DNA损伤相关遗传变异与中国人群肺癌易感性的关联研究  

DNA damage associated genetic variants contribute to lung cancer susceptibility in a Han Chinese population

作　　者：李志华[1] 王玉琢[1] 刘佳[1] 朱猛[1] 杜江波[1] 袁晶[2] 陈卫红[2] 张正东[3] 胡志斌[1] 邬堂春[2] 沈洪兵[1] 

机构地区：[1]南京医科大学公共卫生学院流行病与卫生统计学系,210000 [2]华中科技大学同济医学院公共卫生学院劳动卫生与环境卫生学系环境与健康教育部重点实验室国家环境保护部环境与健康重点实验室 [3]南京医科大学公共卫生学院教育部现代毒理学重点实验室

出　　处：《中华预防医学杂志》2016年第8期721-727,共7页Chinese Journal of Preventive Medicine

基　　金：国家重点基础研究发展计划（2011CB503805）;国家自然科学基金重大项目（81390543）;国家自然科学基金重点项目（81230067）;江苏省临床科技项目（BL2012008）;江苏高校优势学科建设工程（公共卫生与预防医学）

摘　　要：目的 探索DNA损伤相关的遗传变异和中国人群肺癌发病风险的关系。方法 采用病例-对照研究设计，收集2003—2009年就诊于江苏省肿瘤医院以及江苏省人民医院的新发肺癌病例作为病例组，共1 341例。选取同期在相同医院或参加社区健康体检的健康人群作为对照组，共1 982名。每位研究对象采集5 ml外周血，并用同一调查问卷收集流行病学信息。运用Illumina Infinium？芯片对DNA损伤相关的35个单核苷酸变异（SNVs）进行基因分型。应用单因素和多因素logistic回归模型，计算每个位点的OR（95%CI）值。采用HaploReg V4.1和Regulome DB数据库对重点位点进行注释。结果 病例组和对照组的年龄分别为（61.06 ± 10.15）、（61.32 ± 11.07）岁，差异无统计学意义（t=-0.72，P=0.473）。病例组吸烟人数比例高于对照组（61.08%比48.54%, χ2=50.04, P〈0.001），且重度吸烟者所占比例也高于对照组（42.28%比24.07%, χ2=122.32, P〈0.001）。对符合质控标准的34个SNVs，在调整年龄、性别和累计吸烟剂量后，发现2个SNVs与肺癌发生的相关性的差异有统计学意义，分别为rs9267576位点的C〉A变异（CA基因型/CC基因型，OR=1.56, 95%CI： 1.01~2.40）和rs3130683的A〉G变异（AG基因型/AA基因型，OR=1.87，95% CI：1.13~3.09）。以rs3130683、rs9267576和其他协变量采用逐步回归法建立logistic回归模型，最终仅rs3130683保留在模型中，表明rs9267576与肺癌发生的关联可能由rs3130683的效应所致。功能注释结果表明，rs3130683位于启动子和增强子区，是人类白细胞抗原HLA-C、-DQB1、-DRB1、-DRB5的表达数量性状基因座（eQTL）。癌症基因组图谱（TCGA）数据分析结果表明，HLA-C、HLA-DQB1、HLA-DRB1和HLA-DRB5在肺癌组织中的表达水平均低于癌旁组织，分别有81.3%、88.8%、90.7%、90.7%的肺癌组织表达下调，P值分别为6.68×10-15、2.21×10-13、2.20×10-16、2.58×Objective To explore the association between DNA damage-related genetic variants and lung cancer susceptibility in a Han Chinese population.Methods This case-control study enrolled patients from the Cancer Hospital of Jiangsu Province and Jiangsu Province Hospital from 2003 to 2009. Controls were randomly selected from individuals who visited the same hospital or a community-based health examination program during the same time period. A 5 ml venous blood sample was obtained from each participant and epidemiological information was collected on a standard questionnaire. Illumina Infinium？ BeadChip was used for genotyping of 35 DNA damage-related single nucleotide variations （SNVs）, which were identified in our previous study. Multivariate and binary logistic regressions were used to calculate the OR and 95%CI for lung cancer risk. HaploReg V4.1 and Regulome DB were used to understand functional annotation on important SNV.Results The distributions of age （61.06±10.15） vs. （61.32±11.07） years; t=-0.72, P=0.473） and sex （χ2=1.81, P=0.179） were similar between cases and controls. However, the case group had a higher frequency of smokers （61.08% vs. 48.54%; χ2=50.04, P〈0.001） and heavy smokers （42.28% vs. 24.07%; χ2=122.32, P〈0.001）. Among the 34 SNVs that passed quality control, two SNVs were significantly associated with lung cancer risk after adjustments for age, sex and cumulative smoking dose： rs9267576 C〉A （CA genotype/CC genotype, OR=1.56, 95% CI： 1.01-2.40） and rs3130683 A〉G （AG genotype/AA genotype, OR=1.87, 95%CI： 1.13-3.09）. After step-wise logistic regression analysis, only the rs3130683 SNV was retained in the model, indicating that the association between rs9267576 and lung cancer may be due to the effect of rs3130683. Functional annotation indicated that rs3130683 was located in the promoter and enhancer regions, and was an expression quantitative trait loci of HLA. The Cancer Genome Atlas indicated that expression of HLA-C, DQB1, DRB1 and DRB5

关 键 词：DNA损伤 肺肿瘤 单核苷酸变异 PM2.5 

分 类 号：R734.2[医药卫生—肿瘤]