Ancestry informative genetic variants associated with tobacco metabolic and detoxification capacity measured by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) among smokers.

Tobacco use remains the leading preventable cause of cancer mortality worldwide, with marked disparities in cancer incidence and outcomes across racial and ethnic groups. This study investigates the genetic determinants of tobacco carcinogen metabolism among smokers, focusing on ancestry-informative markers (AIMs) near genes involved in metabolic activation (Phase I), detoxification (Phase II), and transport (Phase III) of tobacco-specific carcinogens. Using data from 274 smokers recruited in the United States and the Caribbean, we measured urinary NNAL (a metabolite of NNK) to classify metabolic phenotypes and performed genotyping with a customized array enriched for AIMs. Most participants (94%) were classified as poor metabolizers of NNAL, with a higher prevalence among Black/African American smokers. Multivariable analyses, after adjusting for age, sex, assay batch, and number of cigarettes smoked per day, identified 14 AIMs near Phase I, II, and III pathway genes significantly associated with NNAL metabolizer phenotype, with African ancestry alleles conferring increased odds of poor metabolism. Functional annotation revealed that most significant AIMs overlapped regulatory regions, and the CYP3A5 rs776746 variant demonstrated structural disruption likely to impair enzymatic activity. Majority of participants had high African ancestry and were poor NNAL metabolizers, consistent with the observed association between African ancestry and poor NNAL metabolism. These findings highlight the biological basis for tobacco-related cancer disparities and underscore the importance of integrating genetic ancestry and metabolic phenotyping in risk assessment and personalized prevention strategies for tobacco-associated cancers.