periods. Serum urate concentrations were measured after each treatment and placebo period. Replication analyses were performed in 465 Finnish men and women from the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. They used HCTZ 12.5 mg/day and atenolol/losartan (50 or 100 mg/day) at year 1 of the study, and had serum urate concentration data at baseline and at year 1. The criterion of positive replication in LIFE was Bonferroni-corrected P value < 0.0016 (= 0.05/32) with the same direction of effect as in GENRES. The patients of both studies were genotyped using Illumina HumanOmniExpress BeadChip. Results: In GENRES, mean HCTZ-induced increase in serum urate concentration was 51 &mgr;mol/l. We identified 32 loci that were associated with HCTZ-induced change at P value < 0.00005. In LIFE, one of these loci was replicated positively: rs1002976 near VEGFC gene on chromosome 4 was associated with HCTZ-induced change in GENRES (beta = −16 &mgr;mol/l, P = 0.00002) and in LIFE (beta = −14 &mgr;mol/l, P = 0.0004). eQTL data (GTEx database) indicates that this SNP may be associated with the expression level of VEGFC mRNA. In addition, intergenic rs950569 on chromosome 1 was associated with HCTZ-induced change in serum urate in GENRES (beta = 33 &mgr;mol/l, P = 0.000048) and with borderline significance in LIFE (beta = 21 &mgr;mol/l, P = 0.003). Conclusions: We have identified potential genetic markers for thiazide-induced elevation of serum urate concentration.