發(fā)布時(shí)間：2018-03-29 13:54

  本文選題：肝炎　切入點(diǎn)：丙型　出處：《南京醫(yī)科大學(xué)》2017年碩士論文

【摘要】：第一部分血漿中25-羥基維生素D水平與HCV感染及肝功能情況關(guān)系的研究[背景]丙型肝炎病毒(hepatitis C virus,HCV)感染是慢性肝臟疾病的主要原因之一,HCV感染極易慢性化,并可進(jìn)一步發(fā)展為肝硬化、肝癌,在我國甚至全世界都是重要的公共衛(wèi)生問題。據(jù)世界衛(wèi)生組織統(tǒng)計(jì),目前全球HCV的感染率為0.5%～1%,估計(jì)約0.71億人感染,2015年新發(fā)病例約175萬。但是,HCV感染及慢性化的機(jī)制尚不十分明確。近年來維生素D的免疫調(diào)節(jié)功能在多項(xiàng)研究中得以發(fā)現(xiàn),維生素D水平的改變可能與HCV感染或者肝功能有關(guān)聯(lián)。[目的]了解有償獻(xiàn)血人群血漿中25-羥基維生素D(25-hydroxyvitamin D,25(OH)D)水平及其與HCV感染及相關(guān)肝功能指標(biāo)的關(guān)系。[方法]采取酶聯(lián)免疫吸附法(enzyme linked immunosorbent assay,FLISA)檢測HCV持續(xù)感染者(90例)、自限清除者(92例)和對照(99例)血漿中的25(OH)D水平,運(yùn)用電感耦合等離子體質(zhì)譜法(inductively coupled plasma mass spectrometry,ICP-MS)檢測血漿中銅、鐵、鋅含量,偏相關(guān)和多因素Logistic回歸分析血漿中25(OH)D水平與HCV感染及肝功能情況的關(guān)系。[結(jié)果]HCV持續(xù)感染組及自限清除組的血漿25(OH)D水平均低于健康對照組,HCV持續(xù)感染組血漿中鋅含量低于對照組,鐵含量高于對照組,差異均有統(tǒng)計(jì)學(xué)意義(均有P0.05);以年齡、性別、體質(zhì)指數(shù)(body massindex,BMI)為協(xié)變量的偏相關(guān)分析結(jié)果發(fā)現(xiàn),血漿25(OH)D、鐵水平均與HCV RNA水平呈負(fù)相關(guān)(25(OH)D:r=—0.276,P=0.011;鐵:r=-0.263,P=0.016),未發(fā)現(xiàn)25(OH)D與微量元素水平存在相關(guān)性(均有P0.05);以年齡、性別、BMI、各微量元素含量、25(OH)D等為自變量進(jìn)行單因素和多因素Logistic回歸分析,結(jié)果顯示鐵含量升高是HCV持續(xù)感染者血漿丙氨酸氨基轉(zhuǎn)移酶(alanineamino transferase,ALT)水平升高的危險(xiǎn)因素(OR=1.001,95%CI=1.000-1.002,P=0.030)。[結(jié)論]血漿維生素D水平、微量元素鐵、鋅可能和HCV感染轉(zhuǎn)歸相關(guān),其中鐵水平升高是HCV感染慢性化的獨(dú)立危險(xiǎn)因素。第二部分維生素D結(jié)合蛋白基因多態(tài)性與高危人群HCV感染轉(zhuǎn)歸的關(guān)聯(lián)研究[背景]丙型肝炎病毒(hepatitis C virus,HCV)是常見的經(jīng)血液播散的病原體,在世界范圍內(nèi)的感染率為0.5%～1%。機(jī)體感染病毒呈現(xiàn)不同的轉(zhuǎn)歸,少部分可以在六個(gè)月內(nèi)自限清除,絕大多數(shù)則進(jìn)展為慢性感染甚至可以發(fā)展為肝硬化和肝癌。研究認(rèn)為感染譜間的差異不僅與病毒自身性質(zhì)有關(guān),同時(shí)也與宿主對HCV感染的遺傳易感性及免疫學(xué)因素有關(guān)。關(guān)于維生素D與免疫的關(guān)系是近年來研究的熱點(diǎn),維生素D可能具有潛在的抗病毒、抗炎、抗纖維化以及免疫調(diào)節(jié)作用。而維生素D結(jié)合蛋白(vitamin D binding protein,VDBP),作為維生素D及其代謝物的主要結(jié)合和轉(zhuǎn)運(yùn)載體,可以影響維生素D水平。因此,VDBP基因遺傳變異可能與HCV感染轉(zhuǎn)歸有關(guān)。[目的]探討VDBP基因變異在HCV發(fā)生發(fā)展中的作用機(jī)制,為HCV感染慢性化的免疫機(jī)制以及制定個(gè)體化防治策略提供科學(xué)依據(jù)。[方法]本次病例對照研究共納入HCV感染高危人群2506例(其中HCV持續(xù)感染者886例,自限清除者539例,健康對照1081例),采用多因素Logistic回歸模型分析7個(gè)VDBP基因多態(tài)性位點(diǎn)(rs7041,rs222020,rs1155563,rs4588,rs3733359,rs17467825和rs16847024)的基因型與HCV易感性及慢性化的關(guān)聯(lián),并計(jì)算比值比(odds ratio,OR)及其 95%可信區(qū)間(confidence interva1,CI)。[結(jié)果]多因素Logistic回歸分析結(jié)果顯示,在調(diào)整年齡、性別和感染途徑后,rs7041-G和rs3733359-T均與HCV感染易感性升高有關(guān)。與野生純合基因型TT相比,攜帶rs7041-GG基因型的個(gè)體感染HCV的風(fēng)險(xiǎn)增加了107.5%(調(diào)整 OR=2.075,95%CI=1.384-3.110,P=4.09×10-4;相加模型:調(diào)整 OR=1.276,95%CI=I.095-1.488,P=0.002;隱性模型:調(diào)整 OR=1.961,95%CI=1.321-2.913,P=0.001)。與野生純合基因型CC相比,攜帶rs3733359-CT 基因型的個(gè)體感染HCV 的風(fēng)險(xiǎn)增加了 32.8%(調(diào)整 OR=1.328,95%CI=1.090-1.619,P=0.005)。進(jìn)一步分析顯示,rs7041-G與rs3733359-T這兩個(gè)危險(xiǎn)等位基因與HCV感染風(fēng)險(xiǎn)增高呈顯著的劑量-反應(yīng)關(guān)系(Ptrend=8.16×10-4)。單倍型分析顯示,相比于最常見的單倍型Ars17467825Crs4588Trs7041,攜帶單倍型Ars17467825Crs4588Gr7041的個(gè)體感染HCV 的風(fēng)險(xiǎn)增加了 20.2%(調(diào)整 OR=1.202,95%CI=1.016-1.423,P=0.032)。[結(jié)論]維生素D結(jié)合蛋白基因遺傳變異(rs7041-G和rs3733359-T)可能與高危人群HCV感染易感性升高有關(guān),提示其可能是影響HCV感染轉(zhuǎn)歸的一個(gè)重要因素,為進(jìn)一步闡明中國人群HCV感染的潛在免疫學(xué)機(jī)制提供了理論依據(jù)。
[Abstract]:Study [background] the first part of hepatitis C virus 25- hydroxy vitamin D levels and HCV infection and liver function in the relationship between plasma (hepatitis C virus, HCV) infection is a major cause of chronic liver disease, HCV infection easily and chronicity, can develop into liver cirrhosis, liver cancer, and even in our country the world is an important public health problem. According to the WHO statistics, the current global HCV infection rate was 0.5% ~ 1%, an estimated 71 million people infected, in 2015 about 1 million 750 thousand of new cases. However, the mechanism of HCV infection and chronic hepatitis is still not very clear. In recent years the immune regulating function of vitamin D is found in a number of studies changes in the level of vitamin D, may be associated with HCV infection or liver function. To understand the relevance of paid blood donors with 25- hydroxy vitamin D in plasma of the population (25-hydroxyvitamin D, 25 (OH) D) and HCV infection The relationship between liver function index method]. The enzyme linked immunosorbent assay (enzyme linked immunosorbent assay, FLISA) detection of HCV infection (90 cases), self limiting clearance (92 cases) and control (99 cases) in plasma 25 (OH) D level, using inductively coupled plasma mass spectrometry (inductively coupled plasma mass spectrometry, ICP-MS) in the plasma of copper, iron, zinc content, Logistic partial correlation and multiple regression analysis in plasma 25 (OH) the relationship between D level and HCV infection and liver function. The plasma group]HCV infection and self limiting clearance group 25 (OH) D the water was lower than that of healthy control group, HCV infection group. Plasma zinc content is lower than the control group, the content of iron was higher than the control group, the differences were statistically significant (all P0.05); by age, gender, body mass index (body, massindex, BMI) the results of partial correlation analysis for covariates found that plasma 25 (OH) D. Iron The level of HCV and RNA were negatively correlated with the level of (25 (OH) D:r= - 0.276, P=0.011; iron: r=-0.263, P=0.016), were found in 25 (OH) D is associated with the levels of trace elements (both P0.05); by age, gender, BMI, the content of trace elements, such as D (OH) 25 independent variables were analyzed by univariate and multivariate Logistic regression analysis showed that the iron content is increased HCV infection plasma alanine aminotransferase (alanineamino, transferase, ALT) the risk factors of elevated levels (OR=1.001,95%CI=1.000-1.002, P=0.030) D level. Conclusion] plasma vitamin, trace elements of iron, zinc and HCV infection outcome related to elevated iron levels which are independent risk factors for chronic HCV infection. The second part of the vitamin D binding protein gene polymorphism and HCV infection in high-risk population association study [background] outcome of hepatitis C virus (hepatitis C, virus, HCV) is a common blood The spread of the pathogen in the world within the scope of the infection rate was 0.5% ~ 1%. infection virus showed different outcomes, few can be within six months of self limiting clearance, most progress for chronic infection can even develop into liver cirrhosis and liver cancer. The research results indicate that the difference between the infection spectrum and the virus itself not only about the nature. At the same time with the host of genetic susceptibility and immunological factors of HCV infection. About the relationship between vitamin D and immunity is a research hotspot in recent years, vitamin D has potential antiviral, anti-inflammatory, anti fibrosis and immune regulation. The vitamin D binding protein (vitamin D binding protein, VDBP), as the main combination and transport of vitamin D and its metabolite carrier, can affect the level of vitamin D. Therefore, VDBP gene may be associated with HCV infection. To investigate the outcome of VDBP gene mutation The mechanism of the occurrence and development of HCV, as the immune mechanism of chronic HCV infection and individualized prevention strategies to provide a scientific basis. This method case-control study included 2506 cases of HCV infection in high-risk groups (886 cases, HCV infection in 539 cases, self limiting clearance, with 1081 cases of healthy control) multi factor Logistic regression model analysis of 7 VDBP gene polymorphisms (rs7041, rs222020, rs1155563, rs4588, rs3733359, rs17467825 and rs16847024) Association of genotype and susceptibility to HCV and chronicity, and calculate the odds ratio (odds ratio, OR) and 95% confidence interval (confidence, interva1, CI). The results of multiple factors Logistic regression analysis showed that after adjustment for age, gender and infection, rs7041-G and rs3733359-T were associated with susceptibility to HCV infection increased. Compared with the wild homozygous genotype TT, carrying rs7041-GG genotype A The risk of infection of HCV increased by 107.5% (adjusted OR=2.075,95%CI=1.384-3.110, P=4.09 * 10-4; additive model: adjust OR=1.276,95%CI=I.095-1.488, P=0.002; P=0.001: OR=1.961,95%CI=1.321-2.913 adjustment, recessive model). Compared with the wild homozygous genotype CC with rs3733359-CT genotype HCV infection had a 32.8% increased risk (adjusted OR=1.328,95%CI=1.090-1.619, P=0.005) for further analysis. Rs7041-G and rs3733359-T show that the two risk alleles and the risk of HCV infection showed a dose-response relationship between significantly increased (Ptrend=8.16 * 10-4). Haplotype analysis showed that compared with the most common haplotype Ars17467825Crs4588Trs7041 and haplotype Ars17467825Crs4588Gr7041 carrying HCV infection in individuals with increased risk of 20.2% (OR=1.202,95%CI=1.016-1.423, P=0.032). Conclusion: vitamin D (rs7041- binding protein gene, genetic variation G and rs3733359-T may be associated with an increased susceptibility to HCV infection in high-risk populations, suggesting that it may be an important factor affecting the outcome of HCV infection, providing a theoretical basis for further elucidating the potential immunological mechanism of HCV infection in Chinese population.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R512.63

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