多因子降维法在人群散发性结直肠癌交互作用分析中的应用

金明娟; 刘冰; 张爽爽; 张勇晶; 徐玫; 马新源; 姚开颜; 陈坤

Abstract

金明娟,刘冰,张爽爽,张勇晶,徐玫,马新源,姚开颜,陈坤.多因子降维法在人群散发性结直肠癌交互作用分析中的应用[J].Chinese journal of Epidemiology,2008,29(6):535-539

多因子降维法在人群散发性结直肠癌交互作用分析中的应用

Application of multifactor dimensionality reduction on the interactions between gene-gene,geneenvironment and the risk sporadic colorectal cancer in Chinese population

Received:December 13, 2007

DOI：10.3321/j.issn:0254-6450.2008.06.005

KeyWord: 结直肠肿瘤|基因多态性|单核苷酸多态性|DNA修复基因|多因子降维

English Key Word: Colorectal neoplasm|Genetic polymorphism|Single nucleotide polymorphism|DNA repair gene|Multifactor dimensionality reduction

FundProject:国家自然科学基金资助项目(30471492)；浙江省自然科学基金资助项目(R205319)

Author Name	Affiliation	E-mail
JIN Ming-juan	Department of Epidemiology and Health Statistic, Zhejiang University School of Medical, Hangzhou 310058, China
LIU Bing	Department of Epidemiology and Health Statistic, Zhejiang University School of Medical, Hangzhou 310058, China
ZHANG Shuang-shuang	Department of Epidemiology and Health Statistic, Zhejiang University School of Medical, Hangzhou 310058, China
ZHANG Yong-jing	Department of Epidemiology and Health Statistic, Zhejiang University School of Medical, Hangzhou 310058, China
XU Mei	义乌出入境检验检疫局
MA Xin-yuan	浙江省嘉善县肿瘤防治所
YAO Kai-yan	浙江省嘉善县肿瘤防治所
CHEN Kun	Department of Epidemiology and Health Statistic, Zhejiang University School of Medical, Hangzhou 310058, China	CK@zju．edu．Cn

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Abstract:

目的探讨DNA修复基因多态性与中国南方汉族人群散发性结直肠癌发病的相关性，验证多因子降维法(MDR)应用于多因子疾病基因-基因、基因-环境交互作用分析的可行性．方法采用自然人群为基础的病例对照研究设计，运用PCR-RFLP方法对206例结直肠癌病例和845例正常对照开展OGG1 Ser326Cys，XRCC1 Arg194Trp、Arg280His和Arg399Gln，XPD Lys751Gln和XRCC3 Thr241Met等DNA修复体系常见单核苷酸多态性(SNP)的检测分型．结果个体特征与结直肠癌的关联分析表明，年龄与结直肠癌的发病正相关，高年龄组(≥61岁)与低年龄组(≥42岁至＜61岁)相比，结直肠癌患病风险增高有统计学意义(校正OR=2.04，95%CI:1.49～2.80);家族肿瘤史同样与结直肠癌的发病存在有统计学意义的正相关关系(校正OR=1.51，95%CI:1.05～2.17)．前述各SNP的等位基因和基因型分布频率在正常对照组和病例组间差异均无统计学意义(P＞0.05)．采用MDR对基因-基因、基因-环境交互作用模型的筛选分析表明，最佳的交互作用模型包含了年龄分布、饮酒史、XRCC1 Arg194Trp和OGG1 Ser326Cys等4个因子(平均检验准确度=0.616，交叉验证一致性=10/10，P=0.011);进一步以筛选出的低风险组合为参照，logistic拟合分析发现高风险组合可以使结直肠癌的患病风险增高并有统计学意义(OR=2.72，95%CI:1.66～4.47)．结论 DNA修复基因多态性对中国人散发性结直肠癌风险的遗传影响符合低外显性特征，并与环境因子可能存在着复杂的联合作用．

English Abstract:

Objective To identify the association between risk of sporadic colorectal cancer and the common single nucleotide polymorphisms (SNPs) in DNA repairs genes, gene to gene interactions among them and their gene to environment interactions with common environmental factors. Methods In this population-based case-control study, 206 primary colorectal cancer cases and 845 cancer-free healthy controls were enrolled. Genotyping was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, with the status of subjects case or controls unknown.Multifactor dimensionality reduction (MDR) and logistic analysis were both used for association analysis.Results As compared to the younger age group (≥42,＜61 years), the risk of colorectal cancer in older age group (≥61 years) increased significantly ( OR= 2.04,95%CI: 1.49-2.80). Similar result was observed in the family cancer history ( OR= 1.51, 95%CI : 1.05-2.17 ). However, no significant association between any single DNA repair gene SNPand colorectal cancer risk was discovered. Results from MDR analysis only showed a significant interaction among the four following factors: age, alcohol drinking, XRCC1 Arg194Trp and OGG1 Ser326Cys (the cross-validation consistency = 10/10, the average testing accuracy = 0.616, P=0.011 ). Using a logistic regression model, the"high-risk"individuals had a significantly elevated risk of colorectal cancer compared to those "low- risk" individuals classified by the above MDR model ( OR= 2.72,95%CI : 1.66-4.47 ). Conclusion The impact of polymorphisms in DNA repair genes on the risk of sporadic colorectal cancer exhibited a low-penetrance characteristics while the intricate interactions existing among them and with environmental factors.

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