Precision pharmacogenomics and Indigenous research: A novel approach to tobacco cessation efficacy in American Indian communities

PROJECT SUMMARY: The leading cause of health inequities and premature death in the United States (US) is smoking. Creating equitable access to smoking cessation aids and supporting quit attempts by smokers from diverse racial and ethnic groups are top health priorities. Advancements to personalizing smoking cessation treatment based on

the genetic profiles of individuals is promising but requires further scientific knowledge and research, especially in historically marginalized groups such as American Indian and Alaska Native (AIAN) peoples. Important conversations with AIAN community stakeholders about genomics and innovative community-based

participatory research (CBPR) approaches have set the stage for more Indigenous-centered approaches to science. Merging these advancements to develop an Indigenous pharmacogenomics approach to smoking cessation is lacking in the field and holds promise to support innovative smoking cessation efforts through

personalized treatment and culturally appropriate interventions. This project aims to leverage the promise of genome-wide and epigenome-wide association studies, which have successfully mapped thousands of loci associated with complex traits, as methods to reveal altered mechanism in nicotine metabolism and will result in

a better understanding of the relationship between nicotine metabolism, smoking cessation, and corresponding tobacco-related disease and death in AI communities. Working closely with the Strong Heart Study (SHS) cohort, the longest running study of cardiovascular diseases (CVD) and its risk factors among AI communities, we will

evaluate associations between genomic and epigenomic variation with nicotine metabolism, predict risk factors for smoking behavior and health outcomes, and use a CBPR approach to have conversations and develop a culturally appropriate intervention for smoking and tobacco use in AI communities. The SHS prioritizes research

from American Indian investigators and the topic of nicotine metabolism and its relation to genomic/epigenomic variation and smoking cessation research is a significant area of interest. A three phased approach will be used to promote health equity and smoking cessation efficacy. The phases of this proposal are 1) to identify genetic

and epigenetic influences on nicotine metabolism in AI smokers using a genome-wide and candidate resequencing approach, 2) develop genetic risk scores to examine associations with behavioral traits and comorbidities, and 3) develop a personalized approach to incorporating precision medicine as well as traditional

and cultural knowledge to improve smoking cessation efficacy. Importantly, phase 3 community engagement will be continuous throughout the research proposal, with the diverse AI communities involved in the SHS contributing to study outcomes and future directions guided by these interactions. This study will provide a

framework for tailoring precision medicine with cultural considerations in diverse AI communities and across other racial and ethnic minority groups to advance health equity and reduce substance use.