Mendelian Randomization Study Reveals Causal Pathways for Hypertrophic Cardiomyopathy, Cardiovascular Proteins, and Atrial Fibrillation.

Abstract

Aims/Background Research evidence has demonstrated a significant association between hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF), but the causality and pattern of this link remain unexplored. Therefore, this study investigated the causal relationship between HCM and AF using a two-sample and bidirectional Mendelian randomization (MR) approach. Additionally, this assessed the role of cardiovascular proteins (CPs) associated with cardiovascular diseases between HCM and AF by applying a two-step MR analysis. Methods Data for HCM, AF, and 90 CPs were obtained from the Finn Gen and IEU Open GWAS Project databases. MR-Egger, inverse variance weighting (IVW), weighted median estimator (WME), weighted mode, and simple mode were used to estimate causal inferences. Furthermore, Cochran's Q test, MR-Egger's intercept terms, and Leave-one-out methods determined the heterogeneity, horizontal pleiotropy, and sensitivity. Additionally, mediation effects were used to assess the role of CPs in the relationship between HCM and AF. Results Two-sample and bidirectional MR analysis revealed HCM as a risk factor for AF (odds ratio (OR) = 1.008, 95% confidence interval (CI): 1.001-1.016, p = 0.029) and AF was found to increase the risk of developing HCM (OR = 1.145, 95% CI: 0.963-1.361, p = 0.126). Moreover, Two-step MR analyses indicated that 5 CPs were causally associated with HCM; 12 CPs with AF and 1 CP (Melusin) with both HCM and AF. Additionally, Melusin was observed as a protective factor for both HCM and AF and may serve as a mediator variable for these two conditions (mediation effect 0.0004, mediation ratio 5.5178%, 95% CI: 5.4624-5.5731). Conclusion HCM may increase the risk of developing AF, with Melusin serving as a mediator for this risk.