The impact of enculturation on the epigenetic relationship between chronic stress and hypertension in Yup'ik Alaska Native people

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Project Summary The objective of the proposed research is to identify molecular mechanisms linking the protective role of culture to blood pressure regulation, a major risk factor for stroke in Yup'ik Alaska Native people. The prevalence of stroke is higher among American Indian and Alaska Native (AIAN) populations than in any other U.S. racial/ethnic group. Chronic psychological stress increases the risk for hypertension, and is the most frequently cited stroke risk factor in AIAN populations. The prevalence of stroke has increased over the past 25 years, and is likely brought on by chronic stressors including historical trauma, cultural change and adverse socioeconomic conditions which, in turn, increases the likelihood of unhealthy behavioral coping responses (e.g., smoking, reduced exercise, poor sleep and overeating). However, our previous research has shown that both strong adherence to Yup'ik cultural traditions (enculturation) and dual adherence to Yup'ik and White culture (biculturalism) are associated with healthier blood pressure when compared to Yup'ik individuals adhering to a more Western lifestyle (acculturation). No previous research has identified the molecular events underlying the basis for the protective effects of enculturation/biculturalism-induced resilience (EBIR) on risk for hypertension, representing a critical barrier to the development of culturally effective interventions aimed at promoting health. The proposed research examines the role of EBIR at each step of the stress-disease cascade – a model based on extensive research linking chronic stressful events to biological mechanisms and diseases such as hypertension. We hypothesize that EBIR blocks or buffers adverse individual and environmental stressors resulting in reduced metabolic dysfunction and inflammation, inhibition of epigenetic dysregulation, and maintenance of leukocyte telomere length, all or some of which lead to healthy blood pressure. We test these hypotheses by addressing the following Specific Aims (SAs): SA1 - Conduct latent class analysis using self- reported data about enculturation, biculturalism, and chronic stress from 800 Yup'ik participants to form classes based on their degree of EBIR/stress (SA1a), followed by evaluating the relationship between EBIR/stress latent classes and maladaptive health-related behaviors as well as between blood pressure, the main study outcome measure (SA1b); SA2 - Evaluate the association between EBIR/stress latent classes with metabolic dysfunction (salivary cortisol, fasting plasma glucose and HbA1c levels, and lipid levels), mitochondrial allostatic load, and chronic low-grade inflammation; and SA3 - Determine the impact of EBIR/stress latent classes on epigenome- wide DNA methylation and downstream changes in gene expression (SA3a) as well as quantify the association between methylation sites and blood pressure (SA3b), and test whether differential methylation mediates the association between EBIR/stress latent classes and blood pressure (SA3c). We will also evaluate leukocyte telomere length among individuals in each of the EBIR/stress latent classes (SA3d) in order to determine whether EBIR reduces the impact of chronic stress on premature telomere shortening, an indicator of biological aging.