乙肝后肝硬化易感性与细胞因子基因多态性的关系
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摘要
背景与目的:乙肝病毒(HBV)慢性感染者只有小部分最终发展为乙肝后肝硬化。肝硬化的发生除与环境因素、病毒因素有关外,还与患者的免疫遗传因素密切相关。有关细胞因子基因多态性与HBV感染临床转归的关系已有不少报道,但与乙肝后肝硬化的易感性报道不多,并缺乏系统性。本研究对5个细胞因子基因的8个多态性位点进行检测,以期较系统地分析细胞因子基因多态性与乙肝后肝硬化易感的关系,并筛选出主要的相关位点,为乙肝后肝硬化风险的分子预测奠定基础。
方法:
(1)研究对象:以165例乙肝后肝硬化患者(病例组)及136例HBsAg携带者(对照组)做为研究对象。
(2)基因多态性分析:采用酚-氯仿法提取外周血基因组DNA,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)或序列特异性引物法(PCR-SSP)分析基因位点TNF-α(-308和-238)、IL-1α(-889)、IL-1β(-511和+3953)、IL-10(-592)和IFN-γ(+884和+2109)的基因型。
(3)数据分析:计算各位点基因型和等位基因频率,比较组间各基因型的差异,并进行Hardy-Weinberg平衡吻合度检验。分别以总样本、按性别分层进行单因素Logistic回归分析,计算各基因型及等位基因的比数比(OR)及95%可信区间,以及进行多因素Logistic回归分析筛选独立的易感与保护基因型和等位基因。
结果:
(1)肿瘤坏死因子α基因-308G/A和-238G/A两位点的各基因型及等位基因频率在肝硬化组和HBsAg携带组之间的差异均无统计学意义(P>0.10),单因素和多因素Logistic分析也未显示它们与乙肝肝硬化易感性相关。
(2)白细胞介素1α-889C/T位点的各基因型及等位基因频率在肝硬化组和HBsAg携带组之间的差异无统计学意义(P>0.10),但多因素分析显示该位点与乙肝后肝硬化相关,CC为保护基因型(OR=0.416,P=0.040),T为易感等位基因(OR=2.361,P=0.044)。
(3)白细胞介素1β-511C/T和+3953C/T两位点的各基因型及等位基因频率在肝硬化组和HBsAg携带组之间差异均无统计学意义(P>0.10),但多因素分析显示-511C/T位点与男性肝硬化易感性相关,CC为男性易感基因型(OR=2.719,P=0.036),T为男性保护等位基因(OR=0.411,P=0.056),而+3953C/T位点与女性乙肝后肝硬化易感性可能有一定关系,CC基因型、CT基因型和T等位基因的OR值接近有统计学意义(P=0.071)。
(4)白细胞介素10基因-592A/C位点各基因型和等位基因在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),但单因素分析显示AC基因和C等位基因与肝硬化可能有一定关系,两者的OR值接近有统计学意义(P=0.077、0.057),多因素回归分析显示AC为易感基因型(OR=1.795,P=0.048),C为易感等位基因(OR=1.755,P=0.046);分性别多因素分析显示该位点主要与男性乙肝后肝硬化易感性相关,AC为男性易感等位基因(OR=2.865,P=0.006),C是易感等位基因(OR=2.665,P=0.012)。
(5)干扰素-γ+874T/A位点TT及TA基因型频率在两组间有差异(P=0.038、0.023),单因素回归分析TT、TA基因型和A等位基因与肝硬化可能有一定关系,各自OR值均接近有统计学意义(P=0.064、0.080和0.057),但多因素分析未显示其与肝硬化易感性有关。干扰素-γ+2109 A/G位点各基因型及等位基因频率在肝硬化组和HBsAg携带组之间的差异无统计学意义(P>0.10),多因素Logistic分析也未显示其与肝硬化易感性有关。(6)多因素Logistic回归分析显示IL1α-889、IL1β-511、IL-10 -592、INF +2109位点的某些基因型或等位基因均与男性乙肝肝硬化易感性相关(P=0.006~0.093),但在女性未显示有密切相关的基因型或等位基因,只有INF +2109AA与肝硬化易感性可能有一定关系(P=0.071)。
结论:
(1)肿瘤坏死因子a基因-238G/A位点和-308G/A位点基因多态性均与乙肝后肝硬化易感性无明显相关;
(2)白细胞介素1α-889C/T位点基因多态性与乙肝后肝硬化易感性相关,是独立的相关因素;
(3)白细胞介素1β-511C/T和1β+3953C/T位点基因多态性与乙肝后肝硬化相关,其中-511C/T位点与男性乙肝后肝硬化易感性密切相关,+3953C/T位点与女性乙肝后肝硬化易感性有一定关系;
(4)白细胞介素10 -592A/C位点基因多态性与乙肝后肝硬化易感性相关,尤其与男性乙肝后肝硬化易感性关系密切;
(5)干扰素-γ+874T/A位点多态性与乙肝后肝硬化易感性相关,但可能非独立相关因素,+2109 A/G位点多态性与男性乙肝肝硬化易感性可能有一定关系。
(6)细胞因子基因多态性与男性乙肝后肝硬化易感性关系密切,与女性关系不密切,可能是男性乙肝后肝硬化多于女性的原因之一。
Background and Objective: Only limited patients with chronic hepatitis B virus (HBV) infection will finally develop hepatic cirrhosis. Except environmental and viral factors, the host genetic immune background is closely associated with cirrhosis development. There are many reports about the association of cytokine gene polymorphisms with the clinical outcomes of HBV infection, in which only a few reports are involved in the susceptibility of HBV-related hepatic cirrhosis and also lack of systematic research. The aims of our study were to detect eight gene polymorphisms in five cytokine genes and systematically analyze the relationship between them and the susceptibility of HBV-related hepatic cirrhosis, and screen out the mainly related gene polymorphisms for our future studies about the molecule prediction of the cirrhosis risk in chronic HBV infectors.
Methods:
(1) Subjects: 165 HBV infectors with cirrhosis (case group) and 136 asymptomatic HBsAg carriers (control group) were recruited for the study.
(2) Gene polymorphism analysis: Genomic DNA was extracted from the peripheral blood by phenol-chloroform method. The genotypes of IL-1α(-889), IL-1β(-511, +3953), IL-10 (-592), TNF-α(-308, -238) and IFN-γ(+884, +2109) genes were determined by PCR-RFLP or PCR-SSP.
(3) Data analysis: The genotype and allele frequencies in each site were calculated and their differences between two groups were compared by chi-square test. The Hardy-Weinberg equilibriums of genotypes in each site were verified by chi-square test. The OR and its 95%CI of each genotype and allele were calculated by univariate Logistic regression analysis in total sample and gender-stratified sub-samples. The independent risk and protective genotypes and alleles were screened out by multivariate Logistic regression analyses.
Results:
(1) The differences of all genotype and allele frequencies at positions -308G/A and -238G/A of TNF-αgene were not significant between case group and control group (P>0.10). Univariate and multivariate Logistic regression analyses did not showed that these genotypes and alleles were associated with the susceptibility of HBV-related hepatic cirrhosis.
(2) The differences of all genotype and allele frequencies at position -889C/T of IL-1αgene were not significant between case group and control group (P>0.10). However, multivariate Logistic regression analysis indicated that this polymorphism site was associated with the susceptibility of cirrhosis, in which genotype CC is a protect genotype (OR=0.416,P=0.040) and allele T is the risk allele (OR=2.361,P=0.044).
(3) The differences of all genotype and allele frequencies at positions -511C/T and +3953C/T of IL-1β-889C/T were not significant between case group and control group (P>0.10). But multivariate analysis indicated -511C/T site was associated with the male cirrhosis susceptibility, in which CC was a risk genotype (OR=2.719, P=0.036) and T was a protective allele (OR=0.411, P=0.056), while +3953C/T site might be associated with female cirrhosis susceptibility, the ORs of genotype CC, CT and allele T nearly significant (P=0.071).
(4) The differences of all genotype and allele frequencies at position -592A/C of IL-10 gene were not significant between case group and control group (P>0.10). Univariate analysis indicated the genotype AC and the allele C might be associated with cirrhosis, their ORs nearly significant (P=0.077, 0.057). Multivariate analysis confirmed that AC was a risk genotype (OR=1.795, P=0.048), and C was a risk allele (OR=1.755, P=0.046). Multivariate analysis in gender-stratified sub-samples indicated that this site was mainly associated with the male cirrhosis susceptibility, in which AC was a risk genotype (OR=2.865, P=0.006), C was a risk allele (OR=2.665, P=0.012).
(5) The frequencies of genotype TT and TA of IFN-γ+874 site were significant between case group and control group (P=0.038, 0.023). Univariate analysis indicated that genotype TT and TA and allele A might be associated with liver cirrhosis, their ORs nearly significant (P=0.064, 0.080 and 0.057), but those were not confirmed in multivariate analysis. The differences of all genotype and allele frequencies at position +2109 A/G of IFN-γgene were not significant between case group and control group (P>0.10). Multivariate analyses also indicated that there were not associated with the susceptibility of HBV-related hepatic cirrhosis.
(6) Multivariate analyses showed that some genotypes or alleles in sites IL1α-889, IL1β-511, IL-10 -592 and INF +2109 were associated with the HBV-related cirrhosis susceptibility in male patients (P=0.006~0.093), but did not show significant genotypes or alleles in female patients, only INF +2109 AA was probably associated with female susceptibility of HBV-related hepatic cirrhosis (P=0.071).
Conclusions:
(1) Both of the gene polymorphism sites -238G/A and -308G/A of TNF-αare not associated with the susceptibility of HBV-related hepatic cirrhosis.
(2) The gene polymorphisms of IL-1α-889C/T site are associated with the susceptibility of HBV-related hepatic cirrhosis, and they are independent related factors.
(3) The gene polymorphisms of IL-1β-511C/T and +3953C/T sites are associated with the susceptibility of HBV-related hepatic cirrhosis, in which, -511C/T site is related to male susceptibility of HBV-related hepatic cirrhosis, and +3953C/T site may related to female susceptibility of HBV-related hepatic cirrhosis.
(4) The gene polymorphisms of -592A/C of IL-10 are associated with the susceptibility of HBV-related hepatic cirrhosis, especially in male patients.
(5) The gene polymorphisms of +874T/A of IFN-γare associated with the susceptibility of HBV-related hepatic cirrhosis, but it is not independent related factors. The gene polymorphisms of +2109A/G of IFN-γare probably associated with the male susceptibility of HBV-related hepatic cirrhosis.
(6) Cytokine gene polymorphisms are closely associated with male susceptibility of HBV-related hepatic cirrhosis, but not with female susceptibility. This may be an explanation for HBV-related cirrhosis more frequent in male than female.
方法:
(1)研究对象:以165例乙肝后肝硬化患者(病例组)及136例HBsAg携带者(对照组)做为研究对象。
(2)基因多态性分析:采用酚-氯仿法提取外周血基因组DNA,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)或序列特异性引物法(PCR-SSP)分析基因位点TNF-α(-308和-238)、IL-1α(-889)、IL-1β(-511和+3953)、IL-10(-592)和IFN-γ(+884和+2109)的基因型。
(3)数据分析:计算各位点基因型和等位基因频率,比较组间各基因型的差异,并进行Hardy-Weinberg平衡吻合度检验。分别以总样本、按性别分层进行单因素Logistic回归分析,计算各基因型及等位基因的比数比(OR)及95%可信区间,以及进行多因素Logistic回归分析筛选独立的易感与保护基因型和等位基因。
结果:
(1)肿瘤坏死因子α基因-308G/A和-238G/A两位点的各基因型及等位基因频率在肝硬化组和HBsAg携带组之间的差异均无统计学意义(P>0.10),单因素和多因素Logistic分析也未显示它们与乙肝肝硬化易感性相关。
(2)白细胞介素1α-889C/T位点的各基因型及等位基因频率在肝硬化组和HBsAg携带组之间的差异无统计学意义(P>0.10),但多因素分析显示该位点与乙肝后肝硬化相关,CC为保护基因型(OR=0.416,P=0.040),T为易感等位基因(OR=2.361,P=0.044)。
(3)白细胞介素1β-511C/T和+3953C/T两位点的各基因型及等位基因频率在肝硬化组和HBsAg携带组之间差异均无统计学意义(P>0.10),但多因素分析显示-511C/T位点与男性肝硬化易感性相关,CC为男性易感基因型(OR=2.719,P=0.036),T为男性保护等位基因(OR=0.411,P=0.056),而+3953C/T位点与女性乙肝后肝硬化易感性可能有一定关系,CC基因型、CT基因型和T等位基因的OR值接近有统计学意义(P=0.071)。
(4)白细胞介素10基因-592A/C位点各基因型和等位基因在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),但单因素分析显示AC基因和C等位基因与肝硬化可能有一定关系,两者的OR值接近有统计学意义(P=0.077、0.057),多因素回归分析显示AC为易感基因型(OR=1.795,P=0.048),C为易感等位基因(OR=1.755,P=0.046);分性别多因素分析显示该位点主要与男性乙肝后肝硬化易感性相关,AC为男性易感等位基因(OR=2.865,P=0.006),C是易感等位基因(OR=2.665,P=0.012)。
(5)干扰素-γ+874T/A位点TT及TA基因型频率在两组间有差异(P=0.038、0.023),单因素回归分析TT、TA基因型和A等位基因与肝硬化可能有一定关系,各自OR值均接近有统计学意义(P=0.064、0.080和0.057),但多因素分析未显示其与肝硬化易感性有关。干扰素-γ+2109 A/G位点各基因型及等位基因频率在肝硬化组和HBsAg携带组之间的差异无统计学意义(P>0.10),多因素Logistic分析也未显示其与肝硬化易感性有关。(6)多因素Logistic回归分析显示IL1α-889、IL1β-511、IL-10 -592、INF +2109位点的某些基因型或等位基因均与男性乙肝肝硬化易感性相关(P=0.006~0.093),但在女性未显示有密切相关的基因型或等位基因,只有INF +2109AA与肝硬化易感性可能有一定关系(P=0.071)。
结论:
(1)肿瘤坏死因子a基因-238G/A位点和-308G/A位点基因多态性均与乙肝后肝硬化易感性无明显相关;
(2)白细胞介素1α-889C/T位点基因多态性与乙肝后肝硬化易感性相关,是独立的相关因素;
(3)白细胞介素1β-511C/T和1β+3953C/T位点基因多态性与乙肝后肝硬化相关,其中-511C/T位点与男性乙肝后肝硬化易感性密切相关,+3953C/T位点与女性乙肝后肝硬化易感性有一定关系;
(4)白细胞介素10 -592A/C位点基因多态性与乙肝后肝硬化易感性相关,尤其与男性乙肝后肝硬化易感性关系密切;
(5)干扰素-γ+874T/A位点多态性与乙肝后肝硬化易感性相关,但可能非独立相关因素,+2109 A/G位点多态性与男性乙肝肝硬化易感性可能有一定关系。
(6)细胞因子基因多态性与男性乙肝后肝硬化易感性关系密切,与女性关系不密切,可能是男性乙肝后肝硬化多于女性的原因之一。
Background and Objective: Only limited patients with chronic hepatitis B virus (HBV) infection will finally develop hepatic cirrhosis. Except environmental and viral factors, the host genetic immune background is closely associated with cirrhosis development. There are many reports about the association of cytokine gene polymorphisms with the clinical outcomes of HBV infection, in which only a few reports are involved in the susceptibility of HBV-related hepatic cirrhosis and also lack of systematic research. The aims of our study were to detect eight gene polymorphisms in five cytokine genes and systematically analyze the relationship between them and the susceptibility of HBV-related hepatic cirrhosis, and screen out the mainly related gene polymorphisms for our future studies about the molecule prediction of the cirrhosis risk in chronic HBV infectors.
Methods:
(1) Subjects: 165 HBV infectors with cirrhosis (case group) and 136 asymptomatic HBsAg carriers (control group) were recruited for the study.
(2) Gene polymorphism analysis: Genomic DNA was extracted from the peripheral blood by phenol-chloroform method. The genotypes of IL-1α(-889), IL-1β(-511, +3953), IL-10 (-592), TNF-α(-308, -238) and IFN-γ(+884, +2109) genes were determined by PCR-RFLP or PCR-SSP.
(3) Data analysis: The genotype and allele frequencies in each site were calculated and their differences between two groups were compared by chi-square test. The Hardy-Weinberg equilibriums of genotypes in each site were verified by chi-square test. The OR and its 95%CI of each genotype and allele were calculated by univariate Logistic regression analysis in total sample and gender-stratified sub-samples. The independent risk and protective genotypes and alleles were screened out by multivariate Logistic regression analyses.
Results:
(1) The differences of all genotype and allele frequencies at positions -308G/A and -238G/A of TNF-αgene were not significant between case group and control group (P>0.10). Univariate and multivariate Logistic regression analyses did not showed that these genotypes and alleles were associated with the susceptibility of HBV-related hepatic cirrhosis.
(2) The differences of all genotype and allele frequencies at position -889C/T of IL-1αgene were not significant between case group and control group (P>0.10). However, multivariate Logistic regression analysis indicated that this polymorphism site was associated with the susceptibility of cirrhosis, in which genotype CC is a protect genotype (OR=0.416,P=0.040) and allele T is the risk allele (OR=2.361,P=0.044).
(3) The differences of all genotype and allele frequencies at positions -511C/T and +3953C/T of IL-1β-889C/T were not significant between case group and control group (P>0.10). But multivariate analysis indicated -511C/T site was associated with the male cirrhosis susceptibility, in which CC was a risk genotype (OR=2.719, P=0.036) and T was a protective allele (OR=0.411, P=0.056), while +3953C/T site might be associated with female cirrhosis susceptibility, the ORs of genotype CC, CT and allele T nearly significant (P=0.071).
(4) The differences of all genotype and allele frequencies at position -592A/C of IL-10 gene were not significant between case group and control group (P>0.10). Univariate analysis indicated the genotype AC and the allele C might be associated with cirrhosis, their ORs nearly significant (P=0.077, 0.057). Multivariate analysis confirmed that AC was a risk genotype (OR=1.795, P=0.048), and C was a risk allele (OR=1.755, P=0.046). Multivariate analysis in gender-stratified sub-samples indicated that this site was mainly associated with the male cirrhosis susceptibility, in which AC was a risk genotype (OR=2.865, P=0.006), C was a risk allele (OR=2.665, P=0.012).
(5) The frequencies of genotype TT and TA of IFN-γ+874 site were significant between case group and control group (P=0.038, 0.023). Univariate analysis indicated that genotype TT and TA and allele A might be associated with liver cirrhosis, their ORs nearly significant (P=0.064, 0.080 and 0.057), but those were not confirmed in multivariate analysis. The differences of all genotype and allele frequencies at position +2109 A/G of IFN-γgene were not significant between case group and control group (P>0.10). Multivariate analyses also indicated that there were not associated with the susceptibility of HBV-related hepatic cirrhosis.
(6) Multivariate analyses showed that some genotypes or alleles in sites IL1α-889, IL1β-511, IL-10 -592 and INF +2109 were associated with the HBV-related cirrhosis susceptibility in male patients (P=0.006~0.093), but did not show significant genotypes or alleles in female patients, only INF +2109 AA was probably associated with female susceptibility of HBV-related hepatic cirrhosis (P=0.071).
Conclusions:
(1) Both of the gene polymorphism sites -238G/A and -308G/A of TNF-αare not associated with the susceptibility of HBV-related hepatic cirrhosis.
(2) The gene polymorphisms of IL-1α-889C/T site are associated with the susceptibility of HBV-related hepatic cirrhosis, and they are independent related factors.
(3) The gene polymorphisms of IL-1β-511C/T and +3953C/T sites are associated with the susceptibility of HBV-related hepatic cirrhosis, in which, -511C/T site is related to male susceptibility of HBV-related hepatic cirrhosis, and +3953C/T site may related to female susceptibility of HBV-related hepatic cirrhosis.
(4) The gene polymorphisms of -592A/C of IL-10 are associated with the susceptibility of HBV-related hepatic cirrhosis, especially in male patients.
(5) The gene polymorphisms of +874T/A of IFN-γare associated with the susceptibility of HBV-related hepatic cirrhosis, but it is not independent related factors. The gene polymorphisms of +2109A/G of IFN-γare probably associated with the male susceptibility of HBV-related hepatic cirrhosis.
(6) Cytokine gene polymorphisms are closely associated with male susceptibility of HBV-related hepatic cirrhosis, but not with female susceptibility. This may be an explanation for HBV-related cirrhosis more frequent in male than female.
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