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.