The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans
Joseph Bloom, Anthony L. Hinrichs, Jen C. Wang, Linda B. Von Weymarn, Evan D. Kharasch, Laura J. Bierut, Alison Goate, Sharon E. Murphy
Institute for Public Health
DBBS - Human and Statistical Genetics
DBBS - Biomedical Informatics and Data Science
Objective: To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism. Methods: The conversion of deuterated (D2)-nicotine to D 2-cotinine was quantified in 189 European-Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D 2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes. Results: The final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5′-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02). Conclusion: Among European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.
Pharmacogenetics and Genomics
https://doi.org/10.1097/FPC.0b013e328346e8c0
cytochrome P450 2A6
nicotine metabolism
10.1097/FPC.0b013e328346e8c0
Dive into the research topics of 'The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans'. Together they form a unique fingerprint.
Nicotine Medicine & Life Sciences 100%
Cytochrome P-450 Enzyme System Medicine & Life Sciences 98%
Cotinine Medicine & Life Sciences 59%
Haplotypes Medicine & Life Sciences 34%
Oral Administration Medicine & Life Sciences 23%
Bloom, J., Hinrichs, A. L., Wang, J. C., Von Weymarn, L. B., Kharasch, E. D., Bierut, L. J., Goate, A., & Murphy, S. E. (2011). The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans. Pharmacogenetics and Genomics, 21(7), 403-416. https://doi.org/10.1097/FPC.0b013e328346e8c0
Bloom, Joseph ; Hinrichs, Anthony L. ; Wang, Jen C. et al. / The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans. In: Pharmacogenetics and Genomics. 2011 ; Vol. 21, No. 7. pp. 403-416.
@article{15c4e5c7718745dfafa3cd2e546fa723,
title = "The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans",
abstract = "Objective: To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism. Methods: The conversion of deuterated (D2)-nicotine to D 2-cotinine was quantified in 189 European-Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D 2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes. Results: The final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5′-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02). Conclusion: Among European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.",
keywords = "cotinine, cytochrome P450 2A6, nicotine metabolism",
author = "Joseph Bloom and Hinrichs, {Anthony L.} and Wang, {Jen C.} and {Von Weymarn}, {Linda B.} and Kharasch, {Evan D.} and Bierut, {Laura J.} and Alison Goate and Murphy, {Sharon E.}",
doi = "10.1097/FPC.0b013e328346e8c0",
journal = "Pharmacogenetics and Genomics",
Bloom, J, Hinrichs, AL, Wang, JC, Von Weymarn, LB, Kharasch, ED, Bierut, LJ, Goate, A & Murphy, SE 2011, 'The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans', Pharmacogenetics and Genomics, vol. 21, no. 7, pp. 403-416. https://doi.org/10.1097/FPC.0b013e328346e8c0
The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans. / Bloom, Joseph; Hinrichs, Anthony L.; Wang, Jen C. et al.
In: Pharmacogenetics and Genomics, Vol. 21, No. 7, 07.2011, p. 403-416.
T1 - The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans
AU - Bloom, Joseph
AU - Hinrichs, Anthony L.
AU - Wang, Jen C.
AU - Von Weymarn, Linda B.
AU - Kharasch, Evan D.
AU - Bierut, Laura J.
AU - Goate, Alison
AU - Murphy, Sharon E.
N2 - Objective: To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism. Methods: The conversion of deuterated (D2)-nicotine to D 2-cotinine was quantified in 189 European-Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D 2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes. Results: The final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5′-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02). Conclusion: Among European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.
AB - Objective: To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism. Methods: The conversion of deuterated (D2)-nicotine to D 2-cotinine was quantified in 189 European-Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D 2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes. Results: The final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5′-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02). Conclusion: Among European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.
KW - cotinine
KW - cytochrome P450 2A6
KW - nicotine metabolism
U2 - 10.1097/FPC.0b013e328346e8c0
DO - 10.1097/FPC.0b013e328346e8c0
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
Bloom J, Hinrichs AL, Wang JC, Von Weymarn LB, Kharasch ED, Bierut LJ et al. The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans. Pharmacogenetics and Genomics. 2011 Jul;21(7):403-416. doi: 10.1097/FPC.0b013e328346e8c0