Epigenetic Biomarkers of Lead Exposure and Cardiovascular Disease: Prospective Evidence in the Strong Heart Study

BACKGROUND: Lead is a cardiotoxic metal with a variety of adverse health effects. In the absence of data on bone lead ex-posure, epigenetic biomarkers can serve as indicators of cumulative lead exposure and body burden. Herein, we leveraged novel epigenetic biomarkers of lead exposure to investigate their association with cardiovascular disease (CVD) incidence and mortality. METHODS AND RESULTS: Blood DNA methylation was measured using the Illumina MethylationEPIC BeadChip among 2231 participants of the Strong Heart Study (SHS) at baseline (1989–1991). Epigenetic biomarkers of lead levels in blood, patella, and tibia were estimated using previously identified cytosine-guanine dinucleotide (CpG) sites. CVD incidence and mortality data were available through 2017. Median concentrations of lead epigenetic biomarkers were 13.8 μg/g, 21.3 μg/g, and 2.9 μg/ dL in tibia, patella, and blood, respectively. In adjusted models, the hazard ratio (HR) (95% CI) of CVD mortality per doubling increase in lead epigenetic biomarkers were 1.42 (1.07–1.87) for tibia lead, 1.22 (0.93–1.60) for patella lead, and 1.57 (1.16– 2.11) for blood lead. The corresponding HRs for incident CVD were 0.99 (0.83–1.19), 1.07 (0.89–1.29), and 1.06 (0.87–1.30). The association between the tibia lead epigenetic biomarker and CVD mortality was modified by sex (interaction P value: 0.014), with men at increased risk (HR, 1.42 [95% CI, 1.17–1.72]) compared with women (HR, 1.04 [95% CI, 0.89–1.22]). CONCLUSIONS: Tibia and blood epigenetic biomarkers were associated with increased risk of CVD mortality, potentially reflect-ing the cardiovascular impact of cumulative and recent lead exposures. These findings support that epigenetic biomarkers of lead exposure may capture some of the disease risk associated with lead exposure.