Association of DNA methylation-predicted growth differentiation factor 15 with all-cause mortality among older adults in the United States: A prospective cohort study of NHANES 1999 to 2002

Growth differentiation factor 15 (GDF15) serves as a prominent biomarker across multiple physiological and pathological processes. Increased levels of GDF15 are associated with elevated mortality risk. Nevertheless, the prognostic utility of DNA methylation (DNAm)-predicted GDF15 concentrations for mortality remains inadequately explored. Our study utilized a national cohort to examine the link between GDF15 levels predicted by DNAm and the risk of all-cause mortality. This study employed data from the National Health and Nutrition Examination Survey (NHANES) cycles spanning 1999 to 2002. A regression model was applied to derive DNA methylation (DNAm)-predicted GDF15 concentrations. To evaluate the association linking DNA methylation-predicted GDF15 levels to mortality, we conducted adjusted Cox proportional hazards regression modeling. Dose-response relationships were evaluated using restricted cubic splines (RCS), and subgroup analyses were carried out to strengthen the findings' robustness. Elevated levels of GDF15 predicted via DNA methylation exhibited a marked association with increased all-cause mortality risk (HR = 1.11, 95% CI = 1.05-1.18). Participants within the top tertile of epigenetically estimated GDF15 concentrations exhibited a considerably increased hazard of death (HR = 1.62, 95% CI = 1.27-2.08). Kaplan-Meier curves demonstrated gradually decreasing survival probabilities corresponding to higher epigenetically derived GDF15 levels. A nonlinear dose-response relationship between DNAm-inferred GDF15 concentrations and all-cause mortality was revealed by restricted cubic spline analysis. This positive relationship consistently maintained significance within every prespecified subgroup. Epigenetically estimated GDF15 levels represent an independent predictor of all-cause mortality. This association retains its significance in multiple analytical approaches and across various subpopulations, highlighting the potential of GDF15 as a biomarker for stratifying mortality risk. Future studies are needed to elucidate the biological mechanisms through which GDF15 operates and to evaluate its applicability in clinical settings for reducing mortality risk.