發(fā)布時(shí)間：2018-05-23 19:04

  本文選題：HCV + NSCLC��； 參考：《北京協(xié)和醫(yī)學(xué)院》2014年碩士論文

【摘要】：背景：MHCI類抗原呈遞基因系統(tǒng)在對(duì)抗病毒的有效應(yīng)答中起著關(guān)鍵作用。內(nèi)質(zhì)網(wǎng)氨肽酶1(endoplasmic reticulum aminopeptidase1, ERAP1)是抗原遞呈中的重要分子,已有研究報(bào)道,ERAP1基因的多態(tài)性可影響抗原呈遞,引起免疫應(yīng)答的差異導(dǎo)致與疾病的關(guān)聯(lián)不同。目前的研究集中于自身免疫性疾病,已有多個(gè)研究發(fā)現(xiàn)ERAP1與自身免疫性疾病的發(fā)生發(fā)展密切相關(guān)。那么,ERAP1基因單核苷酸多態(tài)(single nucleotide polymorphism, SNP)是否會(huì)影響抗原呈遞過程從而與丙型肝炎病毒(hepatitis C virus, HCV)感染、非小細(xì)胞性肺癌(non-small cell lung cancer, NSCLC)患病風(fēng)險(xiǎn)相關(guān)有待于進(jìn)一步探討。此外,云南省由于其獨(dú)特的地理位置,成為HCV等血液傳播疾病傳入我國大陸的重要門戶,也使其HCV的分布呈現(xiàn)出與其他地區(qū)不同的特點(diǎn)。因此,本研究首先開展了ERAP1與HCV感染及NSCLC的相關(guān)性研究,在此基礎(chǔ)上,結(jié)合云南人群HCV感染特點(diǎn),對(duì)不同的HCV基因型與ERAP1基因多態(tài)性之間的相關(guān)性進(jìn)行了初步探討。 方法：本研究分為三部分。第一部分以云南地區(qū)HCV感染者376名、正常健康對(duì)照324名為研究對(duì)象,研究ERAP1基因單核苷酸多態(tài)性與HCV感染的相關(guān)性。采用Taq Man探針基因分型方法檢測云南漢族正常人群及HCV感染者的ERAP1基因單核苷酸多態(tài)性,進(jìn)行HCV感染的關(guān)聯(lián)性分析。第二部分以云南地區(qū)HCV一般感染人群(general population, GP)為研究對(duì)象,首先研究一般感染人群中HCV基因型和亞型的流行狀況。采用RT-PCR的方法擴(kuò)增HCV NS5B片段并測序,對(duì)云南一般人群HCV感染者進(jìn)行HCV基因分型,探索云南一般感染人群HCV流行趨勢。在此基礎(chǔ)上,結(jié)合HCV感染者的ERAP1基因信息,分析不同HCV基因型與ERAP1基因多態(tài)性的相關(guān)性。第三部分以云南地區(qū)非小細(xì)胞肺癌患者224例、正常健康對(duì)照組207例為研究對(duì)象,研究ERAP1基因單核苷酸多態(tài)性與非小細(xì)胞肺癌的遺傳易感性。采用Taq Man探針基因分型方法對(duì)ERAP1基因單核苷酸多態(tài)性進(jìn)行分析,探索ERAP1基因單核苷酸多態(tài)性與非小細(xì)胞肺癌患病風(fēng)險(xiǎn)的相關(guān)性。 結(jié)果：(1)HCV感染組和對(duì)照組4個(gè)ERAP1基因SNP位點(diǎn)基因型的分布符合HWE平衡,人群具有代表性。其中rs26618基因型和等位基因型頻率在病例組和對(duì)照組中的差異具有統(tǒng)計(jì)學(xué)意義(P0.05),病例組和對(duì)照組rs27044/rs30187/rs26618/rs26653-CCCG的單倍型頻率差異具有統(tǒng)計(jì)學(xué)意義,P值為0.029(P0.05)。(2)云南地區(qū)一般感染人群存在4種HCV基因型(1、2、3和6),7種HCV亞型(1b、2a、3a、3a、6a、6n和6k)。HCV3型是主要流行的基因型,頻率為0.484,其次是HCV1型(0.283)、6型(0.133)和2型(0.100)；其中HCV3b亞型(0.292)和1b亞型(0.283)是主要流行的亞型。云南一般感染人群HCV的分布呈現(xiàn)出與其他地區(qū)不同的特點(diǎn)：HCV1和3型的頻率在云南和重慶、云南和廣東具有顯著性的差異(P0.05),而在云南和廣西的頻率分布相似；HCV6型的頻率在云南和廣西、廣東、越南、緬甸地區(qū)分布存在顯著性差異(P0.05),而云南和重慶的頻率分布卻相似。另一方面,云南一般感染人群與靜脈吸毒人群HCV基因型分布相比較亦存在顯著性差異：HCV基因型(1、2和6)及其亞型(1b、2a、6a和6n)在一般感染人群與靜脈吸毒人群中的頻率有顯著性差異(P0.05),經(jīng)HCV3a和6a構(gòu)樹分析,一般感染人群與靜脈吸毒人群的HCV基因型分布呈“交叉”樣。ERAP1rs30187位點(diǎn)的基因型頻率在不同的HCV基因型(1,2,3和6)和不同的HCV亞型(lb,2a,3a,3b和6n)中有顯著性的差異(P0.05)。(3) NSCLC病例組和對(duì)照組2個(gè)ERAP1基因SNP位點(diǎn)基因型的分布符合HWE平衡,人群具有代表性。ERAPl基因rs26618和rs26653基因型和等位基因頻率差異有統(tǒng)計(jì)學(xué)意義(P0.05)。病例組和對(duì)照rs26618/rs26653-CG、TC的單倍型頻率差異有統(tǒng)計(jì)學(xué)意義(P0.05)。而ERAP1基因rs26618、rs26653位點(diǎn)的基因型和等位基因的頻率在腺癌和鱗癌、Ⅰ+Ⅱ期和Ⅲ+Ⅳ期非小細(xì)胞肺癌患者中的差異不具有統(tǒng)計(jì)學(xué)意義(P0.05)。 結(jié)論：(1) ERAP1基因多態(tài)性與HCV感染有著顯著的易感關(guān)聯(lián),rs27044/rs30187/rs26618/rs26653-CCCG單倍型可能增加HCV感染的患病風(fēng)險(xiǎn)(OR=1.311,95%CI:1.028-1.671).(2)云南地區(qū)一般感染人群HCV基因型和亞型的分布與靜脈吸毒人群有著明顯的不同,且HCV基因型和亞型正從靜脈吸毒人群向一般感染人群傳播。不同的HCV基因型、亞型與ERAP1基因多態(tài)性有一定的關(guān)聯(lián)。(3) ERAP1基因多態(tài)性與NSCLC的發(fā)生有關(guān),rs26618/rs26653-CG單倍型可能增加NSCLC的患病風(fēng)險(xiǎn)(OR=1.725,95%CI:1.270-2.343), rs26618/rs26653-TC單倍型對(duì)NSCLC可能具有保護(hù)性作用(OR=0.668,95%CI:0.510-0.874).
[Abstract]:Background: MHCI antigen presenting gene system plays a key role in the effective response to the virus. Endoplasmic reticulum aminopeptidase 1 (endoplasmic reticulum aminopeptidase1, ERAP1) is an important molecule in antigen presentation. It has been reported that the polymorphism of the ERAP1 gene can affect the antigenic presentation, causing differences in immune response and disease. The current study is focused on autoimmune diseases. Many studies have found that ERAP1 is closely related to the development of autoimmune diseases. Then, the ERAP1 gene single nucleotide polymorphism (single nucleotide polymorphism, SNP) will affect the antigen presentation process and the hepatitis C virus, HCV, and HCV. The risk of infection, non small cell lung cancer (non-small cell lung cancer, NSCLC) remains to be further discussed. In addition, Yunnan province has become an important gateway to the mainland of our country because of its unique geographical location, and the distribution of HCV is different from other regions. Therefore, this study is the first. The correlation between ERAP1 and HCV infection and NSCLC was first carried out. On this basis, the correlation between different HCV genotypes and ERAP1 gene polymorphisms was preliminarily discussed in combination with the characteristics of HCV infection in Yunnan population.
Methods: This study was divided into three parts. In the first part, the correlation between single nucleotide polymorphisms of ERAP1 gene and HCV infection was studied in 376 people with HCV infection in Yunnan and 324 normal healthy controls. The single nucleotide polymorphisms of ERAP1 gene in the normal and HCV infected people of Yunnan were detected by Taq Man probe genotyping. The correlation analysis of HCV infection. In the second part, the HCV general infection population (general population, GP) in Yunnan area was used as the research object. First, the prevalence of HCV genotype and subtype in the general infection population was studied. RT-PCR was used to amplify NS5B fragment and sequence of HCV in the general population of Yunnan, and HCV gene score was carried out for HCV infected persons in general population of Yunnan. On the basis of ERAP1 gene information of people infected with HCV, the correlation between different HCV genotypes and ERAP1 gene polymorphisms was analyzed on the basis of the ERAP1 gene information of the people infected with Yunnan. The third part was the study of 224 cases of non small cell lung cancer in Yunnan and 207 cases of normal healthy control group, and the single nucleotide polymorphisms of ERAP1 gene were studied. The genetic susceptibility to non small cell lung cancer was analyzed by the Taq Man probe genotyping method, and the correlation between the single nucleotide polymorphisms of the ERAP1 gene and the risk of non small cell lung cancer was explored.
Results: (1) the distribution of the SNP loci of the 4 ERAP1 genes in the HCV infection group and the control group conformed to the HWE balance, and the population was representative. The difference between the rs26618 genotype and the allele genotype frequency in the case group and the control group was statistically significant (P0.05), and the frequency of the haplotype of the case group and the rs27044/rs30187/rs26618/rs26653-CCCG group was the same. The difference was statistically significant, the P value was 0.029 (P0.05). (2) there were 4 HCV genotypes (1,2,3 and 6) in the general infection population in Yunnan, and 7 HCV subtypes (1b, 2a, 3a, 3a, 6a, 6N and 6K) were the main genotypes, the frequency was 0.484, followed by 0.283, 6 (0.133) and 2 (0.100). The distribution of HCV in Yunnan is different from other regions: the frequency of HCV1 and type 3 has significant differences in Yunnan and Chongqing, Yunnan and Guangdong (P0.05), while the frequency distribution in Yunnan and Guangxi is similar; the frequency of HCV6 is divided in Yunnan and Guangxi, Guangdong, Vietnam and Burma. There were significant differences in distribution (P0.05), while the frequency distribution in Yunnan and Chongqing was similar. On the other hand, there was a significant difference in the distribution of HCV genotypes between the general infection population of Yunnan and the intravenous drug users: the HCV genotype (1,2 and 6) and its subtypes (1b, 2a, 6a and 6N) had a significant frequency in the general infection population and the intravenous drug users. P0.05, after HCV3a and 6A tree analysis, the genotype frequencies of the HCV genotype distribution of the general infected people and the intravenous drug users were "cross" like.ERAP1rs30187 loci in different HCV genotypes (1,2,3 and 6) and different HCV subtypes (LB, 2a, 3a, 3b, etc.). (3) 2 cases and control groups The distribution of the genotype SNP loci of the RAP1 gene conforms to the HWE balance, and there is a significant difference in the frequency difference between the rs26618 and rs26653 genotypes and the allele frequencies of the representative.ERAPl genes (P0.05). The frequency difference between the case group and the control rs26618/rs26653-CG, TC is statistically significant (P0.05). The frequencies of genotype and allele were not statistically significant in patients with adenocarcinoma and squamous cell carcinoma, stage I, + II and III + IV patients (P0.05).
Conclusion: (1) there is a significant association between ERAP1 gene polymorphism and HCV infection, and rs27044/rs30187/rs26618/rs26653-CCCG haplotype may increase the risk of HCV infection (OR=1.311,95%CI:1.028-1.671). (2) the distribution of HCV genotypes and subtypes in the general infection population in Yunnan region is significantly different from that of intravenous drug users, and the HCV base The type and subtype are spreading from the intravenous drug users to the general infection population. Different HCV genotypes and subtypes are associated with the polymorphism of the ERAP1 gene. (3) the polymorphism of the ERAP1 gene is associated with the occurrence of NSCLC, and the rs26618/rs26653-CG haplotype may increase the risk of NSCLC (OR=1.725,95%CI:1.270-2.343), and rs26618/rs26653-TC haploidy. Type NSCLC may have protective effects on OR=0.668,95%CI:0.510-0.874.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R512.63;R734.2

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