title: Effects of a functional variant c.353T>C in snai1 on risk of two contextual diseases. Chronic obstructive pulmonary disease and lung cancer.
abstract: BACKGROUND
  Epithelial-mesenchymal transition (EMT) plays a key role in the development of chronic obstructive pulmonary disease (COPD) and lung cancer.
  
  
  OBJECTIVE
  There 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.
  
  
  METHODS
  Seven 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.
  
  
  RESULTS
  An 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: 1 The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Guangzhou Institute of Respiratory Diseases, and.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Yang
authors.forename: Weidong
authors.initials: W
authors.lastname: Ji
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Deng
authors.forename: Fuman
authors.initials: F
authors.lastname: Qiu
authors.forename: Rongrong
authors.initials: R
authors.lastname: Yang
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Fang
authors.forename: Lisha
authors.initials: L
authors.lastname: Zhang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Huang
authors.forename: Chenli
authors.initials: C
authors.lastname: Xie
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.forename: Nanshan
authors.initials: N
authors.lastname: Zhong
authors.forename: Pixin
authors.initials: P
authors.lastname: Ran
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jiachun
authors.initials: J
authors.lastname: Lu
mesh_terms: D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002681:China / Q000453:epidemiology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors