Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
권호 표지

Cigarette Smoking and Polymorphism of the Paraoxonase 1 Gene as Risk factors for Lung Cancer

폐암발생의 위험인자로서 흡연과 Paraoxonase 1 유전자 다형성

  • Lee, Chul-Ho (Department of Preventive Medicine, College of Medicine, Chungbuk National University) ;
  • Lee, Kye Young (Department of Internal Medicine, Dankook University College of Medicine) ;
  • Hong, Yun-Chul (Department of Preventive Medicine, Seoul National University College of Medicine) ;
  • Choe, Kang-Hyeon (Department of Internal Medicine, Chungbuk National University Hospital) ;
  • Kim, Yong-Dae (Department of Preventive Medicine, College of Medicine, Chungbuk National University) ;
  • Kang, Jong-Won (Department of Preventive Medicine, College of Medicine, Chungbuk National University) ;
  • Kim, Heon (Department of Preventive Medicine, College of Medicine, Chungbuk National University) ;
  • Hong, Jang Soo (Department of Internal Medicine, Chungbuk National University Hospital)
  • 이철호 (충북대학교 의과대학 예방의학교실) ;
  • 이계영 (단국대학교 의과대학 내과학교실) ;
  • 홍윤철 (서울대학교 의과대학 예방의학교실) ;
  • 최강현 (충북대학교 의과대학 내과학교실) ;
  • 김용대 (충북대학교 의과대학 예방의학교실) ;
  • 강종원 (충북대학교 의과대학 예방의학교실) ;
  • 김헌 (충북대학교 의과대학 예방의학교실) ;
  • 홍장수 (충북대학교 의과대학 내과학교실)
  • Received : 2004.10.27
  • Accepted : 2005.04.22
  • Published : 2005.05.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background : The paraoxonase enzyme plays a significant role in the detoxification of various organophosphorous compounds in mammals, and paraoxonase (PON) 1 is one of the endogenous free-radical scavenging systems in the human body. In this study, we investigated the interaction between cigarette smoking and the genetic polymorphism of PON1 with lung cancer in Korean males. Methods : Three hundred thirty five patients with lung cancer and an equal number of age-matched controls were enrolled in this study. Every subject was asked to complete a questionnaire concerning their smoking habits and alcohol drinking habits. A 5' exonuclease assay (TaqMan) was used to genotype the PON1 Q192R polymorphism. The effects of smoking habits and drinking habits, the PON1 Q192R polymorphism and their interactions were statistically analyzed. Results : Cigarette smoking and the Q/Q genotype of PON1 were significant risk factors for lung cancer. Individuals carrying the Q/Q genotype of PON1 were at a higher risk for lung cancer as compared with those individuals carrying the Q/R or R/R genotype (odds ratio, 2.84; 95% confidence interval, 1.69 - 4.79). When the groups were further stratified by the smoking status, the Q/Q PON1 was associated with lung cancer among the current or ex-smokers (odds ratio, 2.56; 95% confidence interval, 1.52 - 4.31). Current smokers or ex-smokers who had the Q/Q genotype showed an elevated risk for lung cancer (odds ratio: 15.50, 95% confidence interval: 6.76 - 35.54) as compared with the group of subjects who never smoked, and had the Q/R or R/R genotype. The odds ratios (95% confidence interval) of smokers with the PON1 Q/Q type compared to the nonsmokers with the PON1 Q/R or R/R type were 53.77 (6.55 - 441.14) for squamous cell carcinoma, 6.25 (1.38 - 28.32) for adenocarcinoma, and 59.94 (4.66 - 770.39) for small cell carcinoma, and these results were statistically significant. Conclusion : These results suggest that cigarette smoking and the PON1 Q/Q genotype are risk factors for lung cancer. The combination of cigarette smoking and the PON1 Q/Q genotype significantly increased the lung cancer risk irrespective of the histologic type of cancer.

연구배경 : Paraoxonase는 산소유리기 제거효소의 하나로서, 유기인제 화합물의 독소제거에 있어서 중요한 역할을 한다. 본 연구에서는 한국인 남성에서 PON1 Q192R 유전자 다형성이 흡연과 관련하여 폐암발생에 미치는 영향을 조사하였다. 대상 및 방법 : 연구대상자는 조직 병리학적으로 폐암으로 새롭게 진단받은 남성 환자 335명과, 이들과 3세 이내에서 연령을 짝지은 동수의 대조군으로 하였다. 직접면접조사를 통하여 인적사항과 직업력 그리고 흡연력, 음주력 등을 조사하였다. TaqMan 실시간 중합 효소 연쇄반응을 이용하여 PON1 유전자 다형성을 확인하고, 폐암과 흡연 그리고 PON1 유전자 다형성 유형 사이의 상호 관련성을 통계적으로 분석하였다. 결 과 : 흡연과 PON1 유전자 Q/Q형이 폐암 발생 위험도를 유의하게 증가시켰다. 흡연자에서 PON1 Q/Q형인 사람이 Q/R 혹은 R/R형인 사람에 비하여 폐암에 대한 교차비(95% 신뢰구간)가 2.56(1.52 - 4.31)으로 폐암발생 위험도가 통계적으로 유의하게 증가하였다. 비흡연자이며 PON1 Q/R 혹은 R/R형인 사람을 비교군으로 하였을 때, 비흡연자이며 PON1 Q/Q형인 군, 흡연자이며 Q/R 혹은 R/R형인 군, 흡연자이며 Q/Q형군으로 이행할수록 대응비는 모든 세포유형에서 유의하게 증가하였다. 특히 흡연자이며 Q/Q형인 사람은 비흡연자이며 PON1 Q/R 혹은 R/R형인 사람에 비하여, 편평세포암종은 53.77(6.55 - 441.14)배, 선암종은 6.25(1.38 - 28.32)배, 소세포암종은 59.94(4.66 - 770.39) 배 더 잘 생기는 것으로 나타났다. 결 론 : 흡연과 PON1 Q/Q형은 폐암의 위험인자이며, 흡연과 PON1 Q/Q형은 조직학적 유형에 관계없이 폐암발생 위험도를 서로 상승적으로 증가시키는 것으로 판단된다.

Keywords

References

  1. Central Cancer Registry Center in Korea. Annual report of the central cancer registry in Korea. Seoul: Ministry of Health and Welfare; 2003
  2. Cohen AJ. Outdoor air pollution and lung cancer. Environ Health Perspect 2000;108:743-50 https://doi.org/10.1289/ehp.00108s4743
  3. Kim YD, Lee CH, Nan HM, Kang JW, Kim H. Effects of genetic polymorphisms in metabolic enzymes on the relationships between 8-hydroxydeoxyguanosine levels in human leukocytes and urinary 1-hydroxy-pyrene and 2-naphthol concentrations. J Occup Health 2003;45:160-7 https://doi.org/10.1539/joh.45.160
  4. Caporaso N. Selection of candidate genes for population studies. IARC Sci Publ 1999;148:23-36
  5. Wild CP, Law GR, Roman E. Molecular epidemiology and cancer: promising areas for future research in the post-genomic era. Mutat Res 2002;499:3-12 https://doi.org/10.1016/S0027-5107(01)00290-1
  6. Li WF, Furlong CE, Costa LG. Paraoxonase protects against chlorpyrifos toxicity in mice. Toxicol Lett 1995;76:219-26 https://doi.org/10.1016/0378-4274(95)80006-Y
  7. Pond AL, Chambers HW, Chambers JE. Organopho-sphate detoxication potential of various rat tissues via A-esterase and aliesterase activities. Toxicol Lett 1995;78:245-52 https://doi.org/10.1016/0378-4274(95)03327-H
  8. Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN. The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics 1996;33:498-507 https://doi.org/10.1006/geno.1996.0225
  9. Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE. The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet 1993;3:73-6 https://doi.org/10.1038/ng0193-73
  10. Hong SH, Song J, Min WK, Kim JQ. Genetic variations of the paraoxonase gene in patients with coronary artery disease. Clin Biochem 2001;34:475-81 https://doi.org/10.1016/S0009-9120(01)00257-0
  11. Rodrigo L, Hernandez AF, Lopez-Caballero JJ, Gil F, Pla A. Immunohistochemical evidence for the expression and induction of paraoxonase in rat liver, kidney, lung and brain tissue. Implications for its physiological role. Chem Biol Interact 2001;137:123-37 https://doi.org/10.1016/S0009-2797(01)00225-3
  12. Mango GW, Johnston CJ, Reynolds SD, Finkelstein JN, Plopper CG, Stripp BR. Clara cell secretory protein deficiency increases oxidant stress response in conducting airways. Am J Physiol 1998;275:L348-56
  13. Romanova LK, Goriachkina VL. Cytophysiology of lung bronchiolar secretory cells: source of inflammation 'antimediators'. Arkh Patol 1999;61:20-7
  14. La Du BN, Aviram M, Billecke S, Navab M, Primo-Parmo S, Sorenson RC, et al. On the physiological role(s) of the paraoxonases. Chem Biol Interact 1999;119-120:379-88 https://doi.org/10.1016/S0009-2797(99)00020-4
  15. Davies HG, Richter RJ, Keifer M, Broomfield CA, Sowalla J, Furlong CE. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet 1996;14:334-6 https://doi.org/10.1038/ng1196-334
  16. Marchesani M, Hakkarainen A, Tuomainen TP, Kaikkonen J, Pukkala E, Uimari P, et al. New paraoxonase 1 polymorphism I102V and the risk of prostate cancer in Finnish men. J Natl Cancer Inst 2003;95:812-8 https://doi.org/10.1093/jnci/95.11.812
  17. Furlong CE, Li WF, Richter RJ, Shih DM, Lusis AJ, Alleva E, et al. Genetic and temporal determinants of pesticide sensitivity: role of paraoxonase (PON1). Neurotoxicol 2000;21:91-100
  18. Kondo I, Yamamoto M. Genetic polymorphism of paraoxonase 1 (PON1) and susceptibility to Parkinson's disease. Brain Res 1998;806:271-3 https://doi.org/10.1016/S0006-8993(98)00586-1
  19. Aynacioglu AS, Cascorbi I, Mrozikiewicz PM, Nacak M, Tapanyigit EE, Roots I. Paraoxonase 1 mutations in a Turkish population. Toxicol Appl Pharmacol 1999;157:174-7 https://doi.org/10.1006/taap.1999.8690
  20. American Cancer Society. Tobacco use. In: American Cancer Society, editors. Cancer facts & figures 2001. Atlanta, GA: American Cancer Society; 2001. p. 29-32
  21. World Health Organization. Tobacco or health: a global status report. Geneva: World Health Organization; 1997. p. 10-48
  22. Potter JD, McMichael AJ. Alcohol, beer and lung cancer: a meaningful relationship? Int J Epidemiol 1984;13:240-2 https://doi.org/10.1093/ije/13.2.240
  23. Bartsch H, Rojas M, Alexandrov K, Camus AM, Castegnaro M, Malaveille C, et al. Metabolic polymorphism affecting DNA binding and excretion of carcinogens in humans. Pharmacogenetics 1995;5:S84-90 https://doi.org/10.1097/00008571-199512001-00007
  24. Tward A, Xia YR, Wang XP, Shi YS, Park C, Castellani LW, et al. Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation 2002;106:484-90 https://doi.org/10.1161/01.CIR.0000023623.87083.4F
  25. Senti M, Tomas M, Anglada R, Elosua R, Marrugat J, Covas MI, et al. Interrelationship of smoking, paraoxonase activity, and leisure time physical activity:a population-based study. Eur J Intern Med 2003;14:178-84 https://doi.org/10.1016/S0953-6205(03)00041-4