Genetic and Socio-Contextual Determinants of Cardiovascular and Cognitive Health in Populations of Diverse Ancestries

Abstract

The global demographic shift towards an aging population has led to a significant increase in age-related chronic diseases such as cardiovascular disease (CVD) and dementia. However, the intricate interactions between genetic, socio-contextual, and environmental factors and their molecular impacts on disease risk remain poorly understood. Moreover, most genomic studies have predominantly focused on populations of European ancestry, leaving a critical gap in our understanding of these diseases in other ancestry groups. This dissertation explores the potential molecular consequences of social determinants on disease risk and examines how social context and genetic ancestry may modulate genetic predispositions in multiple ancestry groups. In Aim 1, we conducted an epigenome-wide mediation analysis to investigate whether DNA methylation mediates the relationships between individual- and neighborhood-level social disadvantage and CVD risk factors in US adults from the Multi-Ethnic Study of Atherosclerosis (MESA). We identified 410 CpG sites that may mediate the association between adult socioeconomic status (SES) and body mass index (BMI), and 43 potentially mediating CpG sites between neighborhood socioeconomic disadvantage and high-density lipoprotein cholesterol (HDL-C) independent of BMI. The identified CpG mediators were enriched for expression quantitative trait methylation loci (eQTMs) and the corresponding genes were enriched in pathways involved in inflammation and immune response. In Aim 2, we investigated the association between the ε4 allele of the apolipoprotein E (APOE) gene, the strongest known genetic risk factor for Alzheimer’s disease, and cognitive function in older South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD). We further explored whether age, sex, and education modified these relationships. These analyses are crucial as India, the world’s most populous country, is projected to shoulder ~10% of the global dementia burden by 2050. Additionally, India’s diverse social landscape, with approximately half of the older population lacking formal education, adds complexity to the relationships between genetic factors and dementia. Our findings indicated that carrying the ε4 allele was associated with lower cognitive function, both globally and in specific cognitive domains. Older individuals were more susceptible to the adverse ε4 effects on global cognition, orientation, and language/fluency, while females were more susceptible to its effect on memory and language/fluency. In Aim 3, we extended our investigation to examine the associations between APOE ε4 and ε2 alleles and both cognitive function and lipid levels in older Indians for a more comprehensive understanding of APOE effects on cognitive and cardiovascular health. We characterized these associations across the Indian population, noting heterogeneity across states and union territories. Genetic ancestry, estimated by genome-wide ancestry proportions, was assessed for its modifying effect. Beyond cognitive measures, ε4 was associated with higher levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), while ε2 was associated with lower levels of TC and LDL-C, and higher levels of HDL-C, but not with most cognitive measures. An above-median Ancestral North Indian (ANI) ancestry, which includes contributions from European ancestry, was associated with a stronger effect of ε4 on cognitive function and ε2 on lipid levels. Together, findings of this dissertation advance our understanding of the complex interplay between genetic/epigenetic and socio-contextual factors associated with CVD and dementia in diverse populations. Future studies should further unravel the underlying molecular pathways and inform the development of tailored intervention and prevention strategies addressing the unique health challenges faced by various populations.