维生素D及维生素D结合蛋白基因多态性与高危人群HCV感染转归的关联研究

发布时间：2018-03-29 13:54

本文选题：肝炎　切入点：丙型　出处：《南京医科大学》2017年硕士论文

【摘要】：第一部分血浆中25-羟基维生素D水平与HCV感染及肝功能情况关系的研究[背景]丙型肝炎病毒(hepatitis C virus,HCV)感染是慢性肝脏疾病的主要原因之一,HCV感染极易慢性化,并可进一步发展为肝硬化、肝癌,在我国甚至全世界都是重要的公共卫生问题。据世界卫生组织统计,目前全球HCV的感染率为0.5%～1%,估计约0.71亿人感染,2015年新发病例约175万。但是,HCV感染及慢性化的机制尚不十分明确。近年来维生素D的免疫调节功能在多项研究中得以发现,维生素D水平的改变可能与HCV感染或者肝功能有关联。[目的]了解有偿献血人群血浆中25-羟基维生素D(25-hydroxyvitamin D,25(OH)D)水平及其与HCV感染及相关肝功能指标的关系。[方法]采取酶联免疫吸附法(enzyme linked immunosorbent assay,FLISA)检测HCV持续感染者(90例)、自限清除者(92例)和对照(99例)血浆中的25(OH)D水平,运用电感耦合等离子体质谱法(inductively coupled plasma mass spectrometry,ICP-MS)检测血浆中铜、铁、锌含量,偏相关和多因素Logistic回归分析血浆中25(OH)D水平与HCV感染及肝功能情况的关系。[结果]HCV持续感染组及自限清除组的血浆25(OH)D水平均低于健康对照组,HCV持续感染组血浆中锌含量低于对照组,铁含量高于对照组,差异均有统计学意义(均有P0.05);以年龄、性别、体质指数(body massindex,BMI)为协变量的偏相关分析结果发现,血浆25(OH)D、铁水平均与HCV RNA水平呈负相关(25(OH)D:r=—0.276,P=0.011;铁:r=-0.263,P=0.016),未发现25(OH)D与微量元素水平存在相关性(均有P0.05);以年龄、性别、BMI、各微量元素含量、25(OH)D等为自变量进行单因素和多因素Logistic回归分析,结果显示铁含量升高是HCV持续感染者血浆丙氨酸氨基转移酶(alanineamino transferase,ALT)水平升高的危险因素(OR=1.001,95%CI=1.000-1.002,P=0.030)。[结论]血浆维生素D水平、微量元素铁、锌可能和HCV感染转归相关,其中铁水平升高是HCV感染慢性化的独立危险因素。第二部分维生素D结合蛋白基因多态性与高危人群HCV感染转归的关联研究[背景]丙型肝炎病毒(hepatitis C virus,HCV)是常见的经血液播散的病原体,在世界范围内的感染率为0.5%～1%。机体感染病毒呈现不同的转归,少部分可以在六个月内自限清除,绝大多数则进展为慢性感染甚至可以发展为肝硬化和肝癌。研究认为感染谱间的差异不仅与病毒自身性质有关,同时也与宿主对HCV感染的遗传易感性及免疫学因素有关。关于维生素D与免疫的关系是近年来研究的热点,维生素D可能具有潜在的抗病毒、抗炎、抗纤维化以及免疫调节作用。而维生素D结合蛋白(vitamin D binding protein,VDBP),作为维生素D及其代谢物的主要结合和转运载体,可以影响维生素D水平。因此,VDBP基因遗传变异可能与HCV感染转归有关。[目的]探讨VDBP基因变异在HCV发生发展中的作用机制,为HCV感染慢性化的免疫机制以及制定个体化防治策略提供科学依据。[方法]本次病例对照研究共纳入HCV感染高危人群2506例(其中HCV持续感染者886例,自限清除者539例,健康对照1081例),采用多因素Logistic回归模型分析7个VDBP基因多态性位点(rs7041,rs222020,rs1155563,rs4588,rs3733359,rs17467825和rs16847024)的基因型与HCV易感性及慢性化的关联,并计算比值比(odds ratio,OR)及其 95%可信区间(confidence interva1,CI)。[结果]多因素Logistic回归分析结果显示,在调整年龄、性别和感染途径后,rs7041-G和rs3733359-T均与HCV感染易感性升高有关。与野生纯合基因型TT相比,携带rs7041-GG基因型的个体感染HCV的风险增加了107.5%(调整 OR=2.075,95%CI=1.384-3.110,P=4.09×10-4;相加模型:调整 OR=1.276,95%CI=I.095-1.488,P=0.002;隐性模型:调整 OR=1.961,95%CI=1.321-2.913,P=0.001)。与野生纯合基因型CC相比,携带rs3733359-CT 基因型的个体感染HCV 的风险增加了 32.8%(调整 OR=1.328,95%CI=1.090-1.619,P=0.005)。进一步分析显示,rs7041-G与rs3733359-T这两个危险等位基因与HCV感染风险增高呈显著的剂量-反应关系(Ptrend=8.16×10-4)。单倍型分析显示,相比于最常见的单倍型Ars17467825Crs4588Trs7041,携带单倍型Ars17467825Crs4588Gr7041的个体感染HCV 的风险增加了 20.2%(调整 OR=1.202,95%CI=1.016-1.423,P=0.032)。[结论]维生素D结合蛋白基因遗传变异(rs7041-G和rs3733359-T)可能与高危人群HCV感染易感性升高有关,提示其可能是影响HCV感染转归的一个重要因素,为进一步阐明中国人群HCV感染的潜在免疫学机制提供了理论依据。
[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.

【学位授予单位】：南京医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R512.63

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