Background: Epigenetic biomarkers may provide novel insights into long-term health risk. DNA methylation (DNAm) predicted leptin has been proposed as an epigenetic proxy related to metabolic regulation, but its association with mortality remains underexplored. Objectives: To examine the association between DNAm-predicted leptin levels and all-cause, cardiovascular, and cancer mortality among US adults using The National Health and Nutrition Examination Survey (NHANES) data. Design: Population-based cohort analysis with linkage to the National Death Index. Methods: We analyzed 2531 participants from NHANES 1999–2002 with available DNAm-predicted leptin derived from whole-blood methylation profiles. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality outcomes across quartiles of DNAm-predicted leptin, with sequential adjustment for potential confounders. Subgroup and sensitivity analyses were performed to evaluate robustness. Results: Over a mean follow-up of 17.1 years, 1360 deaths occurred. DNAm-predicted leptin showed a J-shaped association with all-cause mortality. In fully adjusted models, HRs for all-cause mortality were 1.28 (95% CI: 1.00–1.62) for Quartile 1, 1.00 (reference) for Quartile 2, 1.32 (95% CI: 1.01–1.73) for Quartile 3, and 1.35 (95% CI: 1.11–1.64) for Quartile 4. After full adjustment, DNAm-predicted leptin was not statistically significantly associated with cancer mortality, while cardiovascular mortality risk was higher in Quartile 4 compared with Quartile 2. Conclusion: DNAm-predicted leptin was associated with all-cause mortality in a J-shaped pattern, with elevated risk at both lower and higher levels. Associations with cancer mortality were not statistically significant after adjustment, and evidence for cardiovascular mortality was limited to the highest quartile. Larger studies are needed to validate these findings and clarify cause-specific associations. Trial registration: Not applicable.
Fan et al. (Sun,) studied this question.