Mapping Gastroesophageal Reflux Disease and Coronary Artery Disease: A Comprehensive Analysis of Multivariable Mendelian Randomization and Shared Genetic Etiology.

Aims: We employed a robust genetic approach to provide a better understanding of whether Gastroesophageal reflux disease (GERD) contributes to coronary artery disease (CAD) risk from a genetic perspective.

Methods: Multivariable Mendelian Randomization (MVMR) was applied to explore causal links between GERD and CAD using genetic instruments derived from genome-wide association studies (GWAS). The MVMR models were adjusted for key metabolic confounders, including low-density lipoprotein cholesterol (LDL-C), body mass index (BMI), systolic blood pressure (SBP), and glycated hemoglobin (HbA1c). Genetic correlations were estimated using linkage disequilibrium score regression. Cross-trait meta-analyses, Heritability Estimation from Summary Statistics (ρ-HESS) and colocalization analyses were performed to identify pleiotropic genes and shared genetic loci, elucidating the genetic relationship between GERD and CAD.

Results: Genetically predicted GERD was found to be causally linked with CAD (rg = 0.38, P = 2.37E-52), independent of metabolic risk factors, including LDL-C, BMI, SBP, and HbA1c (odds ratio: 1.24, 95% CI: 1.02-1.52, p < 0.05). Cross-trait meta-analyses identified eight novel pleiotropic single nucleotide polymorphisms, four of which were independent of metabolic confounders, including rs11764337 in MAD1L1, rs2240326 in RBM5, rs9615905 in FAM19A5, and rs9837341 in BSN. ρ-HESS and colocalization analysis further revealed shared genetic loci for GERD and CAD, specifically rs4643373 in IGF2BP1 (located in chr17: 45876022-47517400 and posterior probability for H4 > 0.75).

Conclusions: GERD is identified as an independent risk factor for CAD. The discovery of shared genetic loci provides novel insights into the genetic mechanisms underlying GERD and CAD, with IGF2BP1 emerging as a potential therapeutic target for intervention.