候選基因及miRNA基因多態(tài)性與肺癌遺傳易感性的關(guān)聯(lián)研究
發(fā)布時間：2018-08-13 08:37
【摘要】：背景肺癌是最常見的惡性腫瘤。除了吸煙等環(huán)境因素的影響外,遺傳因素也在肺癌的發(fā)生中起到很重要的作用,個體遺傳易感性的差異與肺癌發(fā)生風(fēng)險顯著相關(guān)。在過去的20多年里,候選基因關(guān)聯(lián)研究(candidate-gene association studies)是肺癌遺傳易感性研究的主要方法之一,已經(jīng)有1000多篇文獻基于候選基因策略研究遺傳多態(tài)性與肺癌易感性的關(guān)聯(lián)。盡管這些候選基因關(guān)聯(lián)研究發(fā)現(xiàn)了許多與肺癌發(fā)病風(fēng)險相關(guān)的遺傳變異位點,但是許多研究之間報道的結(jié)果并不一致,很難明確所發(fā)現(xiàn)的位點是否與肺癌發(fā)生風(fēng)險之間存在真實的病因關(guān)聯(lián)。目前缺乏對這些大量的研究證據(jù)的整合系統(tǒng)評價、meta分析和總體流行病學(xué)證據(jù)可靠性的分級評估。此外,目前報道的這些肺癌遺傳關(guān)聯(lián)研究,主要關(guān)注的是位于DNA剪切修復(fù)基因、代謝酶基因、免疫通路相關(guān)基因、細胞凋亡通路基因等蛋白編碼基因上的遺傳變異位點與肺癌易感性的關(guān)系,很少關(guān)注位于非蛋白編碼基因上的遺傳變異位點。然而,人類基因組中存在大量的非編碼RNAs(non-coding RNAs,nc RNAs)。且許多nc RNAs在肺癌及其他多種腫瘤發(fā)生發(fā)展中的重要作用已逐漸被證實,尤其是miRNAs在腫瘤中的功能作用。近年來,研究發(fā)現(xiàn)位于miRNA基因上的單核苷酸多態(tài)性(single nucleotide polymorphisms,SNPs)位點也與某些腫瘤的發(fā)生風(fēng)險相關(guān)聯(lián)。然而目前有關(guān)miRNA基因上的SNPs與肺癌易感性的關(guān)聯(lián)研究還很少,有待進一步發(fā)掘更多新的肺癌易感性相關(guān)的miRNA SNPs位點,為肺癌病因?qū)W研究提供更多新的線索。目的1.采用整合系統(tǒng)評價、meta分析以及流行病學(xué)證據(jù)質(zhì)量分級的方法對目前發(fā)表的所有與肺癌發(fā)生風(fēng)險相關(guān)的候選基因關(guān)聯(lián)研究進行分析,全面識別、驗證和解釋以往報道的遺傳變異位點與肺癌發(fā)生風(fēng)險之間的關(guān)聯(lián)。2.通過生物信息學(xué)分析,篩選位于miRNA基因序列上的潛在功能性SNPs,并基于病例-對照研究的關(guān)聯(lián)分析,探討miRNA基因上的SNPs位點與肺癌發(fā)生風(fēng)險的關(guān)聯(lián),進而發(fā)掘新的與肺癌易感性相關(guān)的位于miRNA基因上的SNPs位點方法1.對截止2015年11月1日發(fā)表的全部關(guān)于肺癌易感性的候選基因關(guān)聯(lián)研究,進行系統(tǒng)性地文獻檢索和文獻評估。對至少被三個獨立研究報道的遺傳變異位點,采用meta分析的方法評估其與肺癌易感性之間的關(guān)聯(lián)。此外我們還根據(jù)種族、病理分型以及吸煙狀態(tài)進行亞組分析。根據(jù)meta分析的結(jié)果,采用威尼斯標(biāo)準(zhǔn)評估具有統(tǒng)計學(xué)意義的關(guān)聯(lián)位點的流行病學(xué)證據(jù)可靠性。進一步采用生物信息學(xué)分析,對與肺癌易感性之間存在顯著性關(guān)聯(lián)且關(guān)聯(lián)具有強流行病學(xué)證據(jù)可靠性的位點進行功能注釋。對于meta分析發(fā)現(xiàn)的與肺癌發(fā)生風(fēng)險之間不具有統(tǒng)計學(xué)意義的關(guān)聯(lián)位點,也對其證據(jù)質(zhì)量進行評估,評估方法基于納入研究之間的異質(zhì)性、潛在偏倚以及meta分析結(jié)果的統(tǒng)計學(xué)效能三個方面。2.通過生物信息學(xué)分析,篩選了13個具有潛在生物學(xué)功能的位于不同miRNA上的SNPs位點。在626例肺癌患者和年齡、性別與病例相匹配的736例正常對照中,采用SNPscanTM分型技術(shù)對篩選的13個SNPs位點進行基因分型。多因素Logistic回歸分析不同基因型與肺癌易感性之間的關(guān)聯(lián);并基于肺癌的病理學(xué)類型和個體的吸煙狀態(tài)進行分層分析,在不同的亞組中評估各SNP位點與肺癌發(fā)生風(fēng)險之間的關(guān)聯(lián)。結(jié)果第一部分:1.經(jīng)過系統(tǒng)性的文獻檢索和文獻篩選,最終我們納入了1018篇符合標(biāo)準(zhǔn)的文獻,這些文獻總共報道了位于754個不同基因或染色體位點上的2910個遺傳變異位點。2.采用meta分析的方法評估其中的246個遺傳變異位點(位于138個不同的基因)與肺癌易感性之間的關(guān)聯(lián)。基于meta分析結(jié)果和威尼斯標(biāo)準(zhǔn)評估發(fā)現(xiàn),22個位點(位于21個不同的基因)與肺癌發(fā)生風(fēng)險顯著相關(guān),且關(guān)聯(lián)具有強的流行病學(xué)證據(jù)可靠性,這22個遺傳變異位點分別是APEX1 rs1130409、APEX1 rs1760944、ATM rs664677、AXIN2 rs2240308、CHRNA3 rs6495309、CHRNA5 rs16969968、CLPTM1L rs402710、CXCR2 rs1126579、CYP1A1 rs4646903、CYP2E1 rs6413432、ERCC1 rs11615、ERCC2rs13181、FGFR4 rs351855、HYKK rs931794、MIR146A rs2910164、MIR196A2 rs11614913、OGG1 rs1052133、PON1 rs662、REV3L rs462779、SOD2 rs4880、TERT rs2736098和TP53rs1042522位點。3.生物信息學(xué)分析表明,在這22個遺傳變異位點中,大部分位點可以通過改變蛋白質(zhì)編碼序列或者影響DNA調(diào)控元件,來影響其所在基因的表達和/或功能。4.Meta分析發(fā)現(xiàn)150個遺傳變異位點(來自98個不同的基因)與肺癌發(fā)生風(fēng)險之間的關(guān)聯(lián)無統(tǒng)計學(xué)意義,證據(jù)質(zhì)量評估發(fā)現(xiàn)其中7個位點(ERCC1 rs16979802、ERCC1rs2298881、ERCC1 rs735482、POLI rs3730668、PPARG rs1801282、PTGS2 rs20417和TNF rs1799724)的meta分析結(jié)果的流行病學(xué)證據(jù)質(zhì)量高,具有較高的可靠性。第二部分:1.通過生物信息學(xué)分析篩選了13個位于不同miRNAs基因上的潛在功能性的SNPs位點(rs11597888 G/A、rs12803915 G/A、rs16867808 T/C、rs2292879 A/G、rs45530340 C/T、rs5997893 G/A、rs61747536 C/T、rs62085660 C/G、rs6464546 G/A、rs6717413 A/G、rs7247237 C/T、rs745666 G/C和rs999665 G/A),進一步關(guān)聯(lián)分析發(fā)現(xiàn)這些SNPs位點總體上與肺癌發(fā)生風(fēng)險之間的關(guān)聯(lián)不具有統(tǒng)計學(xué)意義(P值均大于0.05)。2.基于肺癌病理類型的亞組分析發(fā)現(xiàn),rs11597888(GA)位點的雜合子GA基因型可以顯著增加肺腺癌的發(fā)生風(fēng)險(共顯性模型:校正OR=1.34,95%CI=1.00-1.79,P=0.046);rs62085660(CG)位點的變異型等位基因G和變異基因型(CG+GG)都可以顯著降低肺鱗癌的發(fā)生風(fēng)險(加性模型:校正OR=0.79,95%CI=0.62-1.00,P=0.049;顯性模型:校正OR=0.72,95%CI=0.53-0.98,P=0.035)。3.基于吸煙狀態(tài)的亞組分析發(fā)現(xiàn),rs11597888(GA)位點的變異基因型(GA+AA)可以顯著增加吸煙人群發(fā)生肺癌的風(fēng)險(共顯性模型:校正OR=1.44,95%CI=1.02-2.02,P=0.037;顯性模型:校正OR=1.42,95%CI=1.03-1.96,P=0.033);rs16867808(TC)位點在多種假設(shè)遺傳模型下與吸煙人群發(fā)生肺癌的風(fēng)險顯著相關(guān)(加性模型:校正OR=0.58,95%CI=0.40-0.84,P=0.004;共顯性模型:校正OR=0.55,95%CI=0.35-0.85,P=0.007;顯性模型:校正OR=0.53,95%CI=0.35-0.81,P=0.004)。4.Haplo Reg數(shù)據(jù)庫功能注釋表明,亞組分析中識別的與肺癌易感性顯著相關(guān)的3個位點(rs11597888 G/A、rs62085660 C/G和rs16867808 T/C)都位于肺癌組織及其他多種組織細胞中的DNA調(diào)控元件區(qū)域(啟動子區(qū)域和/或增強子區(qū)域)、Dnase I高敏感區(qū)、相關(guān)轉(zhuǎn)錄因子結(jié)合位點以及可以改變相關(guān)模體(motif),其中rs62085660 C/G和rs16867808 T/C位點還是多種基因的的表達數(shù)量性狀位點(expression quantitative trait locus,e QTLs)。結(jié)論1.基于整合系統(tǒng)評價、meta分析、流行病學(xué)證據(jù)質(zhì)量分級的方法發(fā)現(xiàn),目前在所有報道的肺癌遺傳易感性候選基因關(guān)聯(lián)研究中,約有9%(22/246)遺傳變異位點與肺癌的易感性顯著相關(guān),且流行病學(xué)證據(jù)評估具有較強可靠性。相關(guān)研究以及生物信息學(xué)分析表明,在這些位點中,大部分位點可以通過改變蛋白質(zhì)編碼序列或者影響調(diào)控元件,來影響其所在的基因的表達和/或功能。2.基于病例-對照研究設(shè)計的關(guān)聯(lián)分析發(fā)現(xiàn),rs11597888 G/A(miRNA AL391839.1)、rs62085660 C/G(miRNA AC145343.1)以及rs16867808 T/C(miRNA AL021918.2)位點分別與肺癌的發(fā)生風(fēng)險存在顯著性關(guān)聯(lián),但是這3個SNPs位點與肺癌易感性的關(guān)聯(lián)效應(yīng)只能在特定的亞組人群中觀察到,具體包括:rs11597888(GA)位點與肺腺癌發(fā)生風(fēng)險以及吸煙人群中肺癌發(fā)生風(fēng)險顯著相關(guān);rs62085660(CG)位點與肺鱗癌發(fā)生風(fēng)險顯著相關(guān);rs16867808(TC)位點與吸煙人群中肺癌發(fā)生風(fēng)險顯著相關(guān)。本研究結(jié)果為肺癌遺傳風(fēng)險效應(yīng)相關(guān)的研究提供了最新且全面的證據(jù),同時發(fā)現(xiàn)了與肺癌易感性相關(guān)的新的miRNA SNPs位點,將為后續(xù)肺癌風(fēng)險相關(guān)的研究提供有力的線索,為肺癌的個體化防治提供理論依據(jù)。
[Abstract]:Background Lung cancer is the most common malignancy. In addition to environmental factors such as smoking, genetic factors play an important role in the development of lung cancer. Differences in individual genetic susceptibility are significantly associated with the risk of lung cancer. One of the main methods of genetic susceptibility research, more than 1000 papers have studied the association between genetic polymorphism and lung cancer susceptibility based on candidate gene strategies. There is a lack of integrated systematic evaluation of the large number of studies, meta-analysis, and hierarchical evaluation of the reliability of overall epidemiological evidence. In addition, the reported genetic association studies of lung cancer focus on DNA splicing. The genetic variation sites of repair genes, metabolic enzymes genes, immune pathway related genes, apoptosis pathway genes and other protein coding genes are rarely concerned with the susceptibility to lung cancer. However, a large number of non-coding RNAs (nc RNAs) exist in the human genome. Many of the important roles of NC RNAs in lung cancer and many other tumors have been gradually confirmed, especially the role of microRNAs in tumors. In recent years, studies have found that single nucleotide polymorphisms (SNPs) sites in the microRNA gene are also associated with the risk of some tumors. Previous studies on the association of microRNAs with lung cancer susceptibility are rare. More novel sites of microRNAs associated with lung cancer susceptibility need to be explored to provide new clues for the etiological study of lung cancer. Objective 1. The current publication is based on integrated system assessment, meta-analysis and epidemiological evidence quality grading. All candidate genes associated with lung cancer risk were analyzed to identify, validate and explain the association between previously reported genetic variation sites and lung cancer risk. To explore the association between SNPs on the microRNAs and the risk of lung cancer, and to explore new SNPs on the microRNAs associated with lung cancer susceptibility. 1. Systematic literature search and evaluation of all candidate gene association studies on lung cancer susceptibility published as of November 1, 2015. Meta-analysis was used to assess the association between genetic variants and susceptibility to lung cancer. Subgroup analysis was also performed based on race, pathological typing, and smoking status. Evidence reliability. Further, bioinformatics analysis was used to annotate functional sites that were significantly associated with lung cancer susceptibility and were associated with strong epidemiological evidence reliability. The quality of evidence was assessed for sites that were not statistically relevant to the risk of lung cancer detected by meta-analysis. Based on the heterogeneity of the included studies, potential bias, and statistical efficacy of meta-analysis results, 13 SNPs with potential biological functions on different microRNAs were screened by bioinformatics analysis. In 626 lung cancer patients and 736 age-matched normal controls, sex matched with the case. Multivariate logistic regression analysis was used to analyze the association between different genotypes and susceptibility to lung cancer, and stratified analysis was performed based on pathological types of lung cancer and smoking status of individuals to assess the relationship between SNP loci and lung cancer risk in different subgroups. Result Part I: 1. After systematic literature search and literature screening, we finally included 1018 eligible literatures, which reported 2910 genetic variation sites on 754 different genes or chromosome loci. 2. 246 genetic variation loci (sites) were evaluated by meta-analysis. Based on meta-analysis and Venice Standard Assessment, 22 loci (located in 21 different genes) were found to be significantly associated with the risk of lung cancer, and the association had strong epidemiological evidence reliability. The 22 genetic variation loci were APEX1 rs1130409, APEX1 rs176094. 4, ATM rs66464677, AXIN2 rs66464777, AXIN2 rs2240308, CHRNA 3 rs64646495309, CHRNA 5 rs1696969968, CHRNA 5 rs1696969968, CLPTM1L rs402710, CXCR2 rs1126579, CYP1A1rs46464646903, CYP2E1rs6413413432, ERCC1 rs11611611611611611611615, ERCC2 rs131811 181, FGFR4 rs351855 rs351855, HYKrs93931794 rs931794 rs2910164 19164, MIR1196196A211619119113 11611611619113 11311311311311311311311311311321313, OGG11052132132133, OGG12132132132132133, G11 1 1 SOD2 rs4880, TERT rs2736098 and TP Bioinformatics analysis showed that most of the 22 genetic variants could affect the gene expression and/or function by altering protein coding sequences or influencing DNA regulatory elements. 4. Meta analysis revealed 150 genetic variants (from 98 different genes) associated with lung cancer. There was no significant correlation between risks. Evidence quality assessment found that meta-analysis of 7 sites (ERCC1 rs16979802, ERCC1 rs2298881, ERCC1 rs735482, POLI rs3730668, PPARG rs1801282, PTGS2 rs2041 7 and TNF rs1799724) had high quality and reliability of epidemiological evidence. Thirteen potential functional SNPs loci (rs11597888 G/A, rs12803915 G/A, rs16867808 T/C, rs2292879 A/G, rs45530340 C/T, rs5997893 G/A, rs61747536 C/T, rs62085660 C/G, rs64546 G/A, rs6717413 A/G, rs7247237 C/T, rs745666/C and rs999665 G/A) were analyzed and screened. The association between some SNPs loci and the risk of lung cancer was not statistically significant (P > 0.05). 2. Subgroup analysis based on pathological types of lung cancer revealed that the heterozygote GA genotype at rs11597888 (GA) locus significantly increased the risk of lung adenocarcinoma (co-dominant model: corrected OR = 1.34, 95% CI = 1.00-1.79, P = 0.046); Both variant allele G and variant genotype (CG + GG) at 60 (CG) locus significantly reduced the risk of lung squamous cell carcinoma (additive model: corrected OR = 0.79, 95% CI = 0.62-1.00, P = 0.049; dominant model: corrected OR = 0.72, 95% CI = 0.53-0.98, P = 0.035). 3. Subgroup analysis based on smoking status revealed that variant genotype (GA + AA) at rs11597888 (GA) locus. The risk of lung cancer in smokers was significantly increased (co-dominant model: corrected OR = 1.44, 95% CI = 1.02-2.02, P = 0.037; dominant model: corrected OR = 1.42, 95% CI = 1.03-1.96, P = 0.033); rs16867808 (TC) locus was significantly correlated with the risk of lung cancer in smokers under multiple hypothetical genetic models (additive model: corrected OR = 0.58, 95% CI = 0.40-0.84). Co-dominance model: Corrected OR = 0.55, 95% CI = 0.35-0.85, P = 0.007; Dominant model: Corrected OR = 0.53, 95% CI = 0.35-0.81, P = 0.004). Functional annotations of Haplo Reg database showed that three loci (rs11597888 G/A, rs62085660 C/G and rs16867808 T/C) identified by subgroup analysis were significantly associated with lung cancer susceptibility in lung cancer tissues and other tissues. DNA regulatory element regions (promoter region and/or enhancer region), Dnase I hypersensitive region, related transcription factor binding sites and motifs that can be altered in a variety of tissues and cells. Among them, rs62085660 C/G and rs16867808 T/C loci are quantitative trait loci for expression of multiple genes. Based on the integrated system assessment, meta-analysis and epidemiological evidence quality grading, it was found that about 9% (22/246) of the genetic variant loci were significantly associated with the susceptibility of lung cancer in all the reported association studies of candidate genes for lung cancer genetic susceptibility, and the evaluation of epidemiological evidence was highly reliable. The study and bioinformatics analysis showed that most of these loci could affect the gene expression and/or function by altering the protein coding sequence or influencing regulatory elements. 2. Case-control study design-based association analysis revealed that rs11597888 G/A (microNA AL391839.1), rs62085660 C/G (microNA AC145). 343.1 and rs16867808 T/C (microNA AL021918.2) loci were significantly associated with the risk of lung cancer, respectively. However, the association between these three SNPs and lung cancer susceptibility could only be observed in a specific subgroup of people, including: rs11597888 (GA) locus and the risk of lung adenocarcinoma, and the risk of lung cancer in smokers. The results of this study provide the latest and comprehensive evidence for the study of genetic risk effects of lung cancer. At the same time, we found a new microRNA SNPs locus associated with lung cancer susceptibility. It provides a powerful clue for the follow-up study of lung cancer risk, and provides a theoretical basis for the individual prevention and treatment of lung cancer.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R734.2
本文編號：2180446
[Abstract]:Background Lung cancer is the most common malignancy. In addition to environmental factors such as smoking, genetic factors play an important role in the development of lung cancer. Differences in individual genetic susceptibility are significantly associated with the risk of lung cancer. One of the main methods of genetic susceptibility research, more than 1000 papers have studied the association between genetic polymorphism and lung cancer susceptibility based on candidate gene strategies. There is a lack of integrated systematic evaluation of the large number of studies, meta-analysis, and hierarchical evaluation of the reliability of overall epidemiological evidence. In addition, the reported genetic association studies of lung cancer focus on DNA splicing. The genetic variation sites of repair genes, metabolic enzymes genes, immune pathway related genes, apoptosis pathway genes and other protein coding genes are rarely concerned with the susceptibility to lung cancer. However, a large number of non-coding RNAs (nc RNAs) exist in the human genome. Many of the important roles of NC RNAs in lung cancer and many other tumors have been gradually confirmed, especially the role of microRNAs in tumors. In recent years, studies have found that single nucleotide polymorphisms (SNPs) sites in the microRNA gene are also associated with the risk of some tumors. Previous studies on the association of microRNAs with lung cancer susceptibility are rare. More novel sites of microRNAs associated with lung cancer susceptibility need to be explored to provide new clues for the etiological study of lung cancer. Objective 1. The current publication is based on integrated system assessment, meta-analysis and epidemiological evidence quality grading. All candidate genes associated with lung cancer risk were analyzed to identify, validate and explain the association between previously reported genetic variation sites and lung cancer risk. To explore the association between SNPs on the microRNAs and the risk of lung cancer, and to explore new SNPs on the microRNAs associated with lung cancer susceptibility. 1. Systematic literature search and evaluation of all candidate gene association studies on lung cancer susceptibility published as of November 1, 2015. Meta-analysis was used to assess the association between genetic variants and susceptibility to lung cancer. Subgroup analysis was also performed based on race, pathological typing, and smoking status. Evidence reliability. Further, bioinformatics analysis was used to annotate functional sites that were significantly associated with lung cancer susceptibility and were associated with strong epidemiological evidence reliability. The quality of evidence was assessed for sites that were not statistically relevant to the risk of lung cancer detected by meta-analysis. Based on the heterogeneity of the included studies, potential bias, and statistical efficacy of meta-analysis results, 13 SNPs with potential biological functions on different microRNAs were screened by bioinformatics analysis. In 626 lung cancer patients and 736 age-matched normal controls, sex matched with the case. Multivariate logistic regression analysis was used to analyze the association between different genotypes and susceptibility to lung cancer, and stratified analysis was performed based on pathological types of lung cancer and smoking status of individuals to assess the relationship between SNP loci and lung cancer risk in different subgroups. Result Part I: 1. After systematic literature search and literature screening, we finally included 1018 eligible literatures, which reported 2910 genetic variation sites on 754 different genes or chromosome loci. 2. 246 genetic variation loci (sites) were evaluated by meta-analysis. Based on meta-analysis and Venice Standard Assessment, 22 loci (located in 21 different genes) were found to be significantly associated with the risk of lung cancer, and the association had strong epidemiological evidence reliability. The 22 genetic variation loci were APEX1 rs1130409, APEX1 rs176094. 4, ATM rs66464677, AXIN2 rs66464777, AXIN2 rs2240308, CHRNA 3 rs64646495309, CHRNA 5 rs1696969968, CHRNA 5 rs1696969968, CLPTM1L rs402710, CXCR2 rs1126579, CYP1A1rs46464646903, CYP2E1rs6413413432, ERCC1 rs11611611611611611611615, ERCC2 rs131811 181, FGFR4 rs351855 rs351855, HYKrs93931794 rs931794 rs2910164 19164, MIR1196196A211619119113 11611611619113 11311311311311311311311311311321313, OGG11052132132133, OGG12132132132132133, G11 1 1 SOD2 rs4880, TERT rs2736098 and TP Bioinformatics analysis showed that most of the 22 genetic variants could affect the gene expression and/or function by altering protein coding sequences or influencing DNA regulatory elements. 4. Meta analysis revealed 150 genetic variants (from 98 different genes) associated with lung cancer. There was no significant correlation between risks. Evidence quality assessment found that meta-analysis of 7 sites (ERCC1 rs16979802, ERCC1 rs2298881, ERCC1 rs735482, POLI rs3730668, PPARG rs1801282, PTGS2 rs2041 7 and TNF rs1799724) had high quality and reliability of epidemiological evidence. Thirteen potential functional SNPs loci (rs11597888 G/A, rs12803915 G/A, rs16867808 T/C, rs2292879 A/G, rs45530340 C/T, rs5997893 G/A, rs61747536 C/T, rs62085660 C/G, rs64546 G/A, rs6717413 A/G, rs7247237 C/T, rs745666/C and rs999665 G/A) were analyzed and screened. The association between some SNPs loci and the risk of lung cancer was not statistically significant (P > 0.05). 2. Subgroup analysis based on pathological types of lung cancer revealed that the heterozygote GA genotype at rs11597888 (GA) locus significantly increased the risk of lung adenocarcinoma (co-dominant model: corrected OR = 1.34, 95% CI = 1.00-1.79, P = 0.046); Both variant allele G and variant genotype (CG + GG) at 60 (CG) locus significantly reduced the risk of lung squamous cell carcinoma (additive model: corrected OR = 0.79, 95% CI = 0.62-1.00, P = 0.049; dominant model: corrected OR = 0.72, 95% CI = 0.53-0.98, P = 0.035). 3. Subgroup analysis based on smoking status revealed that variant genotype (GA + AA) at rs11597888 (GA) locus. The risk of lung cancer in smokers was significantly increased (co-dominant model: corrected OR = 1.44, 95% CI = 1.02-2.02, P = 0.037; dominant model: corrected OR = 1.42, 95% CI = 1.03-1.96, P = 0.033); rs16867808 (TC) locus was significantly correlated with the risk of lung cancer in smokers under multiple hypothetical genetic models (additive model: corrected OR = 0.58, 95% CI = 0.40-0.84). Co-dominance model: Corrected OR = 0.55, 95% CI = 0.35-0.85, P = 0.007; Dominant model: Corrected OR = 0.53, 95% CI = 0.35-0.81, P = 0.004). Functional annotations of Haplo Reg database showed that three loci (rs11597888 G/A, rs62085660 C/G and rs16867808 T/C) identified by subgroup analysis were significantly associated with lung cancer susceptibility in lung cancer tissues and other tissues. DNA regulatory element regions (promoter region and/or enhancer region), Dnase I hypersensitive region, related transcription factor binding sites and motifs that can be altered in a variety of tissues and cells. Among them, rs62085660 C/G and rs16867808 T/C loci are quantitative trait loci for expression of multiple genes. Based on the integrated system assessment, meta-analysis and epidemiological evidence quality grading, it was found that about 9% (22/246) of the genetic variant loci were significantly associated with the susceptibility of lung cancer in all the reported association studies of candidate genes for lung cancer genetic susceptibility, and the evaluation of epidemiological evidence was highly reliable. The study and bioinformatics analysis showed that most of these loci could affect the gene expression and/or function by altering the protein coding sequence or influencing regulatory elements. 2. Case-control study design-based association analysis revealed that rs11597888 G/A (microNA AL391839.1), rs62085660 C/G (microNA AC145). 343.1 and rs16867808 T/C (microNA AL021918.2) loci were significantly associated with the risk of lung cancer, respectively. However, the association between these three SNPs and lung cancer susceptibility could only be observed in a specific subgroup of people, including: rs11597888 (GA) locus and the risk of lung adenocarcinoma, and the risk of lung cancer in smokers. The results of this study provide the latest and comprehensive evidence for the study of genetic risk effects of lung cancer. At the same time, we found a new microRNA SNPs locus associated with lung cancer susceptibility. It provides a powerful clue for the follow-up study of lung cancer risk, and provides a theoretical basis for the individual prevention and treatment of lung cancer.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R734.2
【參考文獻】
相關(guān)期刊論文 前1條
1 陳萬青;張思維;鄒小農(nóng);;中國肺癌發(fā)病死亡的估計和流行趨勢研究[J];中國肺癌雜志;2010年05期
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