Exploration of the association of antidiabetic drugs with urolithiasis: A drug-targeted Mendelian randomization study.

OBJECTIVE

Type 2 diabetes mellitus has previously been reported to be potentially associated with urolithiasis. We conducted a Mendelian randomization (MR) study to explore whether there is a causal relationship between genetic susceptibility to common antidiabetic drugs and urolithiasis risk.

METHODS

We used genetic variants from two different sources as instruments to proxy the exposure to antidiabetic drugs for our MR research design. The variants included loci regulating expression traits of the target genes, and genetic variants associated with blood glucose nearby or within antidiabetic drug target genes from genome-wide association studies. We ultimately calculated estimates using inverse-variance weighted MR (IVW-MR) and summary-data-based MR methods.

RESULTS

The Bonferroni-corrected IVW results suggested potassium inwardly rectifying channel subfamily J member 11 (KCNJ11)-mediated blood glucose was associated with a lower risk of urolithiasis (odds ratio [OR]: 0.15; 95% confidence interval [CI]: 0.06-0.39; p=1.19×10-4). Similarly, we also observed a higher expression of KCNJ11 was linked to a decreased risk of urolithiasis in the summary-data-based MR analysis (OR: 0.81 per 1 mmol/L decrement in blood glucose; 95% CI: 0.70-0.95; p=0.008). We found suggestive evidence of the positive relationship between insulin receptor expression and urolithiasis (OR: 5.67; 95% CI: 1.01-31.97; p=0.049), which was not supported when using cis-expression quantitative trait locus as an instrument.

CONCLUSION

This study provided evidence for a potential causal link between KCNJ11-mimicked sulfonylureas and the reduced risk of urolithiasis. Given the limitations of this study, it is essential to investigate further using the latest data from large-scale genetic studies and relevant clinical data to validate our findings from the MR study.