Blood-based DNA methylation biomarkers for cumulative lead exposure: associations with cardiovascular disease incidence and mortality in the Strong Heart Study

Abstract

Lead is a ubiquitous toxicant associated with increased cardiovascular disease (CVD) risk. Blood and bone (patella and tibia) lead are established biomarkers of cumulative lead exposure, but because specialized technologies are needed for analysis, they are typically not available for clinical and epidemiological applications. We recently developed and validated three polygenic biomarkers that estimate lead exposure in blood, patella, and tibia samples based only on blood DNA methylation (DNAm) data. Whether these methylation-biomarkers predict lead-related CVD risk is unknown. We thus investigated the associations of these DNAm lead biomarkers with CVD incidence and mortality in the Strong Heart Study (SHS), a population-based cohort study of CVD in American Indian adults recruited in 1989-1991. The three DNAm lead biomarkers were computed from Illumina EPIC BeadChip blood DNAm data available at baseline among 2,321 SHS participants aged 45-75 years (~41% male). During a median follow-up of ~20 years, 1,023 participants had incident CVD events and 452 died due to CVD. After adjustment for sociodemographic and cardiovascular risk factors, the three DNAm lead biomarkers were associated with CVD mortality, but not with non-fatal CVD events. The hazard ratios (95% CI) for CVD mortality were 1.15 (1.01 - 1.31), 1.12 (1.01 - 1.25), and 1.20 (1.06 - 1.37) per interquartile increase in DNAm-estimated blood, patella, and tibia lead biomarkers. All biomarkers were also associated with coronary heart disease mortality. In subgroup analyses, the associations of lead biomarkers with CVD mortality were stronger in males and ever smokers. These newly developed DNAm lead biomarkers may aid in identifying individuals at risk for CVD mortality resulted from cumulative lead exposure.