Abstract
ABSTRACTBackgroundObservational studies have suggested that uromodulin, produced by the kidneys, may reduce the risk of upper urinary tract infections, but are limited by potential confounding. To address this concern, we conducted a two-sample Mendelian randomization study to explore this association.MethodsWe identified uncorrelated (r2< 0.01) single nucleotide polymorphisms strongly associated (p<5 × 10−6) with urinary and serum uromodulin from two genome-wide association studies. Both studies accounted for kidney function. Genetic associations for the risk of upper urinary tract infections were extracted from an independent genome-wide association study. Inverse-variance weighted and sensitivity analyses were performed.ResultsThe study included 29,315 and 13,956 participants with measured urinary and serum uromodulin, respectively, and 3,873 and 512,608 subjects with and without upper urinary tract infections. A one standard deviation increase in genetically predicted urinary uromodulin was associated with an odds ratio 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 sensitivity analyses.ConclusionIn this two-sample mendelian randomization study we 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. Our findings align with results from traditional observational studies which together support that uromodulin may have a protective role against upper urinary tract infections
Publisher
Cold Spring Harbor Laboratory