Uromodulin and Risk of Upper Urinary Tract Infections: A Mendelian Randomization Study.

Rationale & Objective: Observational studies suggest that uromodulin, produced by the kidneys, is associated with a reduced the risk of upper urinary tract infections, but inferences are limited by potential confounding factors. This study sought to explore further the validity of this association using Mendelian randomization.

Study Design: Two-sample Mendelian randomization study.

Setting & Participants: The study included 29,315 and 13,956 participants from 18 cohorts of mainly European ancestry with measured urinary and serum uromodulin, respectively, and 3,873 and 512,608 participants from the UK Biobank, the Trøndelag Health Study (HUNT), or the Michigan Genomic Initiative with and without upper urinary tract infections.

Exposures: We identified uncorrelated (r< 0.01) single nucleotide polymorphisms strongly associated (p<5 x 10) with urinary and serum uromodulin from the above-mentioned two genome-wide association studies. Both studies accounted for kidney function.

Outcomes: Genetic associations for the risk of upper urinary tract infections extracted from the above-mentioned independent genome-wide association study.

Analytical Approach: Inverse-variance weighted and sensitivity analyses were performed. The strength of each genetic instrument was estimated using the F statistic RESULTS: A one standard deviation increase in genetically predicted urinary uromodulin was associated with an odds ratio (OR) for upper urinary tract infections of 0.80 (95% confidence interval 0.67 to 0.95; p = 0.01). For serum uromodulin, a one standard deviation increase was associated with an odds ratio of 0.95 (95% confidence interval 0.89 to 1.01, p = 0.12). The results were consistent across the sensitivity analyses.

Limitations: Analyses could only be performed on participants of predominantly European ancestry, potentially decreasing the generalizability of our findings.

Conclusions: This two-sample Mendelian randomization study found that increased levels of genetically predicted urinary uromodulin were associated with a reduced risk of upper urinary tract infections. A similar trend was observed for serum uromodulin. These findings support the hypothesis that uromodulin may have a protective role against upper urinary tract infections.