Functional Polymorphisms of <em>CHRNA3</em> Predict Risks of Chronic Obstructive Pulmonary Disease and Lung Cancer in Chinese

<div><p>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 (<em>CHRNA3)</em> 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 (<em>P</em><0.05), and it was associated with advanced stages of COPD (<em>P</em> = 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.</p> </div

Analysis of <i>CHRNA3</i> rs6495309T>C and lung cancer survival.

<p>Abbreviations: MST, median survival time; HR, hazard ratio;</p>a<p>Cox regression analysis was adjusted for age, sex, smoking status, histology, stage, surgery, chemotherapy, and radiotherapy status.</p

Interaction analysis between the rs6495309T>C polymorphism and smoking status on COPD or lung cancer risk.

<p>The smoker avoiders with rs6495309TT genotype are defined as reference. The rs6495309C variant genotype(s) interacted with smoking on risks of both diseases but only interacted with passive smoking on lung cancer risk.</p

Prognosis analysis by the rs6495309T>C genotypes.

<p><b>A,</b> The annual average decline of pre-bronchodilator FEV1 by rs6495309T>C genotypes in COPD patients. <b>B,</b> The annual average decline of pre-bronchodilator FEV1 by rs6495309T>C genotypes in healthy controls. <b>C,</b> Kaplan-Meier survival curve for lung cancer patients by rs6495309T>C genotypes in the Discovery set. <b>D,</b> Kaplan-Meier survival curve for lung cancer patients by rs6495309T>C genotypes in the validation set. The rs6495309CC variant genotype was associated with more rapid decline of pre-bronchodilator FEV1 in both COPD cases and controls, and the rs6495309C genotypes conferred a poor survival for lung cancer.</p

Luciferase expressions in different cell lines under the treatment of tobacco components.

<p><b>A,</b> 16HBE. <b>B,</b> A549. <b>C,</b> NCI-520. Columns, mean from three independent experiments; bars, SD; and the difference of luciferase activity between C/T allele and the luciferase activity levels by chemical treatment (luciferase activity with chemical treatment – luciferase activity without treatment) were analyzed by Student’s <i>t</i> test Tobacco extract, nicotine and NNK could induce a significantly higher increased luciferase activity driven by the rs6495309C allele than that driven by the T allele.</p