Imputation-based association analyses identify new lung cancer susceptibility variants in CDK6 and SH3RF1 and their interactions with smoking in Chinese populations
Imputation-based association analyses identify new lung cancer susceptibility variants in CDK6 and SH3RF1 and their interactions with smoking in Chinese populations
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基于插补的关联分析确定了 CDK6 和 SH3RF1 中新的肺癌易感性变异及其与中国人群吸烟的相互作用
DOI：
10.1093/carcin/bgt145
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发表时间：
2013-09-01
期刊：
影响因子：
4.7
通讯作者：
Wu, Tangchun
中科院分区：
文献类型：
--
作者：
Deng, Qifei;Guo, Huan;Wu, Tangchun
细胞周期调节、细胞凋亡、氧化应激和炎症反应在吸烟诱导肺癌的发生发展中起重要作用。然而，他们的基因变异是否与肺癌易感性相关仍不清楚。在这项研究中，我们进行了基于假设的关联分析，以研究这些途径中常见的遗传变异及其与吸烟的相互作用对肺癌易感性的影响。我们首先从先前肺癌全基因组关联研究的输入数据集中筛选出2331例和3077例对照的798个基因中的24042个未经验证的遗传变异，然后在4133例和4522例对照中进行了额外的两阶段验证。我们发现rs2282987与CDK6在7q21.2处具有显著的全基因组相关性（P < 5.0 × 10(-8)）[比值比(OR) = 1.18，联合P-add = 2.27 × 10(-9)]， rs2706748与SH3RF1在4q32.3处具有一致的相关性（OR = 1.17，联合P-add = 5.10 × 10(-6)）。相互作用分析显示，rs2282987和rs2706748与吸烟状况（p -相互作用分别为1.04 × 10（-2）和3.03 × 10(-2)）和吸烟史（p -相互作用分别为1.21 × 10（-2）和5.21 × 10(-2)）相互作用，对51-60岁受试者的肺癌易感性有贡献。这些结果进一步强调了参与细胞周期调控和凋亡通路的遗传变异对肺癌易感性的贡献，并强调了肺癌病因学中的基因-环境相互作用，特别是在51-60岁的受试者中。
Cell cycle regulation, apoptosis, oxidative stress and inflammation response play critical roles in the development of smoking-induced lung cancer. However, it is still not well known whether their genetic variants are associated with lung cancer susceptibility. In this study, we performed imputation-based association analyses to investigate the influence of common genetic variants in these pathways and their interactions with smoking on lung cancer susceptibility. We first selected 24 042 unvalidated genetic variants in 798 genes from the imputed dataset of the previous lung cancer genome-wide association study in 2331 cases and 3077 controls, and then conducted additional two-stage validations in 4133 cases and 4522 controls. We found a genome-wide significant (P < 5.0 x 10(-8)) association for rs2282987 in CDK6 at 7q21.2 [odds ratio (OR) = 1.18, combined P-add = 2.27 x 10(-9)] and a consistent association for rs2706748 in SH3RF1 at 4q32.3 (OR = 1.17, combined P-add = 5.10 x 10(-6)). Interaction analyses showed that rs2282987 and rs2706748 interacted with both smoking status (P-interaction were 1.04 x 10(-2) and 3.03 x 10(-2), respectively) and smoking history (P-interaction were 1.21 x 10(-2) and 5.21 x 10(-2), respectively) to contribute to lung cancer susceptibility in subjects aged 51-60 years. These results further underscore the contribution of genetic variants involved in pathways of cell cycle regulation and apoptosis to lung cancer susceptibility, and highlight gene-environment interactions in lung cancer etiology, especially in subjects aged 51-60 years.