Epigenetics-by-Sex Interaction for Coronary Artery Disease Risk Conferred by the Cystathionine γ-Lyase Gene Promoter Methylation

Coronary artery disease (CAD) is a major global health burden whereby gene-by-environment-by-sex interactions play an important role. Coronary artery bypass graft (CABG) surgery involves patients with well-documented and severe CAD. Hence, the study of CAD in a context of the CABG surgery serves as an advantageous model for disease phenotype ascertainment and genetic association studies. We report here new observations from a case-control genetic association study on promoter methylation of the cystathionine γ-lyase (CTH) gene and its association with CAD. To the best of our knowledge, this is the first clinical study to show the DNA methylation status of the CTH promoter in relation to this clinical phenotype. CTH encodes for the hydrogen sulfide generating enzyme named CSE in the endothelium that is mechanistically highly relevant for CAD. In a sample of 334 subjects from Greece (178 cases with CAD and who underwent CABG, and 156 controls), CTH promoter methylation was analyzed using a SYBR Green-based quantitative methylation-specific polymerase chain reaction. We found increased methylation in CTH promoter in cases (19.1%) compared to controls (10.3%) (p = 0.024). Gene-by-sex analysis sustained the significant association in men (p = 0.032) but not in women (p = 0.884). By using multivariate analyses after controlling for potential confounders such as smoking, age, and gender, we found that increased CTH gene promoter methylation was associated with CAD in the total sample (odds ratio [OR] = 2.163, 95% confidence interval [CI] 1.038-4.506, p = 0.039) and in men (OR = 2.418, 95% CI 1.048-5.581, p = 0.039) but not in women (OR = 0.542, 95% CI 0.094-3.140, p = 0.495). These observations collectively warrant further precision medicine and biomarker research to examine the CTH methylation status as a putative epigenetic regulator of CAD risk in larger and independent samples.