Functional polymorphisms of CHRNA3 predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese

PLoS One. 2012;7(10):e46071. doi: 10.1371/journal.pone.0046071. Epub 2012 Oct 3.

Abstract

Recently, several genome-wide association studies (GWAS) have identified many susceptible single nucleotide polymorphisms (SNPs) for chronic obstructive pulmonary disease (COPD) and lung cancer which are two closely related diseases. Among those SNPs, some of them are shared by both the diseases, reflecting there is possible genetic similarity between the diseases. Here we tested the hypothesis that whether those shared SNPs are common predictor for risks or prognosis of COPD and lung cancer. Two SNPs (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor alpha 3 (CHRNA3) gene were genotyped in 1511 patients with COPD, 1559 lung cancer cases and 1677 controls in southern and eastern Chinese populations. We found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR = 1.32, 95% C.I. = 1.14-1.54) and lung cancer (OR = 1.57; 95% CI = 1.31-1.87), respectively. The rs6495309CC genotype contributed to more rapid decline of annual Forced expiratory volume in one second (FEV1) in both COPD cases and controls (P<0.05), and it was associated with advanced stages of COPD (P = 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer (HR = 1.41, 95%CI = 1.13-1.75). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G>A. The data show a statistical association and suggest biological plausibility that the rs6495309T>C polymorphism contributed to increased risks and poor prognosis of both COPD and lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Asian People / genetics
  • Case-Control Studies
  • China
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Genotype
  • Haplotypes
  • Humans
  • Kaplan-Meier Estimate
  • Linear Models
  • Lung Neoplasms / ethnology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / physiopathology
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Pulmonary Disease, Chronic Obstructive / ethnology
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Receptors, Nicotinic / genetics*
  • Respiratory Function Tests
  • Risk Factors

Substances

  • Receptors, Nicotinic
  • nicotinic receptor subunit alpha3

Grants and funding

This study was supported by the National Natural Scientific Foundation of China grants 30671813, 30872178, 81072366 (JCL), and partly by 81170043 (PXR), 81001278 (Y. Zhou), 30872142 (WDJ); Guangdong Provincial High Level Experts Grants 2010–79 (JCL); Changjiang Scholars and Innovative Research Team in University grant IRT0961 and Guangdong natural science foundation team grant 10351012003000000 (NSZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.