多位点基因多态性分析与乙肝肝硬化风险的分子预测
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摘要
背景与目的:乙肝肝硬化一般不可逆转,应重在预防。慢性乙肝病毒(HBV)感染者只有少数发展为肝硬化,多数可长期处于无症状HBsAg携带状态,因此从中筛选出肝硬化高危个体并实施个体化预防措施,才是经济而有效的乙肝肝硬化预防策略。基于临床危险因素难以定量预测慢性HBV感染者肝硬化发生风险。单核苷酸多态性(SNP)占人类可遗传变异的90%以上,是目前诠释疾病遗传易感性最好的遗传标记,可用于疾病风险的定量预测。遗传背景差异可能是慢性HBV感染者肝硬化发生风险高低的重要原因。乙肝肝硬化属多基因病,必须筛选出一组相关SNP才能有效地判断个体的发病风险。本研究的目的就是对乙肝肝硬化发生过程中各个环节相关的多个基因多态性位点进行分析,探讨它们与肝硬化易感性的关系,同时建立数学模型对慢性HBV感染者的肝硬化发生风险进行个体化的分子定量预测。目前尚未见乙肝肝硬化易感性相关的多位点基因多态性的系统分析及相应的分子预测模型研究报道。
方法:本研究采用成组病例对照研究设计方案,病例组为乙肝肝硬化患者,对照组为无症状HBsAg携带者。选择11个基因的17个多态性位点(IL-1A-889C/T、IL-1B+3953C/T和-511C/T、IL-10-592A/C、IFN-γ+874T/A和+2109A/G、TNF-α-308G/A和-238G/A、CD14-159C/T、CTLA-4-318C/T、MEH Tyr113His和-613C/T、GSTM1null/normal、MMP-9-1562C/T、ER1+29T/C、AGT-20A/C和-6A/G)进行分析。采取酚-氯仿法抽提患者血凝块基因组DNA。采用PCR-RFLP或PCR-SSP技术对各基因位点进行基因型分析。计算不同组别的基因型和等位基因频率。单因素和多因素非条件Logistic回归分析观察各基因型和等位基因与乙肝肝硬化发生的相关性及其强度(OR值)。采用多因素Logistic逐步回归分析筛选独立的相关基因型或等位基因,建立乙肝肝硬化发生风险的分子预测模型,并对模型的预测效率进行评价。
结果:共有323例患者入选本研究,男226例,女97例,平均年龄51岁。乙肝肝硬化组168例,HBsAg携带组155例。两组间各年龄段例数构成比以及按性别分层统计的两组间各年龄段例数构成比的差异均无统计学意义(P=0.143~0.241)。基因多态性与乙肝肝硬化易感性的研究结果如下:
(1)基于总样本的单因素分析显示,IFN-γ+874T/A多态位点与乙肝肝硬化易感性相关,其中TT是保护基因型(OR=0.55,P=0.039),TA是易感基因型(OR=1.93,P=0.025),A是易感等位基因(OR=1.82,P=0.036);IL-10-592A/C多态位点与乙肝肝硬化易感性弱相关(P=0.057~0.077),其他多态位点无关(P>0.1)。多因素分析显示ER1+29TC为易感基因型(OR=2.00,P=0.024),ER1+29T等位基因、AGT-20AA基因型和C等位基因与乙肝肝硬化弱相关(P=0.059~0.072)。
(2)基于男性样本的单因素分析显示,IL-10-592A/C位点与男性乙肝肝硬化相关,其中AC是易感基因型(OR=1.86, P=0.042),AA基因型和C等位基因与肝硬化弱相关(P=0.076);IFN-γ+874T/A位点TA基因型也与男性乙肝肝硬化弱相关(P=0.074);其他多态位点无关(P>0.1)。多因素分析显示IL-10-592A/C位点的AC基因型(OR=3.79,P=0.002)或A等位基因(OR=3.70,P=0.049)、C等位基因(OR=3.70,P=0.049)均为危险因素。
(3)基于女性样本的单因素分析显示,ER1+29T/C多态位点与女性乙肝肝硬化易感性相关,其中TC为易感基因型(OR=3.28,P=0.006),T为易感等位基因(OR=3.10,P=0.013),CC为保护基因型(OR=0.32,P=0.013);IL-1B+3953C/T位点和MEH-613C/T位点与女性乙肝肝硬化易感性弱相关(P=0.076-0.089),其他多态位点无关(P>0.1)。多因素分析显示危险基因型和等位基因有ER1+29 TC基因型(OR=5.33,P=0.019)或T等位基因(OR=7.63,P=0.017)、CTLA-4-318CT基因型(OR=8.84,P=0.017)或T等位基因(OR=6.33,P=0.031)、IFN-γ+2109 AA基因型(OR=4.38,P=0.032),保护性基因型或等位基因有IL-1B+3593 CT基因型(OR=0.076,P=0.036)或T等位基因(OR=0061,P=0.026)、IFN-γ+2109 G等位基因(OR=0.174,P=0.012)。
(4)基于男女混合样本、男性样本和女性样本的基因多态性检测数据,能分别建立起3个相应的乙肝肝硬化风险预测模型。3个模型对各自的建模病人的预测准确率分别为70.1%、69.3%和79.4%,对各自对应的全部病人的预测准确率分别为67.1%、67.5%和77.9%。以各模型对所对应的全部病人的预测概率值绘制ROC曲线,曲线下面积分别为0.692、0.670和0.813。
结论:根据上述研究结果得出结论如下:
(1)所检测的多个基因多态性位点中,只有少数与慢性HBV感染者肝硬化易感性有关,多数关联不强或不相关;
(2)与乙肝肝硬化相关的基因多态性主要集中在免疫相关基因和雌激素受体α基因,尤其是细胞因子基因;
(3)男性与女性患者乙肝肝硬化易感性相关基因多态性位点有所不同,男性主要涉及细胞因子基因,女性患者除细胞因子基因外,还涉及雌激素受体α和细胞免疫相关基因;
(4)女性患者的乙肝肝硬化与遗传变异的相关性强于男性患者,更多的基因多态性位点与女性患者相关,提示男性乙肝肝硬化的预防应该更重视环境因素控制,而女性乙肝肝硬化的预防应该更重视遗传因素的影响。
(5)基于不同的基因多态性数据(混合样本、男性样本和女性样本),均能建立起有意义的乙肝肝硬化风险预测模型,女性患者的预测模型的预测效率良好,优于男性和不分性别的预测模型。
Background and objectives: HBV-related hepatic cirrhosis is usually irreversible; therefore the key is prevention in cirrhosis control. However, only minority of chronic HBV infectors finally develops cirrhosis, most of them will be asymptomatic HBsAg carriers for a long time. Identifying the infectors with high risk of cirrhosis development and then implementing individualized preventive measures is an economic and effective strategy for preventing cirrhosis. According to clinical risk factors, it is difficult to quantitatively predict the risk of cirrhosis development in chronic HBV infectors. Single nucleotide polymorphisms (SNPs) which account for over 90% genetic variations in human genome are the best genetic markers for explaining the hereditary susceptibility of diseases and suitable for quantitatively prediction. Different genetic background has been believed to be the main cause of cirrhosis development difference in chronic HBV infectors. Since HBV-related cirrhosis is a polygenic disease, a panel of SNPs should be screened out for cirrhosis risk prediction. The aims of the present study were to analyze the relationships between the HBV-related cirrhosis susceptibility and genetic polymorphisms involved in different stages of cirrhosis development and establish mathematic models for quantitatively molecular prediction of cirrhosis risk in chronic HBV infectors individually. So far, there is no report about systematic analysis of multiple genetic polymorphisms associated with HBV-related hepatic cirrhosis susceptibility and cirrhosis risk prediction in terms of them.
Methods: A grouped case-control study was designed for the study, in which the case was HBV infectors with cirrhosis, and the control was asymptomatic HBsAg carriers. Seventeen polymorphism sites of 11 genes were selected for analysis: IL-1A-889C/T, IL-1B+3953C/T and -511C/T, IL-10-592A/C, IFN-γ+874T/A and +2109A/G, TNF-α-308G/A and -238G/A, CD14-159C/T, CTLA-4-318C/T, MEH Tyr113His and -613C/T, GSTM1null/normal, MMP-9-1562C/T, ER1+29T/C, AGT-20A/C and -6A/G. The genomic DNA was extracted from peripheral blood clot of the patients by phenol-chloroform method. PCR-RFLP or PCR-SSP methods were applied to genotype each polymorphism site. Genotype and allele frequencies of each site were calculated in two groups. Univariate and multivariate non-conditional Logistic regression analyses were conducted to observe the association and its intensity of each genotype or allele with the risk of HBV-related cirrhosis. By means of multivariate stepwise Logistic regression analysis, the independent related genotypes or alleles were screened out and mathematic models were created for the molecular prediction of cirrhosis risk in chronic HBV infectors, and their predictive performances were evaluated.
Results: Three hundred and twenty three patients were recruited, including male 226, female 97, with the average age 51.0 years old. Of them, there were 168 patients with HBV-related hepatic cirrhosis and 155 asymptomatic HBsAg carriers. The differences of constituent ratios among age groups were not significant between case and control groups in total or different genders. The results about the genetic polymorphisms and cirrhosis were as follows:
(1) In univariate analyses of total sample, IFN-γ+874T/A site was associated with HBV-related cirrhosis, in which TT were protective genotype (OR=0.55, P=0.039), TA were risk genotype (OR=1.93, P=0.025) and A was risk allele (OR=1.82, P=0.036). IL-10-592A/C site was weakly associated with cirrhosis (P= 0.057~0.077). The other polymorphism sites were not correlated with cirrhosis (P>0.1). Multivariate analysis indicated that ER1+29TC was a risk genotype (OR=2.00, P=0.024) and ER1+29T allele, AGT-20AA genotype and C allele were weakly correlated with cirrhosis (P=0.059~0.072).
(2) In univariate analyses of male sample, IL-10-592 A/C site was associated with male HBV-related cirrhosis, in which AC was a risk genotype (OR=1.86, P=0.042), genotype AA and allele C were weakly correlated (P=0.076). Genotype TA of IFN-γ+874T/A site was also weakly correlated with male cirrhosis (P=0.074), other polymorphism sites were not correlated (P>0.1). Multivariate analyses screened out three risk genotypes or alleles of IL-10-592 site: genotype AC (OR=3.79, P=0.002) or allele A (OR=3.70, P=0.049), C allele (OR=3.70, P=0.049).
(3) In univariate analysis of female sample, ER1+29T/C site was associated with female HBV-related cirrhosis, in which TC was a risk genotype (OR=3.28, P=0.006) , T was risk allele (OR=3.10, P=0.013) and CC was protective genotype (OR=0.32, P=0.013) ; IL-1B+3953C/T and MEH-613C/T sites were weakly correlated with female cirrhosis (P=0.076-0.089); Other polymorphism sites were not correlated (P>0.1). Multivariate analyses showed that the risk genotypes and alleles were ER1+29 TC genotype (OR=5.33, P=0.019) or T allele (OR=7.63, P=0.017), CTLA-4-318 CT genotype (OR=8.84, P=0.017) or T allele (OR=6.33, P=0.031), and IFN-γ+2109 AA genotype (OR=4.38, P=0.032); The protective genotypes and alleles were IL-1B3593 CT genotype (OR=0.076, P=0.036) or T allele (OR=0061, P=0.026) and IFN-γ+2109 G allele (OR=0.174, P=0.012).
(4) Based on the three sets of genetic polymorphism data (gender-mixed patients, male patients and female patients), three prediction models were developed respectively. The prediction accuracies of the three models for their own training sample were 70.1%, 69.3% and 79.4%, respectively; the prediction accuracies for their own total sample were 67.1%, 67.5% and 77.9%, respectively. The areas under the ROC curves created according to the predictive probability values of the three models to corresponding total samples were 0.692, 0.670 and 0.813, respectively.
Conclusions: According to the results above, we conclude:
(1) In the gene polymorphism sites detected, only minority is correlated with cirrhosis susceptibility in chronic HBV infectors, most of them are weakly or not correlated.
(2) Genetic polymorphisms related to HBV-related hepatic cirrhosis are mainly involved in immune-related genes and estrogen receptor-alpha gene, especially the cytokine genes.
(3) There are differences between male and female patients in the gene polymorphisms related to HBV-related cirrhosis. In the male, mainly genetic polymorphisms involved are cytokine genes, while in the female, except cytokine genes, estrogen receptor-alpha gene and cellular-immune related genes were involved.
(4) The association of female HBV-related cirrhosis with genetic variation is closer than that of male patients, more genetic polymorphism sites associated and more intensely correlated in female patients,indicating that environmental risk factor control might be more important for prevention of cirrhosis in male HBV infectors, while in female HBV infectors, more attention should be paid to genetic risk factors.
(5) Based on the different genetic polymorphism data (total patients, male patients and female patients), corresponding models could be developed successfully for predicting HBV-related cirrhosis, respectively. The female-specific predictive model shows a good performance and better than male-specific and gender-mixed predictive models.
方法:本研究采用成组病例对照研究设计方案,病例组为乙肝肝硬化患者,对照组为无症状HBsAg携带者。选择11个基因的17个多态性位点(IL-1A-889C/T、IL-1B+3953C/T和-511C/T、IL-10-592A/C、IFN-γ+874T/A和+2109A/G、TNF-α-308G/A和-238G/A、CD14-159C/T、CTLA-4-318C/T、MEH Tyr113His和-613C/T、GSTM1null/normal、MMP-9-1562C/T、ER1+29T/C、AGT-20A/C和-6A/G)进行分析。采取酚-氯仿法抽提患者血凝块基因组DNA。采用PCR-RFLP或PCR-SSP技术对各基因位点进行基因型分析。计算不同组别的基因型和等位基因频率。单因素和多因素非条件Logistic回归分析观察各基因型和等位基因与乙肝肝硬化发生的相关性及其强度(OR值)。采用多因素Logistic逐步回归分析筛选独立的相关基因型或等位基因,建立乙肝肝硬化发生风险的分子预测模型,并对模型的预测效率进行评价。
结果:共有323例患者入选本研究,男226例,女97例,平均年龄51岁。乙肝肝硬化组168例,HBsAg携带组155例。两组间各年龄段例数构成比以及按性别分层统计的两组间各年龄段例数构成比的差异均无统计学意义(P=0.143~0.241)。基因多态性与乙肝肝硬化易感性的研究结果如下:
(1)基于总样本的单因素分析显示,IFN-γ+874T/A多态位点与乙肝肝硬化易感性相关,其中TT是保护基因型(OR=0.55,P=0.039),TA是易感基因型(OR=1.93,P=0.025),A是易感等位基因(OR=1.82,P=0.036);IL-10-592A/C多态位点与乙肝肝硬化易感性弱相关(P=0.057~0.077),其他多态位点无关(P>0.1)。多因素分析显示ER1+29TC为易感基因型(OR=2.00,P=0.024),ER1+29T等位基因、AGT-20AA基因型和C等位基因与乙肝肝硬化弱相关(P=0.059~0.072)。
(2)基于男性样本的单因素分析显示,IL-10-592A/C位点与男性乙肝肝硬化相关,其中AC是易感基因型(OR=1.86, P=0.042),AA基因型和C等位基因与肝硬化弱相关(P=0.076);IFN-γ+874T/A位点TA基因型也与男性乙肝肝硬化弱相关(P=0.074);其他多态位点无关(P>0.1)。多因素分析显示IL-10-592A/C位点的AC基因型(OR=3.79,P=0.002)或A等位基因(OR=3.70,P=0.049)、C等位基因(OR=3.70,P=0.049)均为危险因素。
(3)基于女性样本的单因素分析显示,ER1+29T/C多态位点与女性乙肝肝硬化易感性相关,其中TC为易感基因型(OR=3.28,P=0.006),T为易感等位基因(OR=3.10,P=0.013),CC为保护基因型(OR=0.32,P=0.013);IL-1B+3953C/T位点和MEH-613C/T位点与女性乙肝肝硬化易感性弱相关(P=0.076-0.089),其他多态位点无关(P>0.1)。多因素分析显示危险基因型和等位基因有ER1+29 TC基因型(OR=5.33,P=0.019)或T等位基因(OR=7.63,P=0.017)、CTLA-4-318CT基因型(OR=8.84,P=0.017)或T等位基因(OR=6.33,P=0.031)、IFN-γ+2109 AA基因型(OR=4.38,P=0.032),保护性基因型或等位基因有IL-1B+3593 CT基因型(OR=0.076,P=0.036)或T等位基因(OR=0061,P=0.026)、IFN-γ+2109 G等位基因(OR=0.174,P=0.012)。
(4)基于男女混合样本、男性样本和女性样本的基因多态性检测数据,能分别建立起3个相应的乙肝肝硬化风险预测模型。3个模型对各自的建模病人的预测准确率分别为70.1%、69.3%和79.4%,对各自对应的全部病人的预测准确率分别为67.1%、67.5%和77.9%。以各模型对所对应的全部病人的预测概率值绘制ROC曲线,曲线下面积分别为0.692、0.670和0.813。
结论:根据上述研究结果得出结论如下:
(1)所检测的多个基因多态性位点中,只有少数与慢性HBV感染者肝硬化易感性有关,多数关联不强或不相关;
(2)与乙肝肝硬化相关的基因多态性主要集中在免疫相关基因和雌激素受体α基因,尤其是细胞因子基因;
(3)男性与女性患者乙肝肝硬化易感性相关基因多态性位点有所不同,男性主要涉及细胞因子基因,女性患者除细胞因子基因外,还涉及雌激素受体α和细胞免疫相关基因;
(4)女性患者的乙肝肝硬化与遗传变异的相关性强于男性患者,更多的基因多态性位点与女性患者相关,提示男性乙肝肝硬化的预防应该更重视环境因素控制,而女性乙肝肝硬化的预防应该更重视遗传因素的影响。
(5)基于不同的基因多态性数据(混合样本、男性样本和女性样本),均能建立起有意义的乙肝肝硬化风险预测模型,女性患者的预测模型的预测效率良好,优于男性和不分性别的预测模型。
Background and objectives: HBV-related hepatic cirrhosis is usually irreversible; therefore the key is prevention in cirrhosis control. However, only minority of chronic HBV infectors finally develops cirrhosis, most of them will be asymptomatic HBsAg carriers for a long time. Identifying the infectors with high risk of cirrhosis development and then implementing individualized preventive measures is an economic and effective strategy for preventing cirrhosis. According to clinical risk factors, it is difficult to quantitatively predict the risk of cirrhosis development in chronic HBV infectors. Single nucleotide polymorphisms (SNPs) which account for over 90% genetic variations in human genome are the best genetic markers for explaining the hereditary susceptibility of diseases and suitable for quantitatively prediction. Different genetic background has been believed to be the main cause of cirrhosis development difference in chronic HBV infectors. Since HBV-related cirrhosis is a polygenic disease, a panel of SNPs should be screened out for cirrhosis risk prediction. The aims of the present study were to analyze the relationships between the HBV-related cirrhosis susceptibility and genetic polymorphisms involved in different stages of cirrhosis development and establish mathematic models for quantitatively molecular prediction of cirrhosis risk in chronic HBV infectors individually. So far, there is no report about systematic analysis of multiple genetic polymorphisms associated with HBV-related hepatic cirrhosis susceptibility and cirrhosis risk prediction in terms of them.
Methods: A grouped case-control study was designed for the study, in which the case was HBV infectors with cirrhosis, and the control was asymptomatic HBsAg carriers. Seventeen polymorphism sites of 11 genes were selected for analysis: IL-1A-889C/T, IL-1B+3953C/T and -511C/T, IL-10-592A/C, IFN-γ+874T/A and +2109A/G, TNF-α-308G/A and -238G/A, CD14-159C/T, CTLA-4-318C/T, MEH Tyr113His and -613C/T, GSTM1null/normal, MMP-9-1562C/T, ER1+29T/C, AGT-20A/C and -6A/G. The genomic DNA was extracted from peripheral blood clot of the patients by phenol-chloroform method. PCR-RFLP or PCR-SSP methods were applied to genotype each polymorphism site. Genotype and allele frequencies of each site were calculated in two groups. Univariate and multivariate non-conditional Logistic regression analyses were conducted to observe the association and its intensity of each genotype or allele with the risk of HBV-related cirrhosis. By means of multivariate stepwise Logistic regression analysis, the independent related genotypes or alleles were screened out and mathematic models were created for the molecular prediction of cirrhosis risk in chronic HBV infectors, and their predictive performances were evaluated.
Results: Three hundred and twenty three patients were recruited, including male 226, female 97, with the average age 51.0 years old. Of them, there were 168 patients with HBV-related hepatic cirrhosis and 155 asymptomatic HBsAg carriers. The differences of constituent ratios among age groups were not significant between case and control groups in total or different genders. The results about the genetic polymorphisms and cirrhosis were as follows:
(1) In univariate analyses of total sample, IFN-γ+874T/A site was associated with HBV-related cirrhosis, in which TT were protective genotype (OR=0.55, P=0.039), TA were risk genotype (OR=1.93, P=0.025) and A was risk allele (OR=1.82, P=0.036). IL-10-592A/C site was weakly associated with cirrhosis (P= 0.057~0.077). The other polymorphism sites were not correlated with cirrhosis (P>0.1). Multivariate analysis indicated that ER1+29TC was a risk genotype (OR=2.00, P=0.024) and ER1+29T allele, AGT-20AA genotype and C allele were weakly correlated with cirrhosis (P=0.059~0.072).
(2) In univariate analyses of male sample, IL-10-592 A/C site was associated with male HBV-related cirrhosis, in which AC was a risk genotype (OR=1.86, P=0.042), genotype AA and allele C were weakly correlated (P=0.076). Genotype TA of IFN-γ+874T/A site was also weakly correlated with male cirrhosis (P=0.074), other polymorphism sites were not correlated (P>0.1). Multivariate analyses screened out three risk genotypes or alleles of IL-10-592 site: genotype AC (OR=3.79, P=0.002) or allele A (OR=3.70, P=0.049), C allele (OR=3.70, P=0.049).
(3) In univariate analysis of female sample, ER1+29T/C site was associated with female HBV-related cirrhosis, in which TC was a risk genotype (OR=3.28, P=0.006) , T was risk allele (OR=3.10, P=0.013) and CC was protective genotype (OR=0.32, P=0.013) ; IL-1B+3953C/T and MEH-613C/T sites were weakly correlated with female cirrhosis (P=0.076-0.089); Other polymorphism sites were not correlated (P>0.1). Multivariate analyses showed that the risk genotypes and alleles were ER1+29 TC genotype (OR=5.33, P=0.019) or T allele (OR=7.63, P=0.017), CTLA-4-318 CT genotype (OR=8.84, P=0.017) or T allele (OR=6.33, P=0.031), and IFN-γ+2109 AA genotype (OR=4.38, P=0.032); The protective genotypes and alleles were IL-1B3593 CT genotype (OR=0.076, P=0.036) or T allele (OR=0061, P=0.026) and IFN-γ+2109 G allele (OR=0.174, P=0.012).
(4) Based on the three sets of genetic polymorphism data (gender-mixed patients, male patients and female patients), three prediction models were developed respectively. The prediction accuracies of the three models for their own training sample were 70.1%, 69.3% and 79.4%, respectively; the prediction accuracies for their own total sample were 67.1%, 67.5% and 77.9%, respectively. The areas under the ROC curves created according to the predictive probability values of the three models to corresponding total samples were 0.692, 0.670 and 0.813, respectively.
Conclusions: According to the results above, we conclude:
(1) In the gene polymorphism sites detected, only minority is correlated with cirrhosis susceptibility in chronic HBV infectors, most of them are weakly or not correlated.
(2) Genetic polymorphisms related to HBV-related hepatic cirrhosis are mainly involved in immune-related genes and estrogen receptor-alpha gene, especially the cytokine genes.
(3) There are differences between male and female patients in the gene polymorphisms related to HBV-related cirrhosis. In the male, mainly genetic polymorphisms involved are cytokine genes, while in the female, except cytokine genes, estrogen receptor-alpha gene and cellular-immune related genes were involved.
(4) The association of female HBV-related cirrhosis with genetic variation is closer than that of male patients, more genetic polymorphism sites associated and more intensely correlated in female patients,indicating that environmental risk factor control might be more important for prevention of cirrhosis in male HBV infectors, while in female HBV infectors, more attention should be paid to genetic risk factors.
(5) Based on the different genetic polymorphism data (total patients, male patients and female patients), corresponding models could be developed successfully for predicting HBV-related cirrhosis, respectively. The female-specific predictive model shows a good performance and better than male-specific and gender-mixed predictive models.
引文
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