Transferability of Ancestry‐Specific and Cross‐Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations

Autor: Neal L. Benowitz, Lisa Sanderson Cox, Rachel F. Tyndale, Nicole L. Nollen, Jo Knight, Michiaki Kubo, Caryn Lerman, Meghan J. Chenoweth, Ahmed El-Boraie, Jennie G. Pouget, Taisei Mushiroda, Koya Fukunaga
Rok vydání: 2021
Předmět:
Adult
Male
Pharmacogenomic Variants
Population
Black People
Biology
Cardiovascular
030226 pharmacology & pharmacy
White People
Article
Cytochrome P-450 CYP2A6
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Clinical Research
Risk Factors
Tobacco
Genetics
Humans
Genetic Predisposition to Disease
Pharmacology (medical)
Pharmacology & Pharmacy
Allele
Cotinine
CYP2A6
education
Cancer
Genetic association
Pharmacology
Principal Component Analysis
education.field_of_study
Tobacco Smoke and Health
Smoking
Robustness (evolution)
Pharmacology and Pharmaceutical Sciences
Middle Aged
Genetic architecture
Black or African American
Good Health and Well Being
Treatment Outcome
chemistry
Evolutionary biology
030220 oncology & carcinogenesis
Respiratory
Female
Smoking Cessation
Pharmacogenetics
Zdroj: Clin Pharmacol Ther
Clinical pharmacology and therapeutics, vol 110, iss 4
ISSN: 1532-6535
0009-9236
DOI: 10.1002/cpt.2135
Popis: The Nicotine Metabolite Ratio (NMR; 3-hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in nonsmokers, former smokers, or intermittent smokers, for example, in evaluating tobacco-related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation. We previously created a CYP2A6 weighted genetic risk score (wGRS) for European (EUR)-ancestry populations by incorporating independent signals from genome-wide association studies to capture a larger proportion of NMR variation. However, CYP2A6 genetic architecture is unique to ancestral populations. In this study, we developed and replicated an African-ancestry (AFR) wGRS, which captured 30-35% of the variation in NMR. We demonstrated model robustness against known environmental sources of NMR variation. Furthermore, despite the vast diversity within AFR populations, we showed that the AFR wGRS was consistent between different US geographical regions and unaltered by fine AFR population substructure. The AFR and EUR wGRSs can distinguish slow from normal metabolizers in their respective populations, and were able to reflect unique smoking cessation pharmacotherapy outcomes previously observed for the NMR. Additionally, we evaluated the utility of a cross-ancestry wGRS, and the capacity of EUR, AFR, and cross-ancestry wGRSs to predict the NMR within stratified or admixed AFR-EUR populations. Overall, our findings establish the clinical benefit of applying ancestry-specific wGRSs, demonstrating superiority of the AFR wGRS in AFRs.
Databáze: OpenAIRE
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