Abstract Body: Background: Lead (Pb) may increase risk of cardiovascular disease (CVD) through several pathways such as endothelial injury, inflammation, oxidative stress, lipid metabolism, and hypertension. Epigenetic biomarkers can be used to estimate cumulative Pb exposure. We tested the hypothesis that greater cumulative Pb exposure estimated through DNA methylation (DNAm)-based biomarkers would be associated with higher risk of CVD.

Methods: We included 3,372 ARIC study participants who had Illumina 450K BeadChip DNAm data and were free of prevalent CVD in 1990-1995. We calculated two DNAm-based biomarkers of estimated cumulative Pb exposure that have been validated against measured tibia and patella bone Pb concentrations in an external sample of men. The tibia score was a weighted average of 138 CpG sites while the patella score used 59 CpG sites. ARIC participants were followed through 2021 for incident coronary heart disease (CHD), stroke, heart failure (HF), and a CVD composite. Cox regression was used.

Results: Participants were an average of 57±5.9 years old, 62% were female and 70% self-identified as Black and 30% as White. There were 1,342 CVD events and 523 CHD events over a median of 22.0 years. For tibia Pb estimates, interactions (p<0.05) with sex were observed (Table). Men in the highest versus lowest quintile of estimated tibia Pb had a hazard ratio (95% CI) of 1.38 (1.03-1.85) for incident CVD and 1.93 (1.24-2.99) for incident CHD, after model 2 adjustments. Magnitudes of association were smaller for HF, and null for stroke. There was no evidence of an association in women. In both sexes, estimated patella Pb was unrelated to both outcomes.

Discussion: Epigenetic estimates of cumulative tibia Pb exposure were associated with risk of incident CVD and CHD in this sample of men from the ARIC cohort. DNAm estimates were derived from a sample of men and may not be generalizable to women. There is a longer half-life of Pb in the tibia (a cortical bone) than in the patella (a trabecular bone). Our findings with estimated tibia Pb may reflect longer-term exposure. Additional research is needed to understand the role of cumulative Pb exposure on CVD risk.