Transferability of Ancestry-Specific and Cross-Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations.
Transferability of Ancestry-Specific and Cross-Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations.
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DOI：
10.1002/cpt.2135
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发表时间：
2021-10
影响因子：
6.7
通讯作者：
Tyndale RF
中科院分区：
文献类型：
--
作者：
El-Boraie A;Chenoweth MJ;Pouget JG;Benowitz NL;Fukunaga K;Mushiroda T;Kubo M;Nollen NL;Sanderson Cox L;Lerman C;Knight J;Tyndale RF
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 non-, former- 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-ancestry populations (EUR) 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.
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DOI：
10.1158/1055-9965.epi-09-1303
发表时间：
2010-05
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Benowitz NL;Dains KM;Dempsey D;Yu L;Jacob P 3rd
通讯作者：
Jacob P 3rd
影响因子：
30.8
作者：
Marchini, Jonathan;Howie, Bryan;Donnelly, Peter
通讯作者：
Donnelly, Peter
影响因子：
2.6
作者：
Bloom J;Hinrichs AL;Wang JC;von Weymarn LB;Kharasch ED;Bierut LJ;Goate A;Murphy SE
通讯作者：
Murphy SE
DOI：
10.1158/1055-9965.epi-14-0427
发表时间：
2014-09
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Chenoweth MJ;Novalen M;Hawk LW Jr;Schnoll RA;George TP;Cinciripini PM;Lerman C;Tyndale RF
通讯作者：
Tyndale RF
影响因子：
3.5
作者：
Cho, Michael H.;Castaldi, Peter J.;Silverman, Edwin K.
通讯作者：
Silverman, Edwin K.