DNA Methylation Mediates the Association Between Individual and Neighborhood Social Disadvantage and Cardiovascular Risk Factors

Abstract

Low socioeconomic status (SES) and living in a disadvantaged neighborhood are associated with poor cardiovascular health. Multiple lines of evidence have linked DNA methylation to both cardiovascular risk factors and social disadvantage indicators. However, limited research has investigated the role of DNA methylation in mediating the associations of individual- and neighborhood-level disadvantage with multiple cardiovascular risk factors in large, multi-ethnic, population-based cohorts. We examined whether disadvantage at the individual level (childhood and adult SES) and neighborhood level (summary neighborhood SES as assessed by Census data and social environment as assessed by perceptions of aesthetic quality, safety, and social cohesion) were associated with 11 cardiovascular risk factors including measures of obesity, diabetes, lipids, and hypertension in 1,154 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). For significant associations, we conducted epigenome-wide mediation analysis to identify methylation sites mediating the relationship between individual/neighborhood disadvantage and cardiovascular risk factors using the JT-Comp method that assesses sparse mediation effects under a composite null hypothesis. In models adjusting for age, sex, race/ethnicity, smoking, medication use, and genetic principal components of ancestry, epigenetic mediation was detected for the associations of adult SES with body mass index (BMI), insulin, and high-density lipoprotein cholesterol (HDL-C), as well as for the association between neighborhood socioeconomic disadvantage and HDL-C at FDR q < 0.05. The 410 CpG mediators identified for the SES-BMI association were enriched for CpGs associated with gene expression (expression quantitative trait methylation loci, or eQTMs), and corresponding genes were enriched in antigen processing and presentation pathways. For cardiovascular risk factors other than BMI, most of the epigenetic mediators lost significance after controlling for BMI. However, 43 methylation sites showed evidence of mediating the neighborhood socioeconomic disadvantage and HDL-C association after BMI adjustment. The identified mediators were enriched for eQTMs, and corresponding genes were enriched in inflammatory and apoptotic pathways. Our findings support the hypothesis that DNA methylation acts as a mediator between individual- and neighborhood-level disadvantage and cardiovascular risk factors, and shed light on the potential underlying epigenetic pathways. Future studies are needed to fully elucidate the biological mechanisms that link social disadvantage to poor cardiovascular health.

Methods for Mediation Analysis with High-Dimensional DNA Methylation Data: Possible Choices and Comparison

“…Site cg10508317 is in the body of the SOCS3 gene, for which a rich body of literature has established links between overexpression and insulin resistance 45 . The same site has also been identified in MESA as a mediator between adult SES and BMI 46 and adult SES and HbA1c 31 based on previous one-at-a-time analyses. Site cg01288337, in the body of the RIN3 gene, has been identified in MESA as a potential mediator between adult SES and HbA1c based on one-at-a-time analysis as well 31 .…”

“…Site 346 cg10508317 is in the body of the SOCS3 gene, for which a rich body of literature has established links 347 between overexpression and insulin resistance 45 . The same site has also been identified in MESA as a 348 mediator between adult SES and BMI 46 and adult SES and HbA1c 31 based on previous one-at-a-time 349…”

Epigenetics of Early Cardiometabolic Disease: Mechanisms and Precision Medicine

“…Wang et al 34 examined whether disadvantages at the individual and neighborhood levels were associated with cardiovascular risk factors, including measures of obesity, diabetes, lipids, and hypertension, in 1154 participants from the MESA study. Moreover, the investigators conducted an epigenome-wide mediation analysis to identify methylation sites mediating the relationship between individual/neighborhood disadvantage and cardiovascular risk factors.…”

Social Determinants of Health and Cerebral Small Vessel Disease: Is Epigenetics a Key Mediator?

“… 64 DNA methylation levels in genes linked to stress reactivity and inflammation have been found to be associated with neighborhood‐related effects, such as neighborhood socioeconomic disadvantage and neighborhood social environment. 65 To explore the link between SES and cardiovascular risk, Wang et al 66 conducted an epigenome‐wide mediation analysis that highlighted 43 DNA methylation sites showing significant evidence of mediating the association between neighborhood socioeconomic disadvantage and high‐density cholesterol levels. The identified mediators showed enrichment for genes involved in monocyte‐to‐macrophage differentiation and macrophage polarity among others, corroborating the established role of inflammation in CVD.…”