Causal effects of antibody-mediated immune responses on myocarditis: A two-sample Mendelian randomization study

Previous studies have suggested a link between viral infections and myocarditis, but the causal nature of this relationship remains unclear. The antibody-mediated immune responses generated after such infections reflect an individual's infection history and immune status, offering insights into disease mechanisms and potential therapeutic targets. We used 46 antibody-mediated immune responses as exposures, with European myocarditis and Finnish nonischemic cardiomyopathy as outcomes. The overlapping results were then identified and further validated using Mendelian randomization based on generalized summary data to ensure accuracy. Our Mendelian randomization based on generalized summary data analysis showed that Epstein-Barr virus-related antibody levels, including EBNA-1 (OR = 1.7225, 95% CI: 1.2692-2.3376, P < .001) and VCA p18 (OR = 1.8108, 95% CI: 1.1919-2.7511, P = .0054), were significantly associated with an increased risk of myocarditis. In addition, polyomavirus-related antibody levels, including anti-polyomavirus 2 IgG seropositivity (OR = 0.5762, 95% CI: 0.4521-0.7344, P < .001), anti-Merkel cell polyomavirus IgG seropositivity (OR = 0.6924, 95% CI: 0.5522-0.8682, P = .0014), and Merkel cell polyomavirus VP1 antibody levels (OR = 0.6093, 95% CI: 0.3989-0.9307, P = .0219), were significantly associated with a reduced risk of myocarditis. Similarly, antibody levels against varicella zoster virus glycoproteins E and I were also inversely associated with myocarditis risk (OR = 0.4478, 95% CI: 0.3035-0.6606, P < .001). We identified 6 antibody-mediated immune responses associated with myocarditis, along with multiple genetic variants linked to these responses. These findings may help prioritize future research directions and guide drug development.