UMOD Genotype and Clinical Outcomes in Heart Failure Patients Treated with Loop Diuretics: A UK Biobank Pharmacogenetic Cohort Study

Uromodulin (UMOD) regulates tubular sodium handling and modulates NKCC2, the molecular target of loop diuretics (LD). Although UMOD variants have been associated with blood pressure and hypertension, their pharmacogenetic relevance in heart failure (HF) remains unknown. We assessed whether the UMOD rs13333226 genotype is associated with clinical outcomes among patients with HF who initiated LD. We assembled a cohort of UK biobank (UKB) participants diagnosed with HF who initiated LD. Patients were followed in an intention-to-treat fashion for up to 12 months. Cox models estimated confounder-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) comparing rs13333226-AA versus rs13333226-AG/GG genotypes. The primary effectiveness outcome was worsening HF, defined as hospitalization for HF or death with HF as the primary cause. Additional effectiveness and safety outcomes were major adverse cardiovascular events (MACE), acute kidney injury (AKI), and all-cause mortality. Secondary analyses stratified by age and sex. Sensitivity analyses restricted follow-up to 3 and 6 months. Among 1,426 HF patients initiating LD (92% furosemide, mean age 68 years, 34% female), the rs13333226-AA genotype was not associated with worsening HF (HR, 0.95; 95% CI, 0.76-1.20), MACE (HR, 0.97; 95% CI, 0.62-1.52), AKI (HR, 1.05; 95% CI, 0.68-1.64), or all-cause mortality (HR, 1.17; 95% CI, 0.76-1.78). There was no effect modification by demographics. Shorter follow-up periods did not affect the results. In HF patients initiating LD, UMOD rs13333226 was not associated with effectiveness or safety outcomes. These findings do not support a clinically meaningful pharmacogenetic role for this variant.