Background/Purpose: Elevated serum urate and reduced fractional excretion of uric acid (FEUA) are common in people on diuretics. Changes in FEUA in response to frusemide are associated with changes in fractional excretion of sodium (FENa). Variants in renal sodium transporters NCC (encoded by SLC12A3) and ENaC (encoded by SCNN1B and SCNN1G beta and gamma subunits, respectively) have been associated with FENa responses to frusemide (Vormfelde et al, Clin Pharmacol Ther 2007). The aim of this study was to determine whether variations in these sodium transporters also have an effect on FEUA or serum urate responses to frusemide administration.

Methods: Data were analysed from a short-term study of 100 healthy participants receiving a 40mg oral tablet of frusemide. The following single nucleotide polymorphisms (SNPs) were genotyped: SCNN1B rs152745, SCNN1G rs13306653 and SLC12A3 rs1529927. A mixed-model approach to repeated measures (analysis of variance; ANOVA) all adjusted for age, sex, and ethnicity was employed. The key primary endpoint was FEUA and the secondary endpoints were serum urate, FENa, and fractional excretion of potassium (FEK).

Results: Oral intake of 40mg frusemide led to marked diuresis and increase in FENa and FEK throughout the study period (ANOVA P<0.0001 for all). FEUA initially increased and then decreased over the study period (P<0.0001). For SCNN1B rs152745, homozygosity for the frusemide response A allele (15% of participants) was associated with a greater increase in FENa (ANOVA P_time*SNP = 0.007) and FEUA (P_time*SNP = 0.02). For SLC12A3 rs1529927, presence of the frusemide response C allele (3% of participants) was associated with a greater increase in FEUA (P_time*SNP = 0.00013) and a trend to increase in FENa (P_time*SNP = 0.09) following frusemide intake. No effects on diuretic responses were observed with SCNN1G rs13306653, and none of tested SNPs had significant effects on serum urate or FEK over the study period.

Conclusion: Two previously reported diuretic-response sodium transporter genes are associated with an elevated FEUA response to frusemide. These findings suggest that genetic variation in SLC12A3 and SCNN1B influence renal uric acid handling in response to diuretics, perhaps through altered renal sodium handling.