Epigenetic Associations with Sociodemographic Factors and Cardiometabolic Profiles Across the Life Course

Abstract

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among U.S. adults. Cardiometabolic risk factors contributing to the development of CVD include hypertension, diabetes, dyslipidemia, overweight and obesity, and inflammation, all of which have long-standing racial/ethnic and socioeconomic disparities in the U.S. DNA methylation, an epigenetic mechanism that regulates transcription without altering the DNA sequence, is associated with cardiometabolic risk factors and CVD. A better understanding of the relationships between methylation-based biomarkers (e.g., individual methylation sites (CpGs), epigenetic clocks, and poly-epigenetic scores (PES)), sociodemographic and behavioral factors, and cardiometabolic profiles can shed light on advancing strategies in the precision health context. This dissertation explores epigenetic associations with sociodemographic factors and cardiometabolic profiles in multi-ancestry U.S. cohorts.

In Aim 1, we investigated the associations between five measures of epigenetic age acceleration and four blood lipid measures in older adults from the Health and Retirement Study (HRS, mean age = 70 years). We also examined whether demographic factors (i.e., age, sex, and educational attainment) modified these relationships. Greater epigenetic age acceleration was associated with lower total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C), and higher triglycerides (TG) (p<0.05), although the effect sizes were relatively small. The associations were stronger in younger participants, females, and those with higher educational attainment.

In Aim 2, we constructed trait-specific PESs for eight cardiometabolic risk factors (systolic and diastolic blood pressure (SBP, DBP), body mass index (BMI), C-reactive protein (CRP), HDL-C, LDL-C, TG, and fasting glucose), and examined their associations with the corresponding cardiometabolic traits in older U.S. adults from the HRS. We next investigated how demographics (i.e., age, sex, and educational attainment) and health behaviors (i.e., smoking, alcohol consumption, and physical activity) modified these associations. All PESs were positively associated with their traits (P < 0.05), and most associations remained consistent across race/ethnic groups. Associations for BMI, HDL-C, and TG were stronger in younger participants, and BMI and HDL-C were also stronger in females. The association for CRP was stronger among those with a high school degree. Finally, the association for HDL-C was stronger among current smokers.

In Aim 3, we utilized the structured life-course modeling approach (SLCMA) to examine the time-sensitive associations between income-to-poverty ratio (IPR) and epigenome-wide methylation at two time points (ages 9 and 15) in U.S. children and adolescents from the Future of Families and Child Wellbeing Study. A total of 269 and 285 CpGs at ages 9 and 15, respectively, were identified with FDR-q<0.05 and >3% of DNA methylation explained by the selected IPR. Most CpGs were associated with IPR in early childhood (at or before age 5) rather than in later childhood (age 9), adolescence (age 15), or accumulated poverty throughout childhood and adolescence. The CpGs identified at both ages were primarily enriched for immune system function.

This dissertation provides a deep characterization of the relationships among epigenetic biomarkers and cardiometabolic risk factors in older adults, identifying subgroups for which these biomarkers perform particularly well. It further identifies methylation profiles in children and adolescents influenced by demographic factors in early life, and points to biological pathways that may underly the link between early life adverse events and later life health outcomes. Together, these findings may help to advance strategies for more precise prevention and early intervention efforts for the U.S. population throughout the life course.