Causal Associations between Paternal Longevity and Risks of Cardiovascular Diseases

Background: Observational studies have suggested that paternal longevity is associated with reduced risks of cardiovascular diseases, yet the causal association remains to be determined. Objectives: To investigate whether Mendelian randomization (MR) results support a causal role of paternal longevity for risks of cardiovascular diseases. Methods: Genetic variants associated with paternal longevity and cardiovascular diseases were obtained from public genome-wide association study data. We used inverse variance weighted MR under a random-effects model to provide causal estimates between paternal longevity and cardiovascular diseases. Results: Paternal longevity was associated with decreased risks of coronary heart disease (odds ratio (OR): 0.08; 95% confidence interval (CI): 0.02-0.37; p = 0.001) and peripheral artery disease (OR: 0.15; 95% CI: 0.03-0.65; p = 0.011). No significant differences were observed in hypertension, atrial fibrillation, heart failure, transient ischemic attack, ischemic stroke, or cardiac death. The weighted median method revealed consistent results between genetically instrumented paternal longevity and decreased risk of coronary heart disease and peripheral artery disease. No significant differences were observed in the MR-Egger results. Multivariable MR consistently indicated causal associations between paternal longevity and decreased cardiovascular diseases. The leave-one-out analysis suggested that the causal associations were not affected by individual single-nucleotide polymorphisms. The intercept of the MR-Egger estimator and funnel plot revealed no indication of horizontal pleiotropic effects. Conclusions: Our MR analyses supported a causal role of paternal longevity for decreased risks of coronary heart disease and peripheral artery disease, which highlighted the need for better monitoring and intervention of cardiovascular diseases in populations with premature paternal death.