DNA修复基因XPD、XPC、XRCC4基因多态性与结直肠癌易感性的相关性研究

发布时间：2018-02-20 16:48

本文关键词： XPD XPC XRCC4 结直肠癌基因多态性　出处：《山东大学》2017年硕士论文　论文类型：学位论文

【摘要】：研究背景结直肠癌(Colorectal Cancer,CRC)是世界上常见的恶性肿瘤之一,其发病原因和机制尚未被完全阐明。在我国,结直肠癌的发病率和死亡率迅速增高,有证据表明,除吸烟、饮酒、高红肉、高脂肪、低纤维素摄入等环境因素外,遗传因素与结直肠癌的发生密切相关,一级亲属中有结直肠癌患者时个体结直肠癌的发病风险明显增高。人类遗传变异最常来源于单核苷酸多态性(SNPs),有证据表明,SNPs可能促进结直肠癌的发生。XPD、XPC、XRCC4是DNA修复基因家族的管家基因,对DNA双链突变修复起重要作用,已有研究表明,XPD、XPC、XRCC4基因的多个多态性位点能够影响XPD、XPC、XRCC4蛋白的表达和功能,与某些疾病如恶性肿瘤、心脑血管疾病、风湿性关节炎、糖尿病等疾病的易感性密切相关。目的探讨多态性位点 XPD rsl3181(codon751A/C)、rs238406(codon156C/A),XPC rs2279017(i11C/A)和 XRCC4 rs3734091(codon247T/C)基因多态性与结直肠癌易感性的关系。方法收集北京地区338例结直肠癌患者和同地区同时期315例健康体检者的外周血提取基因组DNA。采用TaqMan基因型检测技术检测XPD rs13181、rs238406,XPC rs2279017及XRCC4 rs3734091多态性位点基因型。采用拟合优度卡方检验检测每个位点的基因型频率是否符合Hardy-Weinberg平衡定律。采用PHASE2.1软件构建单倍体型并计算单倍体型频率。采用卡方检验分析年龄、性别、吸烟、饮酒等因素在研究对象中的分布。校正了年龄、性别、吸烟、饮酒等因素后采用非条件Logistic回归模型计算调整比值比(adjusted ORs)和95%的可信区间(95%CIs)来分析基因型、等位基因及单倍体型与结直肠癌易感性的相关性。结果病例组XPD rs13181位点基因型GT、等位基因G的频率明显高于对照组(GT,adjusted OR=1.69,95%CI=1.159-2.47,P=0.007;等位基因 G,adjusted OR=1.77,95%CI=1.19-2.64,P=0.005)。病例组 XRCC4 rs3734091 位点基因型 GT和等位基因T的频率显著高于对照组(GT,adjusted OR =9.02,95%CI=5.61-14.50,P0.001;等位基因 T,adjusted OR=4.06,95%CI=2.49-6.61,P0.001)。XPD rs238406和XPCrs2279017位点的基因型和等位基因频率在两组中的分布均无统计学差异(P0.05)。单倍体型分析表明:根据XPDrs238406和rs13181位点基因型构建出的单倍体型GT明显降低了个体患结直肠癌的风险(adjusted OR=0.39,95%CI=0.18-0.85,P=.018)。基因联合效应分析表明:在 XPC rs2279017位点含有等位基因G并且在XRCC4 rs3734091位点含有等位基因T的个体患结直肠癌的风险明显增加(adjusted OR=28.43,95%CI=6.85-117.95,P0.001);在XPD rs13181位点含有等位基因G并且在XRCC4 rs3734091位点含有等位基因T的个体患结直肠癌的风险明显增加(adjusted OR=10.24,95%CI=4.69-22.35,P0.001)。结论1.多态性位点 XPDrs13181、rs238406,XPCrs2279017 和 XRCC4rs3734091均具有多态性;2.XPD rs13181和XRCC4 rs3734091位点的多态性与结直肠癌易感性相关,而XPD rs238406和XPC rs2279017位点的多态性与结直肠癌易感性无关;3.XPD rs238406和rs13181位点基因型单倍体型GT是结直肠癌的危险因素;4.XPD、XPC和XRCC4多态位点等位基因之间的联合效应是结直肠癌发生的较强的危险因素;5.多态性位点XPD rs13181和XRCC4 rs3734091有望成为筛查结直肠癌高危个体,进而进行针对性干预的有效遗传标志物。
[Abstract]:Background: colorectal carcinoma (Colorectal, Cancer, CRC) is one of the most common malignancies in the world, its causes and mechanism has not been fully elucidated. In our country, the incidence and mortality of colorectal cancer increased rapidly, there is evidence that, in addition to smoking, drinking, high red meat, high fat, low fiber intake and other environmental factors outside, the genetic factors and colorectal cancer is closely related to the occurrence of first-degree relatives with colorectal cancer patients when the individual risk of colorectal cancer increased significantly. Human genetic variation most often derived from single nucleotide polymorphisms (SNPs), there is evidence that SNPs may promote the occurrence of colorectal cancer.XPD, XPC, XRCC4 is a housekeeping gene DNA repair gene family, the DNA double strand mutation repair plays an important role, studies have shown that XPD, XPC, XRCC4 gene polymorphic loci could influence the XPD, XPC, expression and function of XRCC4 protein, and some kinds of diseases. Diseases such as malignant tumor, cardiovascular disease, rheumatoid arthritis, closely related to susceptibility to diabetes and other diseases. Objective to investigate the polymorphism of XPD rsl3181 (codon751A/C), rs238406 (codon156C/A), XPC rs2279017 (i11C/A) and XRCC4 rs3734091 (codon247T/C) gene polymorphism and susceptibility to colorectal cancer. Methods peripheral blood the collection of Beijing area in 338 cases of colorectal cancer and 315 healthy subjects at the same time, the genomic DNA. was extracted by TaqMan genotype detection of XPD rs13181, rs238406, XPC rs2279017 and XRCC4 rs3734091 polymorphism genotype. Using chi square goodness of fit test to detect genotype frequencies of each locus is consistent with the Hardy-Weinberg equilibrium law construction of haplotype haplotype frequency was calculated by PHASE2.1 software. By using the chi square test analysis of age, gender, smoking, drinking and other factors in the Study on the distribution of objects. Adjusted for age, sex, smoking, drinking and other factors by non conditional Logistic regression model adjusted odds ratio (adjusted ORs) and 95% confidence interval (95%CIs) to analyze the correlation between genotype, allele and haplotype and colorectal cancer susceptibility. The case group XPD rs13181 genotype GT, G allele frequency was significantly higher than the control group (GT, adjusted, OR=1.69,95%CI=1.159-2.47, P=0.007; allele G, adjusted OR=1.77,95%CI=1.19-2.64, P=0.005). The case group XRCC4 rs3734091 locus genotype GT and allele frequency of T was significantly higher than the control group (GT adjusted, OR =9.02,95%CI=5.61-14.50, P0.001; alleles of T, adjusted OR=4.06,95%CI=2.49-6.61, P0.001) were no significant difference between.XPD rs238406 and XPCrs2279017 loci genotype and allele frequency distribution in the two groups (P0. 05). Haplotype analysis showed that: according to the GT XPDrs238406 haplotype and rs13181 allele type construct significantly reduces the individual risk of colorectal cancer (adjusted, OR=0.39,95%CI=0.18-0.85, P=.018). The combined effects of gene analysis showed that contain allele G and contains in the XRCC4 allele of rs3734091 T in XPC rs2279017 locus of the individual the risk of colorectal cancer increased significantly (adjusted OR=28.43,95%CI=6.85-117.95, P0.001); containing G allele in XRCC4 and containing rs3734091 allele T in XPD locus rs13181 a significantly increased risk of colorectal cancer (adjusted OR=10.24,95%CI=4.69-22.35, P0.001). Conclusion the site 1. polymorphic XPDrs13181, rs238406, XPCrs2279017 and XRCC4rs3734091 have polymorphism; polymorphism and colorectal cancer 2.XPD rs13181 and XRCC4 rs3734091 loci related susceptibility, XPD rs238406 and XPC rs2279017 polymorphism has nothing to do with the susceptibility of colorectal cancer; 3.XPD rs238406 and rs13181 genotypes of the GT haplotype is a risk factor for colorectal cancer; 4.XPD, the combined effect between XPC and XRCC4 polymorphism alleles is a strong risk factor for rectal cancer; 5. polymorphic loci of XPD and rs13181 XRCC4 rs3734091 is expected to become the colorectal cancer screening in high-risk individuals, and effective intervention for genetic markers.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.34

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