Relationship Between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 Variation and Smoking Behaviors and Lung Cancer Risk

Overview

Journal J Natl Cancer Inst

Publisher Oxford University Press

Specialty Oncology

Date 2011 Jul 13

PMID 21747048

Citations 110

Authors

Catherine A Wassenaar

Qiong Dong

Qingyi Wei

Christopher I Amos

Margaret R Spitz

Rachel F Tyndale

Affiliations

Soon will be listed here.

Abstract

Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal-Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.

Citing Articles

PharmVar GeneFocus: CYP2A6.

Langlois A, Chenoweth M, Twesigomwe D, Scantamburlo G, Whirl-Carrillo M, Sangkuhl K Clin Pharmacol Ther. 2024; 116(4):948-962.

PMID: 39051767 PMC: 11452280. DOI: 10.1002/cpt.3387.

Phenotypic Annotation: Using Polygenic Scores to Translate Discoveries From Genome-Wide Association Studies From the Top Down.

Belsky D, Harden K Curr Dir Psychol Sci. 2024; 28(1):82-90.

PMID: 38736689 PMC: 11086979. DOI: 10.1177/0963721418807729.

Interaction between Continuous Pack-Years Smoked and Polygenic Risk Score on Lung Cancer Risk: Prospective Results from the Framingham Heart Study.

Duncan M, Diaz-Zabala H, Jaworski J, Tindle H, Greevy R, Lipworth L Cancer Epidemiol Biomarkers Prev. 2024; 33(4):500-508.

PMID: 38227004 PMC: 10988206. DOI: 10.1158/1055-9965.EPI-23-0571.

Associating CYP2A6 structural variants with ovarian and lung cancer risk in the UK Biobank: replication and extension.

Langlois A, Pouget J, Knight J, Chenoweth M, Tyndale R Eur J Hum Genet. 2023; 32(3):357-360.

PMID: 38097766 PMC: 10923790. DOI: 10.1038/s41431-023-01518-2.

Diagnosis of acute myeloid leukaemia on microarray gene expression data using categorical gradient boosted trees.

Angelakis A, Soulioti I, Filippakis M Heliyon. 2023; 9(10):e20530.

PMID: 37860531 PMC: 10582309. DOI: 10.1016/j.heliyon.2023.e20530.

References

Mwenifumbo J, Zhou Q, Benowitz N, Sellers E, Tyndale R . New CYP2A6 gene deletion and conversion variants in a population of Black African descent. Pharmacogenomics. 2010; 11(2):189-98. PMC: 2922202. DOI: 10.2217/pgs.09.144. View

Hung R, McKay J, Gaborieau V, Boffetta P, Hashibe M, Zaridze D . A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008; 452(7187):633-7. DOI: 10.1038/nature06885. View

Spitz M, Amos C, Dong Q, Lin J, Wu X . The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. J Natl Cancer Inst. 2008; 100(21):1552-6. PMC: 2720751. DOI: 10.1093/jnci/djn363. View

Schabath M, Spitz M, Hong W, Delclos G, Reynolds W, Gunn G . A myeloperoxidase polymorphism associated with reduced risk of lung cancer. Lung Cancer. 2002; 37(1):35-40. DOI: 10.1016/s0169-5002(02)00034-x. View

Sorensen M, Autrup H, Tjonneland A, Overvad K, Raaschou-Nielsen O . Genetic polymorphisms in CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer. Cancer Lett. 2005; 221(2):185-90. DOI: 10.1016/j.canlet.2004.11.012. View

Hecht S . Progress and challenges in selected areas of tobacco carcinogenesis. Chem Res Toxicol. 2007; 21(1):160-71. PMC: 2556958. DOI: 10.1021/tx7002068. View

Taioli E, Zocchetti C, Garte S . Models of interaction between metabolic genes and environmental exposure in cancer susceptibility. Environ Health Perspect. 1998; 106(2):67-70. PMC: 1533018. DOI: 10.1289/ehp.9810667. View

Lam D, Girard L, Ramirez R, Chau W, Suen W, Sheridan S . Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers. Cancer Res. 2007; 67(10):4638-47. DOI: 10.1158/0008-5472.CAN-06-4628. View

Rossini A, de Almeida Simao T, Albano R, Pinto L . CYP2A6 polymorphisms and risk for tobacco-related cancers. Pharmacogenomics. 2008; 9(11):1737-52. DOI: 10.2217/14622416.9.11.1737. View

10.

Thorgeirsson T, Gudbjartsson D, Surakka I, Vink J, Amin N, Geller F . Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet. 2010; 42(5):448-53. PMC: 3080600. DOI: 10.1038/ng.573. View

11.

Thorgeirsson T, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson K . A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature. 2008; 452(7187):638-642. PMC: 4539558. DOI: 10.1038/nature06846. View

12.

Alexandrie A, Nyberg F, Warholm M, Rannug A . Influence of CYP1A1, GSTM1, GSTT1, and NQO1 genotypes and cumulative smoking dose on lung cancer risk in a Swedish population. Cancer Epidemiol Biomarkers Prev. 2004; 13(6):908-14. View

13.

Malaiyandi V, Sellers E, Tyndale R . Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence. Clin Pharmacol Ther. 2005; 77(3):145-58. DOI: 10.1016/j.clpt.2004.10.011. View

14.

Schuller H . Is cancer triggered by altered signalling of nicotinic acetylcholine receptors?. Nat Rev Cancer. 2009; 9(3):195-205. DOI: 10.1038/nrc2590. View

15.

Changeux J . Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nat Rev Neurosci. 2010; 11(6):389-401. DOI: 10.1038/nrn2849. View

16.

Liu P, Vikis H, Wang D, Lu Y, Wang Y, Schwartz A . Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer. J Natl Cancer Inst. 2008; 100(18):1326-30. PMC: 2538550. DOI: 10.1093/jnci/djn268. View

17.

Amos C, Wu X, Broderick P, Gorlov I, Gu J, Eisen T . Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008; 40(5):616-22. PMC: 2713680. DOI: 10.1038/ng.109. View

18.

Benowitz N, Swan G, Jacob 3rd P, Lessov-Schlaggar C, Tyndale R . CYP2A6 genotype and the metabolism and disposition kinetics of nicotine. Clin Pharmacol Ther. 2006; 80(5):457-67. DOI: 10.1016/j.clpt.2006.08.011. View

19.

Shiffman S . Light and intermittent smokers: background and perspective. Nicotine Tob Res. 2009; 11(2):122-5. PMC: 2658906. DOI: 10.1093/ntr/ntn020. View

20.

. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet. 2010; 42(5):441-7. PMC: 2914600. DOI: 10.1038/ng.571. View