DNA修復(fù)基因多態(tài)性與膠質(zhì)瘤發(fā)病相關(guān)關(guān)系研究
發(fā)布時(shí)間：2018-09-18 11:36
【摘要】：第一部分 目的：神經(jīng)系統(tǒng)腫瘤占所有腫瘤類型的2%,據(jù)統(tǒng)計(jì)全球每年神經(jīng)系統(tǒng)腫瘤發(fā)病率大約為4.2/105-5.4/105,膠質(zhì)瘤占神經(jīng)系統(tǒng)腫瘤的80%。目前膠質(zhì)瘤的發(fā)病原因尚不清楚,唯一確定的環(huán)境暴露因素只有輻射暴露,同時(shí)遺傳因素也在膠質(zhì)瘤的發(fā)病中起到了重要的作用。單核苷酸多態(tài)性可以影響到基因表達(dá)產(chǎn)物發(fā)生改變或出現(xiàn)數(shù)量的變化,從而使得基因的表達(dá)出現(xiàn)不同,出現(xiàn)遺傳特征的差異。人體內(nèi)眾多DNA修復(fù)基因的單核苷酸多態(tài)性就使得相應(yīng)的修復(fù)酶具有多樣性,個(gè)體間對(duì)DNA修復(fù)的能力就具有差異。BER和NER是最重要的DNA損傷修復(fù)途徑,本研究采用PCR-RFLP的方法,檢測(cè)DNA修復(fù)基因中NER途徑中ERCC1, ERCC2的三個(gè)主要SNP與膠質(zhì)瘤的發(fā)病的相關(guān)關(guān)系。本研究擬采用病例對(duì)照研究,收集集312名由病理確診的膠質(zhì)瘤作為病例和312名在我院進(jìn)行健康體檢的病人作為對(duì)照,并按照性別和年齡1：1配對(duì)。 方法：采用Qiagen Blood Kit血基因組DNA試劑盒提取DNA,應(yīng)用Sequenom MassARRAY(?)技術(shù)平臺(tái)和基質(zhì)輔助激光解吸電離飛行時(shí)間質(zhì)譜技術(shù)(Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry, MALDI-TOF-MS)檢測(cè)ERCC1Asn118Asn、ERCC2Lys751Gln和ERCC2Asp312Asn基因多態(tài)性。并采用條件logistic regression建立膠質(zhì)瘤危險(xiǎn)性與ERCC1Asn118Asn、ERCC2Lys751Gln和ERCC2Asp312Asn基因多態(tài)性相關(guān)關(guān)系。 結(jié)果：膠質(zhì)瘤家族史和電離輻射暴露均能增加患者患膠質(zhì)瘤的風(fēng)險(xiǎn)。ERCC1Asn118Asn、ERCC2Lys751Gln和ERCC2Asp312Asn在對(duì)照組中的基因型頻率分布符合Hardy-Weinberg遺傳平衡定律。多因素條件Logistic回歸分析,與攜帶ERCC2751AA基因型相比,發(fā)現(xiàn)攜帶ERCC2751CC基因型可以增加患膠質(zhì)瘤的風(fēng)險(xiǎn),相應(yīng)的OR (95%CI)值為2.47(1.46,3.74)。與ERCC2751A等位基因型相比,攜帶ERCC2751C等位基因可以增加患膠質(zhì)瘤的風(fēng)險(xiǎn),相應(yīng)的OR (95%CI)為1.58(1.29,2.15)。在交互作用的模型當(dāng)中,ERCC2751AC+CC基因型電離輻射暴露史的交互作用系數(shù)為γ=2.15,可見(jiàn)攜帶ERCC2751AC+CC基因?qū)﹄婋x輻射的效應(yīng)有放大作用,屬于正向交互。 結(jié)論：ERCC2Lys751Gln基因多態(tài)性能夠增加患者患膠質(zhì)瘤的風(fēng)險(xiǎn),并與電離輻射暴露史有一定交互作用。但未發(fā)現(xiàn)ERCC1Asn118Asn和ERCC2Asp312Asn基因多態(tài)性與膠質(zhì)瘤的相關(guān)關(guān)系。 第二部分 目的：腫瘤的發(fā)生被認(rèn)為是一種多因素、多環(huán)節(jié)的綜合性疾病,不僅涉及到人體本身,人體基因組而且還與外部環(huán)境的改變息息相關(guān)。X線修復(fù)交叉互補(bǔ)基因1(X-ray repair cross-complementing group1, XRCC1)是1990年從轉(zhuǎn)染的中國(guó)倉(cāng)鼠卵巢細(xì)胞株CHO突變體的EM9細(xì)胞的基因文庫(kù)中克隆得到篩選得到的。XRCC1基因的前期研究已經(jīng)證實(shí),XRCC1基因的缺失后會(huì)引起細(xì)胞對(duì)電離輻射、DNA交聯(lián)劑等物質(zhì)更加敏感,從而導(dǎo)致各種各樣的基因損傷作用。本研究選取了XRCC1基因的三個(gè)多態(tài)性位點(diǎn)作為研究對(duì)象,以患者外周血為目標(biāo),提取基因組DNA,采用SNP分型技術(shù)進(jìn)行多態(tài)性與膠質(zhì)瘤相關(guān)性分析。 方法：采用Qiagen Blood Kit血基因組DNA試劑盒提取DNA,應(yīng)用Sequenom MassARRAY(?)技術(shù)平臺(tái)和基質(zhì)輔助激光解吸電離飛行時(shí)間質(zhì)譜技術(shù)(Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry, MALDI-TOF-MS)檢測(cè)XRCC1Arg194Trp、Arg399G1n和Arg280His基因多態(tài)性。并采用條件logistic regression建立膠質(zhì)瘤危險(xiǎn)性與XRCCl Arg194Trp、 Arg399G1n和Arg280His基因多態(tài)性相關(guān)關(guān)系。 結(jié)果：XRCC1Arg194Trp、XRCC1Arg399G1n和XRCC1Arg280His在對(duì)照組中的基因型頻率分布符合Hardy-Weinberg平衡。多因素logistic回歸分析結(jié)果顯示,對(duì)于XRCC1Arg194Trp等位基因而言,攜帶TT基因型可以增加患者患膠質(zhì)瘤的風(fēng)險(xiǎn),相應(yīng)的OR值為1.66,95%的置信區(qū)間為1.49-1.89之間。對(duì)于XRCC1Arg399G1n基因型,攜帶AA基因型可以增加患者患膠質(zhì)瘤的風(fēng)險(xiǎn),相應(yīng)的OR值為1.48,95%的置信區(qū)間為1.27-1.85之間。在交互作用的模型當(dāng)中,XRCC1194CT+CC和XRCC1399GA+AA與電離輻射均有交互作用。電離輻射能夠增加患膠質(zhì)瘤的風(fēng)險(xiǎn)和概率,二者具有協(xié)同效應(yīng)。 結(jié)論：XRCC1Arg194Trp和XRCC1Arg399G1n基因多態(tài)性能夠增加患者患膠質(zhì)瘤的風(fēng)險(xiǎn),并與電離輻射暴露史有一定交互作用。但未發(fā)現(xiàn)XRCC1Arg280His基因多態(tài)性與膠質(zhì)瘤的相關(guān)關(guān)系。
[Abstract]:Part one
Objective: Nervous system tumors account for 2% of all tumor types. According to statistics, the annual incidence of nervous system tumors is about 4.2/105-5.4/105 in the world, and gliomas account for 80% of all nervous system tumors. Mononucleotide polymorphisms can affect the change of gene expression products or the quantity of gene expression products, thus making the gene expression different and the genetic characteristics different. BER and NER are the most important DNA repair pathways. In this study, three major SNPs of ERCC1 and ERCC2 in the NER pathway of DNA repair genes were detected by PCR-RFLP. A case-control study was conducted to collect 312 pathologically confirmed gliomas. The control group consisted of 312 patients undergoing physical examination in our hospital and matched by sex and age 1:1.
METHODS: DNA was extracted by Qiagen Blood Kit blood genomic DNA kit, and ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp were detected by Sequenom MassARRAY (?) platform and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). The association between the risk of glioma and the polymorphisms of ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp312Asn was established by conditional logistic regression.
Results: Family history of gliomas and exposure to ionizing radiation increased the risk of gliomas. The genotype frequencies of ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp312Asn in the control group were in accordance with Hardy-Weinberg's law of genetic balance. Multivariate conditional logistic regression analysis showed that ERCC-2751AA genotype was more likely to be carried than ERCC2751AA genotype. 2751CC genotype increased the risk of glioma with an OR (95% CI) of 2.47 (1.46, 3.74). Compared with ERCC2751A genotype, carrying ERCC2751C allele increased the risk of glioma with an OR (95% CI) of 1.58 (1.29, 2.15). In the interaction model, ERCC2751AC + CC genotype had a history of exposure to ionizing radiation. The interaction coefficient is gamma=2.15, which shows that carrying ERCC2751AC+CC gene amplifies the effect of ionizing radiation and belongs to positive interaction.
Conclusion: ERCC2Lys751Gln gene polymorphism can increase the risk of glioma and interact with the history of ionizing radiation exposure, but there is no correlation between ERCC1Asn118Asn and ERCC2Asp312Asn gene polymorphism and glioma.
The second part
Objective: Tumor genesis is considered to be a multifactorial, multilinking, complex disease involving not only the human body itself, but also the human genome. X-ray repair cross-complementing group 1 (XRCC1) is a Chinese hamster ovarian cell line CHO transfected in 1990. The mutant EM9 cells were cloned and screened. Previous studies of the XRCC1 gene have confirmed that the deletion of the XRCC1 gene will cause cells to be more sensitive to ionizing radiation, DNA crosslinking agents and other substances, resulting in a variety of gene damage. Subjects: Genomic DNA was extracted from peripheral blood of patients and the correlation between polymorphism and glioma was analyzed by SNP typing.
METHODS: DNA was extracted by Qiagen Blood Kit blood genomic DNA kit, and XRCC1Arg194Trp, Arg399G1n and Arg280 substrates were detected by Sequenom Mass ARRAY (?) platform and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-HisTOF-MS). Conditional logistic regression was used to establish the association between the risk of glioma and the polymorphisms of XRCCl Arg194Trp, Arg399G1n and Arg280His genes.
Results: Genotype frequencies of XRCC1Arg194Trp, XRCC1Arg399G1n and XRCC1Arg280His in the control group were in accordance with Hardy-Weinberg equilibrium. Multivariate logistic regression analysis showed that TT genotype could increase the risk of glioma in patients with XRCC1Arg194Trp allele, and the corresponding OR value was 1.66,95% confidence interval. For the XRCC1Arg399G1n genotype, carrying the AA genotype increased the risk of glioma with an OR of 1.48 and a 95% confidence interval of 1.27-1.85. In the interaction model, both XRCC1194CT + CC and XRCC1399GA + AA interacted with ionizing radiation. Ionizing radiation increased the risk of glioma Risk and probability, the two have synergistic effect.
CONCLUSION: XRCC1Arg194Trp and XRCC1Arg399G1n gene polymorphisms can increase the risk of glioma and interact with the history of ionizing radiation exposure.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R739.41
本文編號(hào)：2247784
[Abstract]:Part one
Objective: Nervous system tumors account for 2% of all tumor types. According to statistics, the annual incidence of nervous system tumors is about 4.2/105-5.4/105 in the world, and gliomas account for 80% of all nervous system tumors. Mononucleotide polymorphisms can affect the change of gene expression products or the quantity of gene expression products, thus making the gene expression different and the genetic characteristics different. BER and NER are the most important DNA repair pathways. In this study, three major SNPs of ERCC1 and ERCC2 in the NER pathway of DNA repair genes were detected by PCR-RFLP. A case-control study was conducted to collect 312 pathologically confirmed gliomas. The control group consisted of 312 patients undergoing physical examination in our hospital and matched by sex and age 1:1.
METHODS: DNA was extracted by Qiagen Blood Kit blood genomic DNA kit, and ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp were detected by Sequenom MassARRAY (?) platform and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). The association between the risk of glioma and the polymorphisms of ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp312Asn was established by conditional logistic regression.
Results: Family history of gliomas and exposure to ionizing radiation increased the risk of gliomas. The genotype frequencies of ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp312Asn in the control group were in accordance with Hardy-Weinberg's law of genetic balance. Multivariate conditional logistic regression analysis showed that ERCC-2751AA genotype was more likely to be carried than ERCC2751AA genotype. 2751CC genotype increased the risk of glioma with an OR (95% CI) of 2.47 (1.46, 3.74). Compared with ERCC2751A genotype, carrying ERCC2751C allele increased the risk of glioma with an OR (95% CI) of 1.58 (1.29, 2.15). In the interaction model, ERCC2751AC + CC genotype had a history of exposure to ionizing radiation. The interaction coefficient is gamma=2.15, which shows that carrying ERCC2751AC+CC gene amplifies the effect of ionizing radiation and belongs to positive interaction.
Conclusion: ERCC2Lys751Gln gene polymorphism can increase the risk of glioma and interact with the history of ionizing radiation exposure, but there is no correlation between ERCC1Asn118Asn and ERCC2Asp312Asn gene polymorphism and glioma.
The second part
Objective: Tumor genesis is considered to be a multifactorial, multilinking, complex disease involving not only the human body itself, but also the human genome. X-ray repair cross-complementing group 1 (XRCC1) is a Chinese hamster ovarian cell line CHO transfected in 1990. The mutant EM9 cells were cloned and screened. Previous studies of the XRCC1 gene have confirmed that the deletion of the XRCC1 gene will cause cells to be more sensitive to ionizing radiation, DNA crosslinking agents and other substances, resulting in a variety of gene damage. Subjects: Genomic DNA was extracted from peripheral blood of patients and the correlation between polymorphism and glioma was analyzed by SNP typing.
METHODS: DNA was extracted by Qiagen Blood Kit blood genomic DNA kit, and XRCC1Arg194Trp, Arg399G1n and Arg280 substrates were detected by Sequenom Mass ARRAY (?) platform and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-HisTOF-MS). Conditional logistic regression was used to establish the association between the risk of glioma and the polymorphisms of XRCCl Arg194Trp, Arg399G1n and Arg280His genes.
Results: Genotype frequencies of XRCC1Arg194Trp, XRCC1Arg399G1n and XRCC1Arg280His in the control group were in accordance with Hardy-Weinberg equilibrium. Multivariate logistic regression analysis showed that TT genotype could increase the risk of glioma in patients with XRCC1Arg194Trp allele, and the corresponding OR value was 1.66,95% confidence interval. For the XRCC1Arg399G1n genotype, carrying the AA genotype increased the risk of glioma with an OR of 1.48 and a 95% confidence interval of 1.27-1.85. In the interaction model, both XRCC1194CT + CC and XRCC1399GA + AA interacted with ionizing radiation. Ionizing radiation increased the risk of glioma Risk and probability, the two have synergistic effect.
CONCLUSION: XRCC1Arg194Trp and XRCC1Arg399G1n gene polymorphisms can increase the risk of glioma and interact with the history of ionizing radiation exposure.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R739.41
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