Antibody-mediated immune responses and cardiovascular disease: a Mendelian randomization study

Cardiovascular diseases represent the leading cause of global mortality and disability, posing a severe threat to human health. Accumulating evidence suggests that antigen-antibody-mediated immune responses may be involved in the pathogenesis of various cardiovascular conditions; however, whether these associations reflect causal relationships has long remained unclear. To address this question, we conducted a bidirectional two-sample Mendelian randomization study leveraging summary-level data from genome-wide association studies. In this analysis, 46 antibody-mediated immune traits were evaluated as exposures, and 11 cardiovascular outcomes, including aortic aneurysm, aortic valve stenosis, atrial fibrillation, coronary artery disease, dilated cardiomyopathy, atrioventricular block, heart failure with reduced ejection fraction, hypertrophic cardiomyopathy, infective endocarditis, myocarditis, and pericarditis, were examined as outcomes. Our results revealed several significant causal associations: genetically predicted higher levels of Epstein-Barr virus EBNA-1 antibodies were associated with increased risks of myocarditis and aortic valve stenosis, while elevated VCA p18 antibody levels were linked to a higher risk of myocarditis. Furthermore, increased antibody levels against BK polyomavirus VP1 were causally associated with greater risks of aortic valve stenosis and dilated cardiomyopathy. In contrast, higher levels of antibodies against varicella-zoster virus glycoproteins and human herpesvirus 6 IE1B were associated with reduced risks of myocarditis and aortic aneurysm, respectively. These findings not only help clarify the causal role of immune-mediated mechanisms in cardiovascular pathogenesis but also provide a theoretical foundation for the future development of immune-targeted strategies for prevention and treatment.