Effects of a Functional Variant c.353T>C in Snai1 leon Risk of Two Contextual Diseases
Effects of a Functional Variant c.353T>C in Snai1 leon Risk of Two Contextual Diseases
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DOI：
10.1164/rccm.201307-1355oc
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发表时间：
2014-01-15
影响因子：
24.7
通讯作者：
Lu, Jiachun
中科院分区：
文献类型：
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作者：
Yang, Lei;Yang, Xiaorong;Lu, Jiachun
基本原理：上皮间质转化（Epithelial-mesenchymal transition，EMT）在慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）和肺癌的发生发展中起着重要作用。我们假设这些基因中的生殖系变异可能影响这两种疾病的发展。方法：在两个两阶段的病例对照研究中，对2，072例肺癌患者和2，077名对照受试者以及1，791例COPD患者和1，940名对照受试者进行了7种基因变异的基因分型，以显示它们与这两种疾病的发展的相关性。外显子变体c.353T>C（p.Val118Ala）的Snai 1具有降低肺癌风险的作用（CT/CC vs. TT：比值比[OR]，0.76; 95%置信区间[CI]，0.65-0.90）和COPD（CC vs. CT vs. TT：OR，0.75; 95% CI，0.63-0.89），c.353T>C通过COPD间接影响肺癌风险（COPD占该变体对肺癌影响的6.78%）。此外，c.353T>C与吸烟患者的肺癌分期相关（P= 0.013），并且具有c.353C基因型的患者在诊断时发生转移的可能性低于具有c.353TT基因型的患者（OR，0.60; 95%CI，0.41-0.88）。编码p.118Ala的c.353C等位基因减弱了Snai 1上调间充质生物标志物的能力（即，纤连蛋白和波形蛋白）表达，并促进EMT样变化，包括形态学变化、细胞迁移和侵袭。然而，这些影响并没有观察到其他variants.Conclusions：Snai 1的功能性种系变异c.353T.C（p.Val118Ala）赋予一贯降低肺癌和COPD的风险，这种变异影响肺癌的风险，通过COPD的调解作用。
Rationale: Epithelial-mesenchymal transition (EMT) plays a key role in the development of chronic obstructive pulmonary disease (COPD) and lung cancer.Objectives: 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.Measurements and Main 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.