Impact of Umod Genotype on Clinical Outcomes Among Patients With Heart Failure Initiating Loop Diuretics: A Uk Biobank Pharmacogenetic Cohort Study

Objective: Uromodulin (UMOD) modulates the Na–K–Cl cotransporter activity and has been linked to hypertension. Moreover, the rs13333226 single nucleotide polymorphism in the UMOD gene may influence blood pressure, thus lowering the efficacy of loop diuretics (LD) in hypertension. Given that treatment with LD has an important impact on volume control and hospitalization rates in patients with heart failure (HF), our cohort study aimed to assess whether the rs13333226 genotype was associated with the risk of adverse clinical outcomes among HF patients initiating LD. Design and method: We used the UK Biobank (UKB) linked to primary care records, hospitalizations, and vital statistics. We identified UKB participants diagnosed with HF who initiated LD. LD initiation defined cohort entry. Cohort members 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) of HF exacerbation (hospitalization with HF or death due to HF), major adverse cardiovascular events (MACE), acute kidney injury (AKI) (hospitalization with AKI or death due to AKI), and all-cause mortality associated with the rs13333226-AA genotype versus the rs13333226-AG/GG genotypes among HF patients initiating LD. In secondary analyses, we stratified by age and sex. In sensitivity analyses, we restricted follow-up to 3 and 6 months. Results: The cohort included 1426 HF patients initiating LD (92% furosemide). Mean age was 68 years, 34% of cohort members were female, mean body mass index was 30 kg/m2, and mean estimated glomerular filtration rate was 66 mL/min/1.73m2. Clinical characteristics were very similar between ‘AA patients’ (n=948) and ‘AG/GG patients’ (n=478). Among HF patients initiating LD, the rs13333226-AA genotype was not associated with the risk of HF exacerbation (HR, 0.95; 95% CI, 0.76-1.20), MACE (HR, 0.96; 95% CI, 0.61-1.51), AKI (HR, 1.11; 95% CI, 0.71-1.73), or all-cause mortality (HR, 1.16; 95% CI, 0.76-1.77), versus the rs13333226-AG or -GG genotypes. There was no effect modification by demographics. Shorter follow-up periods did not affect the results. Conclusions: We found no evidence that the UMOD rs13333226 genotype was associated with differences in clinical outcomes among HF patients initiating LD.