Association study of the CTH 1364 G>T polymorphism with coronary artery disease in the Greek population.

Background Cystathionine γ-lyase enzyme, which is encoded by the CTH gene, is responsible for hydrogen sulfide (H2S) production in the endothelium. The CTH 1364 G>T polymorphism may alter the CTH expression and H2S bioavailability, thus leading to atherosclerosis and coronary artery disease (CAD). We examined the potential association of the CTH 1364 G>T polymorphism with CAD. Methods The CTH 1364 G>T polymorphism was determined in 178 coronary artery bypass grafting (CABG) patients and 156 non-atherosclerotic controls of Greek Caucasian origin using the PCR-RFLP method. Results No significant difference in the frequency of the CTH 1364 G>T genotypes (p = 0.281) and alleles (p = 0.265) was found between the CABG patients and controls. After conducting stratification according to sex, analysis showed a numerical difference in the CTH 1364 TT genotype frequency in female participants that did not reach statistical significance (16.3% and 8.5% in the CABG and controls, respectively, p = 0.26). The frequency of the CTH 1364 TT genotype between the male CABG patients and controls did not differ (p = 0.507). Conclusions The CTH 1364 G>T polymorphism was not associated with CAD in the studied population. However, interestingly, a higher - if not significantly so - CTH 1364 TT genotype frequency was present in female CABG patients compared with female controls. Larger studies are necessary to conclude on the potential overall or gender-driven association between CTH 1364 G>T gene polymorphism and CAD.

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.