Abstract P393: Uromodulin Genotype And Response To Loop Diuretics - The BHF UMOD Genotype Blinded Trial

Abstract

Background: Genome-wide association studies identified the major A allele of SNP rs13333226 to be associated with increased BP and uromodulin excretion. Observational studies indicate those with rs13333226-AA genotype have greater BP lowering in response to loop diuretics. Methods: This genotype blinded multi-centre trial (NCT03354897) enrolled hypertensive participants without diabetes aged ≥18 years with home SBP >135 mmHg and/or DBP >85 mmHg despite treatment with ≥1 non diuretic antihypertensive drug for ≥3 months. Participants were prescribed torasemide 5mg daily for 16 weeks with ABPM BP measured at baseline, 8 and 16 weeks. Primary endpoint was change in 24h ABPM SBP between baseline and end of treatment by genotype (AA vs AG/GG). Results: We screened 251 patients, with 222 prescribed torasemide; 174 had genotype data and took ≥80% of dispensed torasemide over the study period. Drop in mean ABPM SBP at 16 weeks compared to baseline was twice as large for AA than AG/GG genotypes (AA -6.57 mmHg change (95% CI -8.44, -4.69), p<0.0001; AG/GG -3.22 (-5.93, -0.51) mmHg change, p=0.021). Mean ABPM SBP in AA group steadily declined from 139 mmHg at baseline to 132.6 mmHg at end of treatment, in contrast, the AG/GG group began with a marginally lower value mean ABPM SBP, showed a marked drop at 8 weeks, followed by a rebound at 16 weeks, ending slightly higher than those in the AA group. Conclusions: The rs13333226-AA genotype identifies a group of hypertensive patients who show a larger, more stable BP reduction in response to torasemide adding further support for a biological uromodulin-NKCC2 interaction, and a role for genotype directed earlier use of loop diuretics in hypertension management.