J Korean Med Sci.  2012 Dec;27(12):1536-1540. 10.3346/jkms.2012.27.12.1536.

A Functional Polymorphism in the CHRNA3 Gene and Risk of Chronic Obstructive Pulmonary Disease in a Korean Population

Affiliations
  • 1Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea. jaeyong@knu.ac.kr
  • 2Department of Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Korea.
  • 3Cancer Research Center, Yanbian University School of Basic Science, Yanji, Jilin, China.

Abstract

A genome-wide association study has identified the 15q25 region as being associated with the risk of chronic obstructive pulmonary disease (COPD) in Caucasians. This study intended as a confirmatory assessment of this association in a Korean population. The rs6495309C > T polymorphism in the promoter of nicotinic acetylcholine receptor alpha subunit 3 (CHRNA3) gene was investigated in a case-control study that consisted of 406 patients with COPD and 394 healthy control subjects. The rs6495309 CT or TT genotype was associated with a significantly decreased risk of COPD when compared to the rs6495309 CC genotype (adjusted odds ratio = 0.69, 95% confidence interval = 0.50-0.95, P = 0.023). The effect of the rs6495309C > T on the risk of COPD was more evident in moderate to very severe COPD than in mild COPD under a dominant model for the variant T allele (P = 0.024 for homogeneity). The CHRNA3 rs6495309C > T polymorphism on chromosome 15q25 is associated with the risk of COPD in a Korean population.

Keyword

CHRNA3; Pulmonary Disease, Chronic Obstructive; Polymorphism

MeSH Terms

Adult
Aged
Alleles
Asian Continental Ancestry Group/*genetics
Case-Control Studies
Female
Forced Expiratory Volume
Genotype
Humans
Male
Middle Aged
Odds Ratio
*Polymorphism, Single Nucleotide
Pulmonary Disease, Chronic Obstructive/*genetics/physiopathology
Receptors, Nicotinic/*genetics
Republic of Korea
Risk Factors
Smoking
Receptors, Nicotinic

Figure

  • Fig. 1 Reconstructed linkage disequilibrium (LD) plot using potentially functional single nucleotide polymorphisms with minor allele frequency ≥ 5% from HapMap JPT data in the CHRNA5/CHRNA3 locus. The black boxes indicate strong LD (confidence interval for strong LD: upper 0.98, low 0.7; fraction of strong LD in informative comparisons must be at least 0.95). The white boxes indicate strong recombination (upper confidence interval maximum 0.9). The triangles indicate haplotype blocks. The numbers in the squares are |D'| (× 100) values. Vertical bold arrow indicates the CHRNA3 rs6495309 location.


Reference

1. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007. 176:532–555.
2. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet. 2007. 370:765–773.
3. Groneberg DA, Chung KF. Models of chronic obstructive pulmonary disease. Respir Res. 2004. 5:18.
4. Løkke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: a 25 year follow up study of the general population. Thorax. 2006. 61:935–939.
5. Sampsonas F, Karkoulias K, Kaparianos A, Spiropoulos K. Genetics of chronic obstructive pulmonary disease, beyond α1-antitrypsin deficiency. Curr Med Chem. 2006. 13:2857–2873.
6. Cha SI, Kang HG, Choi JE, Kim MJ, Park J, Lee WK, Kim CH, Jung TH, Park JY. SERPINE2 polymorphisms and chronic obstructive pulmonary disease. J Korean Med Sci. 2009. 24:1119–1125.
7. Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC, Feng S, Hersh CP, Bakke P, Gulsvik A, et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet. 2009. 5:e1000421.
8. Ioannidis JP, Thomas G, Daly MJ. Validating, augmenting and refining genome-wide association signals. Nat Rev Genet. 2009. 10:318–329.
9. Frazer KA, Murray SS, Schork NJ, Topol EJ. Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009. 10:241–251.
10. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, et al. Finding the missing heritability of complex disease. Nature. 2009. 461:747–753.
11. Hirschhorn JN. Genomewide association studies: illuminating biologic pathways. N Engl J Med. 2009. 360:1699–1701.
12. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008. 40:616–622.
13. Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008. 452:633–637.
14. Pillai SG, Kong X, Edwards LD, Cho MH, Anderson WH, Coxson HO, Lomas DA, Silverman EK. ECLIPSE and ICGN Investigators. Loci identified by genome-wide association studies influence different disease-related phenotypes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010. 182:1498–1505.
15. Wu C, Hu Z, Yu D, Huang L, Jin G, Liang J, Guo H, Tan W, Zhang M, Qian J, et al. Genetic variants on chromosome 15q25 associated with lung cancer risk in Chinese populations. Cancer Res. 2009. 69:5065–5072.
16. Caulfield MP, Birdsall NJ. International Union of Pharmacology, XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998. 50:279–290.
17. Canning BJ. Reflex regulation of airway smooth muscle tone. J Appl Physiol. 2006. 101:971–985.
18. Rogers DF. Motor control of airway goblet cells and glands. Respir Physiol. 2001. 125:129–144.
19. Gwilt CR, Donnelly LE, Rogers DF. The non-neuronal cholinergic system in the airways: an unappreciated regulatory role in pulmonary inflammation? Pharmacol Ther. 2007. 115:208–222.
20. Carlisle DL, Hopkins TM, Gaither-Davis A, Silhanek MJ, Luketich JD, Christie NA, Siegfried JM. Nicotine signals through muscle-type and neuronal nicotinic acetylcholine receptors in both human bronchial epithelial cells and airway fibroblasts. Respir Res. 2004. 5:27.
21. Wessler I, Kirkpatrick CJ, Racké K. Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: expression and function in humans. Pharmacol Ther. 1998. 77:59–79.
22. Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau O, et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet. 2007. 16:36–49.
23. Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X, Saccone NL, Saccone SF, Bertelsen S, Fox L, et al. Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry. 2008. 165:1163–1171.
24. Li MD, Xu Q, Lou XY, Payne TJ, Niu T, Ma JZ. Association and interaction analysis of variants in CHRNA5/CHRNA3/CHRNB4 gene cluster with nicotine dependence in African and European Americans. Am J Med Genet B Neuropsychiatr Genet. 2010. 153B:745–756.
25. Jin G, Bae EY, Yang E, Lee EB, Lee WK, Choi JE, Jeon HS, Yoo SS, Lee SY, Lee J, et al. A functional polymorphism on chromosome 15q25 associated with survival of early stage non-small cell lung cancer. J Thorac Oncol. 2012. 7:808–814.
Full Text Links
  • JKMS
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr