Sociocultural factors, DNA methylation and Risk of Diabetes in Hispanics/Latinos

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Hispanics/Latinos, the largest and fastest-growing minority group in the US, are disproportionately affected by type 2 diabetes (T2D). Sociocultural, psychosocial, and behavioral factors [collectively called “socioenvironmental factors” hereafter] are believed to contribute to T2D disparity in Hispanics/Latinos, but the mechanisms through which they get under the skin are unclear. DNA methylation (DNAm), one of the most studied epigenetic modifications, is responsive to various socioenvironmental exposures across an individual’s life course, and aberrant DNAm has been associated with aging and age-related diseases including T2D. To date, little is known about the genomewide DNAm patterns associated with socioenvironmental exposures [in totality named “socioenvironmental exposome”]. The mechanisms through which socioenvironmental exposome becomes biologically embedded into aging and risk of T2D have not been well studied in a nationally representative sample of Hispanics/Latinos. Building on our prior work, we hypothesize that altered DNAm evoked by socioenvironmental risk and protective factors contributes to risk for T2D in Hispanics/Latinos. Our objectives here are to characterize the socioenvironmental exposome in relation to risk of T2D, and identify key biological pathways through which socioenvironmental exposome affects risk of diabetes, independent of known risk factors. To achieve this, we leverage a wealth of deep clinical phenotypes and socioenvironmental factors collected by the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and its ancillary study - the Sociocultural Ancillary Study (SCAS). Using peripheral blood genomic DNA collected at baseline (2008-2011) from 3,323 non-diabetic Hispanics/Latinos (aged 18-74) followed through 2024, we will first identify unique latent constructs using a unified theoretical framework and then conduct epigenomewide association studies (EWAS) to identify methylated genes/regions in response to each unique socioenvironmental construct (Aim 1). Findings from Hispanics/Latinos will be replicated in non- Hispanic Whites, African Americans, and American Indians (total N=7,184). In Aim 2, we will prospectively determine whether socioenvironment-induced DNAm predict the onset and progression of T2D, independent of standard clinical factors. In Aim 3, we will perform integrated genetic and epigenetic analyses to identify causal epigenetic mediators and molecular pathways through which socioenvironmental exposome become biologically embedded into diabetes risk in Hispanics/Latinos. Successful completion of this project will identify modifiable genes and causal pathways through which socioenvironmental factors become biologically embedded in Hispanic cardiometabolic health. Such results may provide novel mechanistic insights into disease pathology, and are likely to lead to culturally tailored precision strategies for diabetes prevention and intervention, thereby reducing diabetes disparity in this minority population.