Methylation Signals of Early Atherosclerosis in At-Risk Youth: A Multi-Omic Analysis of the Future of Families Cardiovascular Study

Abstract

Cardiovascular disease (CVD) remains the leading cause of death worldwide, with atherosclerosis as its primary underlying pathology. Since evidence of disease can manifest at a young age, understanding its early-stage mechanisms of pathogenesis is crucial for preventing and managing CVD. To contribute to this goal, this thesis leverages both epigenetic and genetic data from over 1,200 individuals in the Future of Families and Child Wellbeing Study (FFCWS), whose carotid intima-media thickness (CIMT) was measured as a marker for atherosclerosis. Three complementary epigenomic and genomic methods were employed: a candidate CpG analysis to identify trends in site-specific methylation over time, an epigenome-wide analysis to detect differentially methylated regions that recur throughout adolescence, and Mendelian Randomization to elucidate potential causal effects of methylation on CIMT. Across the three methods, sets of CpGs on 15 genes—SOCS3, CPT1A, HIVEP3, PLEKHB1, SPATC1L, TSBP1, FADS1/FADS2, HCG27, HOXA-AS2, HOXA3, HOXA4, HOXA6, MGST3, TNXB, and ZFP57—were significantly associated with CIMT. These genes emerge as promising candidates for further investigation into the mechanisms of atherosclerosis development, which is especially important given the study’s focus on an ethnically diverse and historically underrepresented cohort. These findings provide a foundation for future research into gene regulation and epigenetic biomarkers for early-stage CVD, which may ultimately improve overall tracking, prevention, and management of the disease.