Fig. 5: Forest plot: association analysis of heteroplasmy count (MHC)-associated DNA methylation score with mortality and incident CVD. | Nature Communications

Fig. 5: Forest plot: association analysis of heteroplasmy count (MHC)-associated DNA methylation score with mortality and incident CVD.

From: Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy

Fig. 5

We applied elastic net–regularized Cox proportional hazards regression in the Framingham Heart Study (FHS) training cohort to identify heteroplasmy count (MHC)-associated CpGs, yielding 57 associated with all-cause mortality in panel A and 18 associated with cardiovascular disease (CVD) in panel B. Statistical significance of regression coefficients was assessed using two-sided Wald z-tests. The forest plot presents hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between weighted MHC-CpG scores and outcomes (mortality and incident CVD) across training and testing cohorts, adjusted for age, self-reported sex, and smoking status (never, former, current). In FHS, the 57- and 18-CpG scores yielded HRs (95% CI) of 1.61 (1.50–1.72) for all-cause mortality and 1.29 (1.23–1.36) for CVD, respectively. Internal validation in the Jackson Heart Study (JHS) and the Multi-Ethnic Study of Atherosclerosis (MESA) showed, for all-cause mortality, HRs (95% CI) of 0.99 (0.77–1.28) in MESA White American (EA) participants, 1.18 (1.06–1.31) in JHS, and 1.02 (0.70–1.48) in MESA African American (AA) participants for the 57-CpG score. For CVD, the 18-CpG score yielded HRs (95% CI) of 0.97 (0.78–1.21) in MESA EA, 1.19 (1.05–1.36) in JHS, and 1.41 (0.97–2.04) in MESA AA. Meta-analysis of JHS and MESA participants produced HRs (95% CI) of 1.12 (0.99–1.27) for all-cause mortality and 1.15 (0.97–1.36) for CVD. External validation in the Health and Retirement Study (HRS), which was not used for CpG selection, found that for all-cause mortality, the 57-CpG score yielded HRs (95% CI) of 1.28 (1.16–1.42) in EA, 1.62 (1.31–2.01) in AA, and 1.78 (1.18–2.70) in Hispanic American (HA) participants. For CVD, the 18-CpG score yielded HRs of 1.07 (0.97–1.19) in EA, 0.83 (0.59–1.16) in AA, and 1.48 (1.06–2.05) in HA. Meta-analysis of MESA, JHS, and HRS participants produced HRs (95% CI) of 1.27 (1.09–1.48) for all-cause mortality and 1.12 (0.99–1.26) for CVD.

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