• Lei Yang, Xiaorong Yang, Weidong Ji, Jieqiong Deng, Fuman Qiu, Rongrong Yang, Wenxiang Fang, Lisha Zhang, Dongsheng Huang, Chenli Xie, Haibo Zhang, Nanshan Zhong, Pixin Ran, Yifeng Zhou, and Jiachun Lu.
• 1 The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Guangzhou Institute of Respiratory Diseases, and.
• Am. J. Respir. Crit. Care Med. 2014 Jan 15; 189 (2): 139148139-48.

RationaleEpithelial-mesenchymal transition (EMT) plays a key role in the development of chronic obstructive pulmonary disease (COPD) and lung cancer.ObjectivesThere are five major EMT regulatory genes (Snai1, Slug, Zeb1, Zeb2, and Twist1) involved in EMT. We hypothesized that germline variants in these genes may influence the development of both diseases.MethodsSeven genetic variants were genotyped in two two-stage case-control studies with 2,072 lung cancer cases and 2,077 control subjects, and 1,791 patients with COPD and 1,940 control subjects to show their associations with development of both diseases.Measurements And Main ResultsAn exon variant c.353T>C(p.Val118Ala) of Snai1 harbored decreased risks of lung cancer (CT/CC vs. TT: odds ratio [OR], 0.76; 95% confidence interval [CI], 0.65-0.90) and COPD (CC vs. CT vs. TT: OR, 0.75; 95% CI, 0.63-0.89), and c.353T>C affected lung cancer risk indirectly through COPD (COPD accounted for 6.78% of effect that the variant had on lung cancer). Moreover, c.353T>C was correlated with lung cancer stages in smoking patients (P = 0.013), and those with the c.353C genotypes were less likely to have metastasis at diagnosis than those with the c.353TT genotype (OR, 0.60; 95% CI, 0.41-0.88). The c.353C allele encoding p.118Ala attenuated Snai1's ability to up-regulate mesenchymal biomarkers (i.e., fibronectin and vimentin) expression, and to promote EMT-like changes, including morphologic changes, cell migration, and invasion. However, these effects were not observed for the other variants.ConclusionsThe functional germline variant c.353T>C (p.Val118Ala) of Snai1 confers consistently decreased risks of lung cancer and COPD, and this variant affects lung cancer risk through a mediation effect of COPD.

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