Tuberculosis and Respiratory Diseases

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

Polymorphisms in the SERPINA1 Gene and the Risk of Chronic Obstructive Pulmonary Disease in a Korean Population

한국인에서 SERPINA1 유전자 다형성과 만성폐쇄성폐질환의 위험도

  • Cha, Seung-Ick (Department of Internal Medicine, School of Medicine, Kyungpook National University) ;
  • Choi, Jin Eun (Department of Biochemistry, School of Medicine, Kyungpook National University) ;
  • Lee, Jong Myung (Department of Internal Medicine, School of Medicine, Kyungpook National University) ;
  • Yoo, Seung Soo (Department of Internal Medicine, School of Medicine, Kyungpook National University) ;
  • Kim, Chang-Ho (Department of Internal Medicine, School of Medicine, Kyungpook National University) ;
  • Lee, Won Kee (Department of Preventive Medicine, School of Medicine, Kyungpook National University) ;
  • Jung, Tae-Hoon (Department of Internal Medicine, School of Medicine, Kyungpook National University) ;
  • Kim, Nung Soo (Department of Internal Medicine, School of Medicine, Kyungpook National University) ;
  • Park, Jae Yong (Department of Internal Medicine, School of Medicine, Kyungpook National University)
  • 차승익 (경북대학교 의학전문대학원 내과학교실) ;
  • 최진은 (경북대학교 의학전문대학원 생화학교실) ;
  • 이종명 (경북대학교 의학전문대학원 내과학교실) ;
  • 유승수 (경북대학교 의학전문대학원 내과학교실) ;
  • 김창호 (경북대학교 의학전문대학원 내과학교실) ;
  • 이원기 (경북대학교 의학전문대학원 예방의학교실) ;
  • 정태훈 (경북대학교 의학전문대학원 내과학교실) ;
  • 김능수 (경북대학교 의학전문대학원 내과학교실) ;
  • 박재용 (경북대학교 의학전문대학원 내과학교실)
  • Received : 2008.08.07
  • Accepted : 2008.08.22
  • Published : 2008.10.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background: We conducted a case-control study to evaluate the potential association between SERPINA1 genotypes ($M1_{Val}$, $M1_{Ala}$, S, and Z) and the risk COPD. Methods: The study population consisted of 93 patients with COPD and 112 healthy controls. The polymerase chain reaction and restriction fragment length polymorphism for detecting the SERPINA1 variants. Results: The M2 allele of the SERPINA1 gene was significantly associated with the risk of COPD in Koreans. The effect of the M2 allele on the risk of COPD was more pronounced in the subgroup<64 years. Conclusion: These results suggest that SERPINA1 polymorphisms may contribute to a genetic predisposition for COPD. However, additional studies with larger sample sizes are required to confirm our findings.

연구배경: 만성폐쇄성폐질환의 대부분은 흡연과 연관되어 발생하지만 흡연자의 약 10~20%에서만 만성폐쇄성폐 질환이 발생하는 현상은 질환의 발생에 개체의 유전적인 소인이 관여함을 시사한다. 저자들은 ${\alpha}1-antitrypsin$ 단백질을 암호화하는 SERPINA1 유전자의 다형성에 따른 만성폐쇄성폐질환의 위험도를 조사하였다. 방 법: 경북대학교병원 호흡기내과에서 만성폐쇄성폐질환으로 진단 받은 93명의 환자와 112명의 정상인을 대상으로 하였다. SERPINA1 유전자의 $M1_{val}$, $M1_{Ala}$, M2, S와 Z 대립유전자(allele)는 중합효소연쇄반응과 restriction fragment length polymorphism을 이용하여 조사하였다. 결 과: 환자군과 대조군 모두에서 S 및 Z allele은 없었으며, $M1_{Val}$ allele의 빈도는 환자군에서 유의하게 낮았다(73.6% vs. 82.7%, p=0.03). $M1_{Val}/M1_{Val}$ 유전자형인 경우에 비해 M2 혹은 $M1_{Ala}$ allele을 갖는 유전자형인 경우 만성 폐쇄성폐질환의 대응비는 1.86 (95% CI: 1.02~3.41, p=0.04)으로 유의하게 높았다. M2 allele 갖는 유전자형인 경우 대응비는 1.77 (95% CI: 0.96~3.27, p=0.07)이었으며, 연령에 따라 구분한 경우 64세 미만에서는 M2 allele을 갖는 경우 대응비가 3.09 (95% CI: 1.16~8.21, p=0.02)로 유의하게 높았다. 결 론: SERPINA1 유전자의 유전자형은 만성폐쇄성폐질환의 위험도를 결정하는 인자로 생각되나, 보다 많은 예를 대상으로 한 연구가 필요할 것으로 생각된다.

Keywords

References

  1. Sethi JM, Rochester CL. Smoking and chronic obstructive pulmonary disease. Clin Chest Med 2000;21:67-86. https://doi.org/10.1016/S0272-5231(05)70008-3
  2. Barnes PJ. Genetics and pulmonary medicine. 9. Molecular genetics of chronic obstructive pulmonary disease. Thorax 1999;54:245-52. https://doi.org/10.1136/thx.54.3.245
  3. Silverman EK, Chapman HA, Drazen JM, Weiss ST, Rosner B, Campbell EJ, et al. Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease: risk to relatives for airflow obstruction and chronic bronchitis. Am J Respir Crit Care Med 1998;157:1770-8. https://doi.org/10.1164/ajrccm.157.6.9706014
  4. Sandford AJ, Pare PD. Genetic risk factors for chronic obstructive pulmonary disease. Clin Chest Med 2000;21: 633-43. https://doi.org/10.1016/S0272-5231(05)70173-8
  5. Hersh CP, Demeo DL, Silverman EK. Chapter 10. Chronic obstructive pulmonary disease. In: Silverman EK, Shapiro SD, Lomas DA, Weiss ST, editors. Respiratory genetics. 1st ed. London: Edward Arnold Publishers; 2005. p. 253-96.
  6. Travis J, Salvesen GS. Human plasma proteinase inhibitors. Annu Rev Biochem 1983;52:655-709. https://doi.org/10.1146/annurev.bi.52.070183.003255
  7. Brantly ML, Paul LD, Miller BH, Falk RT, Wu M, Crystal RG. Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis 1988;138:327-36. https://doi.org/10.1164/ajrccm/138.2.327
  8. Crystal RG. ${\alpha}$1-antitrypsin deficiency, emphysema and liver disease: genetic basis and strategies for therapy. J Clin Invest 1990;85:1343-52. https://doi.org/10.1172/JCI114578
  9. Fagerhol MK, Laurell CB. The Pi system-inherited variants of serum alpha 1-antitrypsin. Prog Med Genet 1970;7:96-111.
  10. Mittman C, Barbela T, Lieberman J. Alpha 1-antitrypsin deficiency as an indicator of susceptibility to pulmonary disease. J Occup Med 1973;15:33-8.
  11. ${\alpha}$1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ 1997;75:397-415.
  12. Crystal RG, Brantly ML, Hubbard RC, Curiel DT, States DJ, Holmes MD. The ${\alpha}$1-antitrypsin gene and its mutations: clinical consequences and strategies for therapy. Chest 1989;95:196-208. https://doi.org/10.1378/chest.95.1.196
  13. Gaillard MC, Kilroe-Smith TA, Nogueira C, Dunn D, Jenkins T, Fine B, et al. Alpha-1-protease inhibitor in bronchial asthma: phenotypes and biochemical characteristics. Am Rev Respir Dis 1992;145:1311-5. https://doi.org/10.1164/ajrccm/145.6.1311
  14. Gaillard MC, Zwi S, Nogueira CM, Ludewick H, Feldman C, Frankel A, et al. Ethnic differences in the occurrence of the M1(ala213) haplotype of alpha-1-antitrypsin in asthmatic and non-asthmatic black and white South Africans. Clin Genet 1994;45:122-7. https://doi.org/10.1111/j.1399-0004.1994.tb04008.x
  15. Rieger S, Riemer H, Mannhalter C. Multiplex PCR assay for the detection of genetic variants of ${\alpha}$1-antitrypsin. Clin Chem 1999;45:688-90.
  16. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256-76. https://doi.org/10.1164/ajrccm.163.5.2101039
  17. Lucotte G, Sesboue R. Polymerase chain reaction detection of S and Z alpha-1-antitrypsin variants by duplex PCR assay. Mol Cell Probes 1999;13:389-91. https://doi.org/10.1006/mcpr.1999.0264
  18. Park JY, Choi JE, Cha SI, Bae NC, Chae PH, Lee JY, et al. Prevalence of ${\alpha}$1-antitrypsin genotypes in Koreans. Tuber Respir Dis 2001;50:229-35. https://doi.org/10.4046/trd.2001.50.2.229
  19. Silverman EK, Speizer FE. Risk factors for the development of chronic obstructive pulmonary disease. Med Clin North Am 1996;80:501-22. https://doi.org/10.1016/S0025-7125(05)70451-X
  20. Silverman EK, Palmer LJ, Mosley JD, Barth M, Senter JM, Brown A, et al. Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease. Am J Hum Genet 2002;70:1229-39. https://doi.org/10.1086/340316
  21. Vineis P. Molecular epidemiology: low-dose carcinogens and genetic susceptibility. Int J Cancer 1997;71:1-3.
  22. Nakachi K, Imai K, Hayashi S, Watanabe J, Kawajiri K. Genetic susceptibility to squamous cell carcinoma of the lung in relation to cigarette smoking dose. Cancer Res 1991;51:5177-80.
  23. Xu LL, Wain JC, Miller DP, Thurston SW, Su L, Lynch TJ, et al. The NAD(P)H:quinone oxidoreductase 1 gene polymorphism and lung cancer: differential susceptibility based on smoking behavior. Cancer Epidemiol Biomarkers Prev 2001;10:303-9.
  24. Billingsley GD, Walter MA, Hammond GL, Cox DW. Physical mapping of four serpin genes: alpha 1-antitrypsin, alpha 1-antichymotrypsin, corticosteroid-binding globulin, and protein C inhibitor, within a 280-kb region on chromosome 14q32.1. Am J Hum Genet 1993;52:343-53.
  25. Rollini P, Fournier RE. A 370-kb cosmid contig of the serpin gene cluster on human chromosome 14q32.1: molecular linkage of the genes encoding alpha 1-antichymotrypsin, protein C inhibitor, kallistatin, alpha 1-antitrypsin, and corticosteroid-binding globulin. Genomics 1997;46:409-15. https://doi.org/10.1006/geno.1997.5077
  26. Lieberman J, Winter B, Sastre A. Alpha 1-antitrypsin Pi-types in 965 COPD patients. Chest 1986;89:370-3. https://doi.org/10.1378/chest.89.3.370