PROJECT SUMMARY/ABSTRACT Native Hawaiians and Pacific Islanders (NHPIs) experience a disproportionately higher prevalence of cardiometabolic diseases, primarily Type-2 diabetes mellitus (DM), than other U.S. racial/ethnic populations. Compared to White residents, NHPIs have a ~2.5-fold higher incidence and earlier onset of diagnosed DM with significant differences in DM disparities appearing at age 35. NHPIs also have the lowest levels of educational attainment, lowest mean income, highest rates of poverty, and higher exposures to DM risk factors compared to other major racial/ethnic groups in Hawaii, and also reside in environments that include low neighborhood socioeconomic status (nSES). The coincidence of disparities in DM prevalence and adverse social environments implicate complex interactions that may impact gene pathways relevant to the onset of DM. However, the interactions between the social environment and biological mechanism(s) that underlie DM health disparities of NHPIs are unknown. The detrimental effects of social environments, such as nSES, may include an increased prevalence of chronic low-grade inflammation known to contribute to DM. Epigenetic mechanisms (e.g. DNA methylation) regulate transcription of pro-inflammatory genes of monocytes, a key mediator of inflammation. Our preliminary data in NHPIs with DM that completed a lifestyle intervention revealed significant genome-wide changes to the DNA methylation and gene expression states of pro-inflammatory genes that were associated with their monocyte inflammatory activity and glycemic control. In another study, we observed significant changes to the gut microbiome, dysbiosis of which may also be an underlying attribute of DM, in NHPI youth that correlated with social network influences and health behaviors that modified their risk for DM. Lifestyle- associated changes to the gut microbiome impacts DNA methylation through bioavailability of substrates essential to the epigenetic machinery. Thus, we propose a hypothesis that the social environment conditions the epigenomic landscape and gut microbiome composition that regulate inflammation and metabolic pathways underlying DM. To test this hypothesis, we aim to identify an epigenetic signature of DM risk in monocytes from a new cohort of NHPIs and that of their social networks, and examine associations with neighborhood- and interpersonal-level social factors using a cross-sectional study design (Aim 1). We will then explore the mechanistic basis to which this signature may underlie innate DM-relevant traits by examining associations with inflammation, inflammatory activity, and gut microbiome composition/diversity (Aim 2). Finally, we will determine the degree to which this signature may prospectively be predictive of DM outcome (Aim 3). Addressing these aims will yield novel datasets of NHPIs in a health disparate population for determining the relationship between the “immunoepigenetic-gut microbiome axis” and DM risk withi...