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Uromodulin and Risk of Upper Urinary Tract Infections: A Mendelian Randomization Study
Kristin Vardheim Liyanarachi1, Helene Flatby2, Stein Hallan3
1Mid-Norway Center for Sepsis Research, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; Department of Infectious Diseases, Clinic of Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
Rationale & Objective:
Observational studies suggest that uromodulin, produced by the kidneys, is associated with a reduced risk of upper urinary tract infections (UTIs), but inferences are limited by potential confounding factors. This study sought to explore further the validity of this association using Mendelian randomization (MR).
Study Design:
Two-sample MR 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 levels, respectively, and 3,873 and 512,608 participants from the UK Biobank, the Trøndelag Health Study, or the Michigan Genomic Initiative with and without upper UTIs.
Exposures:
We identified uncorrelated (r2 < 0.01) single nucleotide variations that were strongly associated (P < 5 × 10-6) with urinary and serum uromodulin levels from the aforementioned two genome-wide association studies. Both studies accounted for kidney function.
Outcomes:
Genetic associations for the risk of upper UTIs extracted from the aforementioned 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 1-standard deviation increase in genetically predicted urinary uromodulin level was associated with an odds ratio (OR) for upper UTIs of 0.80 (95% CI, 0.67-0.95; P = 0.01). A 1-standard deviation increase in serum uromodulin was not statistically associated with elevated odds of upper UTIs, OR = 0.95 (95% CI, 0.89-1.01; P = 0.12). These findings were consistent across the sensitivity analyses.
Limitations:
Analyses could be performed on only participants of predominantly European ancestry, potentially decreasing the generalizability of our findings.
Conclusions:
This two-sample MR study found that increased levels of genetically predicted urinary uromodulin were associated with a reduced risk of upper UTIs. These findings support the hypothesis that uromodulin may have a protective role against upper UTIs.
Plain-Language Summary:
Traditional studies have suggested that uromodulin, a protein produced by the kidneys, may reduce the risk of urinary tract infections (UTIs). The certainty of these findings is limited by the potential influence of unmeasured confounding factors. Therefore, we decided to address this concern by using genetic data to perform a two-sample Mendelian randomization analysis, a technique known to limit the influence of such factors. Our findings support the hypothesis that uromodulin in urine may have a protective role against upper UTIs. The findings were consistent across sensitivity and sex-specific analyses. Further research into the implications of these findings for the treatment of UTIs as well as the possible utility of urinary uromodulin as a diagnostic marker is warranted.
Insights
Genetically predicted higher urinary uromodulin levels are associated with a reduced risk of upper urinary tract infections (UTIs). This supports uromodulin
Area of Science:
- Nephrology
- Genetics
- Infectious Diseases
Background:
- Observational studies suggest a link between kidney-produced uromodulin and reduced upper urinary tract infection (UTI) risk.
- Potential confounding factors in traditional studies limit the certainty of this association.
- Mendelian randomization (MR) can mitigate confounding to explore causal relationships.
Purpose of the Study:
- To investigate the causal association between uromodulin levels and the risk of upper UTIs using a two-sample MR approach.
- To determine if genetically predicted uromodulin has a protective effect against upper UTIs.
Main Methods:
- A two-sample Mendelian randomization study design was employed.
- Genetic variants strongly associated with urinary and serum uromodulin levels were identified from large genome-wide association studies (GWAS).
- Inverse variance-weighted and sensitivity analyses were conducted using UK Biobank and other cohort data for upper UTI risk.
Main Results:
- A 1-SD increase in genetically predicted urinary uromodulin was associated with a significantly reduced odds of upper UTIs (OR = 0.80, P = 0.01).
- No statistically significant association was found between genetically predicted serum uromodulin and upper UTI risk (OR = 0.95, P = 0.12).
- Findings remained consistent across sensitivity analyses, including sex-specific analyses.
Conclusions:
- Genetically predicted higher urinary uromodulin levels are associated with a lower risk of upper UTIs.
- These results support the hypothesis that uromodulin plays a protective role against upper UTIs.
- Further research is warranted to explore uromodulin's therapeutic and diagnostic potential for UTIs.
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