Genetic evidence linking gastroesophageal reflux disease to chronic kidney disease and kidney failure: a two-step Mendelian randomization study

To investigate the causal association between gastroesophageal reflux disease (GERD) and chronic kidney disease (CKD) progression and its potential metabolic mediators. Summary-level data were extracted from the overall genome-wide association studies of the FinnGen and UK Biobank databases. This study employed two-sample, bidirectional, two-step, and multivariable Mendelian randomization (MR) techniques, utilizing single-nucleotide polymorphisms (SNPs) as genetic instruments for exposure and mediators, thereby minimizing bias due to confounders and reverse causation. We harnessed summary-level data from a genome-wide association study of GERD, proposed mediators, and CKD progression, including CKD, kidney failure, and dialysis-dependent kidney failure. The total effect of GERD on CKD progression was decomposed into direct effects and indirect effects through multiple mediators. GERD was associated with an increased risk of CKD (odds ratio [OR]: 1.18, 95% confidence interval [CI]: 1.05-1.33), kidney failure (1.23, 1.11-1.36), dialysis-dependent kidney failure (1.26, 1.19-1.34), whereas the reverse causality hypothesis did not hold. Type 2 diabetes mellitus (T2DM) mediated 14.33%-43.24% of the effect of GERD on CKD progression, which was followed by systolic blood pressure (mediation: 3.85%-5.46%). These results supported a potentially causal damage effect of GERD against CKD progression, which T2DM and SBP considerably mediate. Interventions with these factors could significantly decrease the burden of CKD attributable to GERD.