Association of DNA methylation epigenetic markers with all-cause mortality and cardiovascular disease-related mortality in diabetic population: a machine learning-based retrospective cohort study

BACKGROUND: Diabetes has a large and diverse population, with individuals exhibiting significant heterogeneity in the disease. The factors influencing survival and prognosis are complex, making early intervention in diabetic populations particularly challenging. Research has demonstrated a close relationship between DNA methylation (DNAm) clocks and aging as well as various diseases, showing superior predictive capabilities. However, the relationship between DNAm clocks and long-term survival in diabetic patients, particularly concerning cardiovascular-related mortality, remains unclear. METHODS: We analyzed the data of the diabetes population cohort in the National Health and Nutrition Examination Survey, which was followed for 20 years. We employed eight machine learning (ML) models to analyze 29 potential DNAm derived epigenetic markers and utilized Cox regression models to assess the risks of all-cause mortality and cardiovascular disease-related mortality in the diabetic population. Additionally, we applied restricted cubic spline (RCS) to analyze potential influence trends. RESULTS: A total of 454 people with diabetes were followed up, with a median follow-up time of 177.6 months. Through machine learning methods, we identified several high-performing DNAm markers, finding that four epigenetic biomarkers, ZhangAge (HR = 2.86, 95% CI: 2.19-3.73, P < 0.001), GrimAge2Mort (HR = 3.06, 95% CI: 2.26-4.14, P < 0.001), TIMP1Mort (HR = 2.95, 95% CI: 2.18-4.01, P < 0.001), and PhenoAge (HR = 2.94, 95% CI: 1.23-3.88, P < 0.001), were significantly associated with all-cause mortality in the diabetic population. Further research indicated that GrimAge2 Mort (HR = 2.86, 95% CI: 1.30-6.29, P = 0.009) and TIMP1Mort (HR = 4.08, 95% CI: 2.17-7.68, P < 0.001) were associated with cardiovascular disease-related mortality. RCS curves demonstrated that the mortality risk for all diabetic patients increased with rising levels of these DNAm epigenetic markers. CONCLUSION: We found four DNAm-derived epigenetic markers (ZhangAge, GrimAge2 Mort, TIMP1Mort, PhenoAge) that are associated with all-cause mortality risk in the diabetic population. Further research suggested that GrimAge and PhenoAge influence the risk of cardiovascular-related mortality.