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. 2003 Jul;58(7):623–628. doi: 10.1136/thorax.58.7.623

Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema

N Minematsu 1, H Nakamura 1, M Iwata 1, H Tateno 1, T Nakajima 1, S Takahashi 1, S Fujishima 1, K Yamaguchi 1
PMCID: PMC1746722  PMID: 12832682

Abstract

Methods: 203 current or ex-smokers (lifelong cigarette consumption (CC) ≥10 pack years) with subclinical and established COPD phenotypes were clinically evaluated and pulmonary function tests and a chest CT scan were performed (smoker group). The non-smoker group consisted of 123 healthy volunteers. CYP2A6 genotypes were determined in both groups.

Results: The percentage of subjects with a CYP2A6del allele (genotype D) was lower in heavy smokers (20.5%, n=88, CC &ge;60 pack years) than in light smokers (37.4%, n=115, CC 10–59 pack years, χ2=6.8, p=0.01) or non-smokers (36.1%, n=122, χ2=6.0, p=0.01); lower in ex-smokers (20.7%, n=111) than in current smokers (41.3%, n=92, χ2=10.1, p<0.01); and lower in smokers with a high LAA (low attenuation area) score on the chest CT scan (18.4%, n=76, LAA &ge;8.0) than in those with a low LAA score (37.0%, n=127, LAA <8.0, χ2=7.8, p<0.01).

Conclusions: Subjects with the CYP2A6del allele tend not to be heavy habitual smokers but can be light habitual smokers. The CYP2A6del polymorphism may inhibit smokers from giving up smoking, but appears to function as a protective factor against the development of pulmonary emphysema independent of smoking habit.

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Selected References

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  1. Cantlay A. M., Lamb D., Gillooly M., Norrman J., Morrison D., Smith C. A., Harrison D. J. Association between the CYP1A1 gene polymorphism and susceptibility to emphysema and lung cancer. Clin Mol Pathol. 1995 Aug;48(4):M210–M214. doi: 10.1136/mp.48.4.m210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Caraballo R. S., Giovino G. A., Pechacek T. F., Mowery P. D., Richter P. A., Strauss W. J., Sharp D. J., Eriksen M. P., Pirkle J. L., Maurer K. R. Racial and ethnic differences in serum cotinine levels of cigarette smokers: Third National Health and Nutrition Examination Survey, 1988-1991. JAMA. 1998 Jul 8;280(2):135–139. doi: 10.1001/jama.280.2.135. [DOI] [PubMed] [Google Scholar]
  3. Chen G. F., Tang Y. M., Green B., Lin D. X., Guengerich F. P., Daly A. K., Caporaso N. E., Kadlubar F. F. Low frequency of CYP2A6 gene polymorphism as revealed by a one-step polymerase chain reaction method. Pharmacogenetics. 1999 Jun;9(3):327–332. doi: 10.1097/00008571-199906000-00007. [DOI] [PubMed] [Google Scholar]
  4. Clark K. D., Wardrobe-Wong N., Elliott J. J., Gill P. T., Tait N. P., Snashall P. D. Patterns of lung disease in a "normal" smoking population: are emphysema and airflow obstruction found together? Chest. 2001 Sep;120(3):743–747. doi: 10.1378/chest.120.3.743. [DOI] [PubMed] [Google Scholar]
  5. Fernandez-Salguero P., Hoffman S. M., Cholerton S., Mohrenweiser H., Raunio H., Rautio A., Pelkonen O., Huang J. D., Evans W. E., Idle J. R. A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am J Hum Genet. 1995 Sep;57(3):651–660. [PMC free article] [PubMed] [Google Scholar]
  6. Fletcher C., Peto R. The natural history of chronic airflow obstruction. Br Med J. 1977 Jun 25;1(6077):1645–1648. doi: 10.1136/bmj.1.6077.1645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Goddard P. R., Nicholson E. M., Laszlo G., Watt I. Computed tomography in pulmonary emphysema. Clin Radiol. 1982 Jul;33(4):379–387. doi: 10.1016/s0009-9260(82)80301-2. [DOI] [PubMed] [Google Scholar]
  8. Kitagawa K., Kunugita N., Katoh T., Yang M., Kawamoto T. The significance of the homozygous CYP2A6 deletion on nicotine metabolism: a new genotyping method of CYP2A6 using a single PCR-RFLP. Biochem Biophys Res Commun. 1999 Aug 19;262(1):146–151. doi: 10.1006/bbrc.1999.1182. [DOI] [PubMed] [Google Scholar]
  9. Kitagawa K., Kunugita N., Kitagawa M., Kawamoto T. CYP2A6*6, a novel polymorphism in cytochrome p450 2A6, has a single amino acid substitution (R128Q) that inactivates enzymatic activity. J Biol Chem. 2001 Feb 16;276(21):17830–17835. doi: 10.1074/jbc.M009432200. [DOI] [PubMed] [Google Scholar]
  10. Mishima M., Hirai T., Itoh H., Nakano Y., Sakai H., Muro S., Nishimura K., Oku Y., Chin K., Ohi M. Complexity of terminal airspace geometry assessed by lung computed tomography in normal subjects and patients with chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8829–8834. doi: 10.1073/pnas.96.16.8829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Miyamoto M., Umetsu Y., Dosaka-Akita H., Sawamura Y., Yokota J., Kunitoh H., Nemoto N., Sato K., Ariyoshi N., Kamataki T. CYP2A6 gene deletion reduces susceptibility to lung cancer. Biochem Biophys Res Commun. 1999 Aug 11;261(3):658–660. doi: 10.1006/bbrc.1999.1089. [DOI] [PubMed] [Google Scholar]
  12. Nakano Y., Muro S., Sakai H., Hirai T., Chin K., Tsukino M., Nishimura K., Itoh H., Paré P. D., Hogg J. C. Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function. Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):1102–1108. doi: 10.1164/ajrccm.162.3.9907120. [DOI] [PubMed] [Google Scholar]
  13. Nishida S., Kambe M., Sewake N., Takano M., Kawane H. [Pulmonary function in healthy subjects and its prediction. 5. Pulmonary diffusing capacity in adults (author's transl)]. Rinsho Byori. 1976;24(11):941–947. [PubMed] [Google Scholar]
  14. Nunoya K., Yokoi T., Kimura K., Inoue K., Kodama T., Funayama M., Nagashima K., Funae Y., Green C., Kinoshita M. A new deleted allele in the human cytochrome P450 2A6 (CYP2A6) gene found in individuals showing poor metabolic capacity to coumarin and (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502). Pharmacogenetics. 1998 Jun;8(3):239–249. doi: 10.1097/00008571-199806000-00006. [DOI] [PubMed] [Google Scholar]
  15. Oscarson M., McLellan R. A., Gullstén H., Yue Q. Y., Lang M. A., Bernal M. L., Sinues B., Hirvonen A., Raunio H., Pelkonen O. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett. 1999 Apr 1;448(1):105–110. doi: 10.1016/s0014-5793(99)00359-2. [DOI] [PubMed] [Google Scholar]
  16. Pianezza M. L., Sellers E. M., Tyndale R. F. Nicotine metabolism defect reduces smoking. Nature. 1998 Jun 25;393(6687):750–750. doi: 10.1038/31623. [DOI] [PubMed] [Google Scholar]
  17. Rao Y., Hoffmann E., Zia M., Bodin L., Zeman M., Sellers E. M., Tyndale R. F. Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. Mol Pharmacol. 2000 Oct;58(4):747–755. doi: 10.1124/mol.58.4.747. [DOI] [PubMed] [Google Scholar]
  18. Roberts C. M., MacRae K. D., Winning A. J., Adams L., Seed W. A. Reference values and prediction equations for normal lung function in a non-smoking white urban population. Thorax. 1991 Sep;46(9):643–650. doi: 10.1136/thx.46.9.643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Robson A. G., Innes J. A. Short term variability of single breath carbon monoxide transfer factor. Thorax. 2001 May;56(5):358–361. doi: 10.1136/thorax.56.5.358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sellers E. M. Pharmacogenetics and ethnoracial differences in smoking. JAMA. 1998 Jul 8;280(2):179–180. doi: 10.1001/jama.280.2.179. [DOI] [PubMed] [Google Scholar]
  21. Soejima K., Yamaguchi K., Kohda E., Takeshita K., Ito Y., Mastubara H., Oguma T., Inoue T., Okubo Y., Amakawa K. Longitudinal follow-up study of smoking-induced lung density changes by high-resolution computed tomography. Am J Respir Crit Care Med. 2000 Apr;161(4 Pt 1):1264–1273. doi: 10.1164/ajrccm.161.4.9905040. [DOI] [PubMed] [Google Scholar]
  22. Yamano S., Tatsuno J., Gonzalez F. J. The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes. Biochemistry. 1990 Feb 6;29(5):1322–1329. doi: 10.1021/bi00457a031. [DOI] [PubMed] [Google Scholar]

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