Association between antibody-mediated immune responses and gastroesophageal reflux disease: Evidence from genetic studies

Studies have proven an association between the specific antibody-mediated immune response and gastroesophageal reflux disease (GERD); however, the exact causal associations remain unclear. Our research aims to evaluate the causal relationships between the genetic susceptibility to 46 antibody-mediated immune responses and GERD, with the bidirectional two-sample Mendelian randomization (TSMR) and to explore the mediating effects of 91 circulating inflammatory cytokines by a two-step MR analysis. Multiple MR analysis methods, including inverse variance weighted, MR-Egger, weighted mode, weighted median, simple mode, and MR pleiotropy residual sum and outlier, were employed for the bidirectional TSMR analysis. Besides, sensitivity analyses, such as Cochran Q statistics, MR-Egger intercept, MR pleiotropy residual sum and outlier global test, and the leave-one-out method were implemented to identify potential heterogeneity and pleiotropy. In the forward MR analysis, the inverse variance weighted method demonstrated that anti-cytomegalovirus (anti-CMV) IgG seropositivity (OR = 1.031, 95% CI: 1.000–1.062, P = .048), levels of human herpes virus (HHV) 7 U14 antibody (OR = 1.097, 95% CI: 1.032–1.167, P = .003), and herpes simplex virus 1 (HSV-1) mgG-1 antibody (OR = 1.069, 95% CI: 1.020–1.119, P = .005), which have higher genetic prediction, are positively related to GERD risks. Reverse MR analysis revealed GERD increased the level of Epstein–Barr virus VCA p18 antibody (OR = 1.255, 95% CI: 1.028–1.533, P = .026), while decreased the anti-CMV IgG seropositivity (OR = 0.663, 95% CI: 0.444–0.991, P = .045) and HHV 7 U14 antibody level (OR = 0.777, 95% CI: 0.630–0.958, P = .018) as well. Besides, other antibodies, including anti-Helicobacter pylori (H pylori) IgG, H pylori CagA, and H pylori VacA demonstrated no correlations (neither positive nor negative) with GERD risks. Surprisingly, TSMR showed that 91 cytokines seemed not to mediate HSV-1 mgG-1 to enhance GERD risks. The research provided convincing evidence for establishing a causal relationship between antibody-mediated immune responses and GERD, proving that genetic-prediction-based HSV-1 mgG-1 could increase GERD risk and that inflammatory factors may not be involved in mediating this association. Besides, GERD was found to reduce Epstein–Barr virus VCA p18 antibody. Moreover, we revealed the bidirectional causal relationships between GERD and the antibodies, including anti-CMV IgG, HHV 7 U14. This research may contribute to a better understanding of the mechanism that triggers GERD, also emphasizing the clinical potential of therapeutic interventions targeting antibody-mediated immune responses.