Causal relationship between leukocyte telomere length and two cardiomyopathies based on a bidirectional Mendelian randomization approach

This study aims to employ the Mendelian randomization (MR) approach to investigate the relationship between leukocyte telomere length (TL) and 2 prevalent forms of cardiomyopathies. Using R software (4.3.1) for MR study, independent genetic variants associated with leukocyte TL were extracted from the Integrative Epidemiology Unit database, while cardiomyopathies data were pooled from FinnGen and European Bioinformatics Institute databases. Analytical methodologies included inverse-variance weighting, MR-Egger regression, and weighted median methods. Further analyses involved MR-Egger intercept and MR-PRESSO for handling horizontal pleiotropy and Cochran Q test for study heterogeneity. Our forward Mendelian randomization study indicates a positive correlation between longer leukocyte TL and the risk of 2 forms of cardiomyopathies: the longer the leukocyte telomere, the higher is the risk of cardiomyopathies. Specifically, for hypertrophic obstructive cardiomyopathy the OR is 2.23 (95% CI: 1.19-4.14, P = .01), for hypertrophic cardiomyopathy the OR is 1.80 (95% CI: 1.14-2.85, P = .01), and for dilated cardiomyopathy the OR is 1.32 (95% CI: 1.01-1.71, P = .04). In contrast, our reverse Mendelian randomization showed that cardiomyopathies were not directly associated with TL, and the inverse-variance-weighted test was not statistically significant for any of the 3 (P > .05). The reliability tests for the forward Mendelian randomization, including both MR-Egger intercept and MR-PRESSO tests, show no evidence of horizontal pleiotropy, and Cochran Q test indicates no heterogeneity. The "leave-one-out" sensitivity analysis revealed no outlier genes. The reliability tests for the reverse Mendelian randomization, including both MR-Egger intercept and MR-PRESSO tests, also indicate no genetic pleiotropy. Despite the heterogeneity shown in our study between hypertrophic cardiomyopathy and leukocyte TL, the sensitivity analysis did not identify any anomalies. Our Mendelian randomization study suggests that longer leukocyte TL is associated with an increased risk of hypertrophic obstructive cardiomyopathy, hypertrophic cardiomyopathy, and dilated cardiomyopathy. However, the onset of these 2 kinds of disease does not directly lead to changes in leukocyte TL.