PROJECT SUMMARY / ABSTRACT Native Hawaiian women (NatHW) experience substantial health disparities compared to women of other races/ethnicities, evidenced by their short healthy life expectancy and high all-cause and cancer mortality rates. Reasons for NatHW’s health disparities likely involve a combination of causes, including genetic susceptibility, individual and contextual socioeconomic status (SES), obesity and related lifestyle factors, smoking, healthcare access and quality, and the environment. The multifactorial basis of disparities requires an array of information and integrative approaches in research. Herein, we propose to use epigenetic biomarkers, known to reflect and mediate the combined effects of some of the genetic and environmental stressors, to enhance our mechanistic understanding of NatHW’s disparities in key carcinogenic metabolic traits. We will base the study in the Multiethnic Cohort Study (MEC), which is following the largest number of otherwise understudied Native Hawaiians (~7,850 women, ~6,120 men), as well as >201,000 older adults of mainly four other ethnicities (African American, Japanese American, Latino, white) since 1993-1996 with comprehensive characterization. Research to date indicates that there are significant sex and racial/ethnic differences in the human DNA methylome and in DNA methylation age (DNAm-age) acceleration. Thus, to enable an initial study in the MEC of leukocyte DNA methylation as a likely mediator of NatHW’s health disparities, we request a supplement to the MEC grant (U01 CA164973) in response to NOT-OD-20-048. We will analyze the archived leukocyte DNA samples in the Adiposity Phenotype Study (APS), which is a cross-sectional subset of the MEC, using the Illumina HumanMethylation EPIC bead chips. This will allow us to compare genome-wide methylation patterns and DNAm-age parameters in 140 NatHW and 140 white women, aged 60-77 years at the time of blood collection. We plan to (Aim 1) compare the DNA methylation patterns by constructing a DNA methylation score (DNAm- score) for NatHW vs. white women using penalized logistic regression of ethnicity on methylation at CpGs, adjusted for % Native Hawaiian genetic ancestry. Based on the selected differentially methylated genes, we will infer the biological functions in pathway analysis. We hypothesize that we will discover a DNA methylation signature and accelerated DNAm-age for NatHW vs. white women. We will then (Aim 2) quantify the proportion of the excess metabolic risk in NatHW compared to white women, namely higher insulin, triglycerides, visceral fat, and liver fat, respectively, mediated through the DNA methylome, based on the DNAm-score and DNAm- age. Finally, we will (Aim 3) identify behavioral and environmental determinants of the DNAm-score or DNAm- age among the wealth of data in the MEC-APS (adulthood weight gain, total body fat, lifetime smoking, diet quality, alcohol and meat intake, physical in/activity, sleep hours, and individ...