基于候选基因的慢性乙型肝炎、肝癌和鼻咽癌的遗传关联研究
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摘要
我国是人口大国，有世界上最丰富的疾病人群，疾病谱兼有发达国家和发展中国家的特征。我国特有或高发的疾病如肝癌、鼻咽癌的发生率即使在我国较发达地区亦明显高于西方；尤其是病毒性肝炎，仍是我国最严重、最广泛的传染病。上述对我国公众健康造成巨大危害的疾病的发生均有其遗传基础，其主要形式是单核苷酸多态性(single nucleotide polymorphism，SNP)。如果检测和确定与上述疾病相关基因的易感SNP、致病SNP以及具诊断价值的SNP，将有助于上述疾病的诊断，治疗和预防。
乙型肝炎病毒(Hepatitis B virus，HBV)感染是世界范围内主要的传染病之一。人群感染HBV后有约有10％的个体发展为持续感染者，持续感染者个体间临床转归不一，可表现为无症状携带者、慢性乙型肝炎、肝硬化甚至肝癌。HBV持续感染后导致肝炎的主要机制是由于免疫细胞对病毒抗原诱导的肝细胞的杀伤作用。共刺激分子做为免疫应答的第二信号，在免疫调节中起重要作用。有大量研究报道，共刺激分子基因多态性与许多免疫相关的疾病关联，但与HBV持续感染的疾病严重程度的关联研究尚未见报道。我们研究的目的是在共刺激分子基因中寻找与HBV持续感染严重程度的易感基因和易感SNP。我们共选取了15个共刺激分子基因，包括TNFRSF4(tumor necrosis factor receptor superfamily，member 4，肿瘤坏死因子受体超家族成员4)及其配体TNFSF4，TNFRSF9(tumor necrosis factorreceptor superfamily，member 9，肿瘤坏死因子受体超家族成员9)及其配体TNFSF9，ICOS(inducible T-cell co-stimulator，可诱导T细胞共刺激因子)及其配体ICOSL，PDCD1(programmed cell death 1，程序性细胞死亡因子1)及其配体CD274和PDCD1LG2，CD28和CTLA4(cytotoxic T-lymphocyte-associated antigen 4，细胞毒T淋巴细胞相关抗原4)及其配体CD80和CD86，CD40及其配体CD40L，共41个SNP位点。用多聚酶链式反应—限制酶切片段长度多态(polymerase chain reaction-restriction fragment length polymorphism，PCR-RFLP)法和测序法在192例无症状携带者、73例慢性乙肝患者中进行分型。通过非条件logistical回归分析，校正性别和年龄，并对P值进行多重检验校正。研究结果表明，CTLA4启动子区的T-1722C位点与疾病严重程度相关，与携带至少一个C等位型的个体相比，携带TT基因型的个体HBV持续感染后发生慢性炎症的风险显著增加(OR=2.66，95％CI=1.46-4.88，P=0.001)。CTLA4为慢性乙型肝炎的易感基因，其启动子区的T-1722C为易感SNP。
肝癌主要由HBV、HCV(Hepatitis C virus)感染，黄曲霉毒素污染的食物和水源及过度饮酒导致，但并不是所有的风险因素暴露者都患癌，提示机体的遗传因素也对致癌机制有重要的影响。鼻咽癌也是在我国比较流行的有明显的种族地域性的恶性肿瘤，尤其在中国南方，发病率高达15-50/100000，几乎是白种人发病率的100倍。鼻咽癌的发生是由EB病毒感染、环境风险因素和基因易感性共同作用的结果。而越来越多的证据表明DNA合成缺陷和基因的异常甲基化会增加患癌风险。而5，10-亚甲基四氢叶酸还原酶(5，10-methylenetetrahydrofolate reductase，MTHFR)在其中起关键作用。我们因而推测该基因的多态性与肝癌和鼻咽癌的易感性相关。我们选取了MTHFR的两个功能性位点C677T和A1298C，在328例HBV相关的肝癌病例、593例鼻咽癌病例和480例健康对照中通过PCR-RFLP法进行了分型。采用非条件logistical回归分析，校正性别、年龄、吸烟和饮酒状态、吸烟水平因素，结果表明C677T和A1298C与肝癌易感性、鼻咽癌易感性及其严重程度均无关联。进一步按性别、年龄、吸烟和饮酒状态、吸烟水平因素进行分层分析，结果仍无关联。我们的研究表明MTHFR的C677T和A1298C位点可能在肝癌和鼻咽癌的易感性机制中不发挥重要作用。
Our country with the largest population has most abundant disease population in the world. Spectrums of disease in China have both characteristics of developed countries and developing countries. Some proper or high incidence disease in China, such as nasopharyngeal carcinoma(NPC), hepatocellular carcinoma(HCC) and chronic hepatitis B(CHB), which is the most serious and common infectious in China, remain higher incidence in developed region of China than in western country. Above-mentioned diseases, which endanger public health, all have its heredity. The main form of this heredity is single nucleotide polymorphism (SNP). The identification of susceptibility genes contributing to these disorders may help to clarify the pathogenesis and improve the prevention and treatment of these malignancies.
Hepatitis B virus (HBV) infection is one of the major infectious diseases. The clinical course of HBV infection varies from spontaneous recovery after acute hepatitis to chronic persistent infection, including asymptomatic carrier, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The immune response initiated by the T-cell response to HBV antigens is thought to be fundamental for viral clearance and disease pathogenesis in HBV infection. Activation of lymphocytes requires a second signal through constitutively expressed co-stimulatory receptors and ligands. We evaluated 41 htSNP of 15 co-stimulators genes (include TNFRSF4, TNFSF4, CD40, CD40L, TNFRSF9, TNFSF9, CD80, CD86, CD28, CTLA4, PDCD1, CD274, PDCD1LG2, ICOS, and ICOSL) and their effects on the diseases progression of HBV infection association in a population-based case-control study of 192 asymptomatic carriers (ASC), 73 chronic hepatitis B (CHB) patients. The polymorphisms were genotyped with Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between these polymorphisms and disease status was evaluated with unconditional logistic regression and adjusted for age, sex, status of smoking and drinking, and pack-years of smoking. Considering multiple testing, we adjusted P value by Bonferroni and False discovery rate (FDR) method. Our study shows that T-1722C polymorphism in CTLA4 promoter region is associated with CHB susceptibility. Individuals with the T/T homozygous were over twice as likely (OR = 2.66, 95% CI = 1.46-4.88, P = 0.0015) to develop the disease compared with those C/T or T/T genotypes. Our results implicate that CTLA4 in susceptibility to CHB, while T-1722C is susceptible SNP for CHB. CTLA4 may play an important role in pathogenesis of CHB.
In China, hepatitis B virus infection is main risk factor, together with aflatoxin intake from contaminated food. However, not all individuals explored to risk factor develop HCC. NPC is the serious health problems in southern Chinese, with an incidence rate ranging from 15 to 50/100000. These incidence rates are almost 100-fold higher than in the Caucasian populations. So host genetic factors may play important roles in these disease progressions. There is growing evidence that chromosomal and genetic alterations arising from flawed DNA synthesis or altered methylation of oncogenes and tumor suppressor genes may influence susceptibility to cancers. The 5,10-methylenetetrahydrofolate reductase (MTHFR) acts at a critical juncture in DNA synthesis and methylation. We examined whether these two functional polymorphisms, i.e. C677T and A1298C, were related to the risk of hepatocellular carcinoma (HCC) and nasopharyngeal carcinoma (NPC) in Chinese population. The C677T and A1298C polymorphism were genotyped in 328 patients with HBV related HCC, 593 patients with NPC and 480 control by PCR-RFLP method. The association between these polymorphisms and disease status was evaluated while controlling for confounding factors. However, we found no evidence for significant association between the C677T and A1298C polymorphism and risk of HCC and NPC. When the analyses were stratified by age, sex, status of smoking and drinking, and pack-years of smoking, the association remained negative. Our findings therefore suggest that the MTHFR C677T and A1298C polymorphisms may not play a major role in mediating susceptibility to HCC and NPC.
乙型肝炎病毒(Hepatitis B virus，HBV)感染是世界范围内主要的传染病之一。人群感染HBV后有约有10％的个体发展为持续感染者，持续感染者个体间临床转归不一，可表现为无症状携带者、慢性乙型肝炎、肝硬化甚至肝癌。HBV持续感染后导致肝炎的主要机制是由于免疫细胞对病毒抗原诱导的肝细胞的杀伤作用。共刺激分子做为免疫应答的第二信号，在免疫调节中起重要作用。有大量研究报道，共刺激分子基因多态性与许多免疫相关的疾病关联，但与HBV持续感染的疾病严重程度的关联研究尚未见报道。我们研究的目的是在共刺激分子基因中寻找与HBV持续感染严重程度的易感基因和易感SNP。我们共选取了15个共刺激分子基因，包括TNFRSF4(tumor necrosis factor receptor superfamily，member 4，肿瘤坏死因子受体超家族成员4)及其配体TNFSF4，TNFRSF9(tumor necrosis factorreceptor superfamily，member 9，肿瘤坏死因子受体超家族成员9)及其配体TNFSF9，ICOS(inducible T-cell co-stimulator，可诱导T细胞共刺激因子)及其配体ICOSL，PDCD1(programmed cell death 1，程序性细胞死亡因子1)及其配体CD274和PDCD1LG2，CD28和CTLA4(cytotoxic T-lymphocyte-associated antigen 4，细胞毒T淋巴细胞相关抗原4)及其配体CD80和CD86，CD40及其配体CD40L，共41个SNP位点。用多聚酶链式反应—限制酶切片段长度多态(polymerase chain reaction-restriction fragment length polymorphism，PCR-RFLP)法和测序法在192例无症状携带者、73例慢性乙肝患者中进行分型。通过非条件logistical回归分析，校正性别和年龄，并对P值进行多重检验校正。研究结果表明，CTLA4启动子区的T-1722C位点与疾病严重程度相关，与携带至少一个C等位型的个体相比，携带TT基因型的个体HBV持续感染后发生慢性炎症的风险显著增加(OR=2.66，95％CI=1.46-4.88，P=0.001)。CTLA4为慢性乙型肝炎的易感基因，其启动子区的T-1722C为易感SNP。
肝癌主要由HBV、HCV(Hepatitis C virus)感染，黄曲霉毒素污染的食物和水源及过度饮酒导致，但并不是所有的风险因素暴露者都患癌，提示机体的遗传因素也对致癌机制有重要的影响。鼻咽癌也是在我国比较流行的有明显的种族地域性的恶性肿瘤，尤其在中国南方，发病率高达15-50/100000，几乎是白种人发病率的100倍。鼻咽癌的发生是由EB病毒感染、环境风险因素和基因易感性共同作用的结果。而越来越多的证据表明DNA合成缺陷和基因的异常甲基化会增加患癌风险。而5，10-亚甲基四氢叶酸还原酶(5，10-methylenetetrahydrofolate reductase，MTHFR)在其中起关键作用。我们因而推测该基因的多态性与肝癌和鼻咽癌的易感性相关。我们选取了MTHFR的两个功能性位点C677T和A1298C，在328例HBV相关的肝癌病例、593例鼻咽癌病例和480例健康对照中通过PCR-RFLP法进行了分型。采用非条件logistical回归分析，校正性别、年龄、吸烟和饮酒状态、吸烟水平因素，结果表明C677T和A1298C与肝癌易感性、鼻咽癌易感性及其严重程度均无关联。进一步按性别、年龄、吸烟和饮酒状态、吸烟水平因素进行分层分析，结果仍无关联。我们的研究表明MTHFR的C677T和A1298C位点可能在肝癌和鼻咽癌的易感性机制中不发挥重要作用。
Our country with the largest population has most abundant disease population in the world. Spectrums of disease in China have both characteristics of developed countries and developing countries. Some proper or high incidence disease in China, such as nasopharyngeal carcinoma(NPC), hepatocellular carcinoma(HCC) and chronic hepatitis B(CHB), which is the most serious and common infectious in China, remain higher incidence in developed region of China than in western country. Above-mentioned diseases, which endanger public health, all have its heredity. The main form of this heredity is single nucleotide polymorphism (SNP). The identification of susceptibility genes contributing to these disorders may help to clarify the pathogenesis and improve the prevention and treatment of these malignancies.
Hepatitis B virus (HBV) infection is one of the major infectious diseases. The clinical course of HBV infection varies from spontaneous recovery after acute hepatitis to chronic persistent infection, including asymptomatic carrier, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The immune response initiated by the T-cell response to HBV antigens is thought to be fundamental for viral clearance and disease pathogenesis in HBV infection. Activation of lymphocytes requires a second signal through constitutively expressed co-stimulatory receptors and ligands. We evaluated 41 htSNP of 15 co-stimulators genes (include TNFRSF4, TNFSF4, CD40, CD40L, TNFRSF9, TNFSF9, CD80, CD86, CD28, CTLA4, PDCD1, CD274, PDCD1LG2, ICOS, and ICOSL) and their effects on the diseases progression of HBV infection association in a population-based case-control study of 192 asymptomatic carriers (ASC), 73 chronic hepatitis B (CHB) patients. The polymorphisms were genotyped with Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between these polymorphisms and disease status was evaluated with unconditional logistic regression and adjusted for age, sex, status of smoking and drinking, and pack-years of smoking. Considering multiple testing, we adjusted P value by Bonferroni and False discovery rate (FDR) method. Our study shows that T-1722C polymorphism in CTLA4 promoter region is associated with CHB susceptibility. Individuals with the T/T homozygous were over twice as likely (OR = 2.66, 95% CI = 1.46-4.88, P = 0.0015) to develop the disease compared with those C/T or T/T genotypes. Our results implicate that CTLA4 in susceptibility to CHB, while T-1722C is susceptible SNP for CHB. CTLA4 may play an important role in pathogenesis of CHB.
In China, hepatitis B virus infection is main risk factor, together with aflatoxin intake from contaminated food. However, not all individuals explored to risk factor develop HCC. NPC is the serious health problems in southern Chinese, with an incidence rate ranging from 15 to 50/100000. These incidence rates are almost 100-fold higher than in the Caucasian populations. So host genetic factors may play important roles in these disease progressions. There is growing evidence that chromosomal and genetic alterations arising from flawed DNA synthesis or altered methylation of oncogenes and tumor suppressor genes may influence susceptibility to cancers. The 5,10-methylenetetrahydrofolate reductase (MTHFR) acts at a critical juncture in DNA synthesis and methylation. We examined whether these two functional polymorphisms, i.e. C677T and A1298C, were related to the risk of hepatocellular carcinoma (HCC) and nasopharyngeal carcinoma (NPC) in Chinese population. The C677T and A1298C polymorphism were genotyped in 328 patients with HBV related HCC, 593 patients with NPC and 480 control by PCR-RFLP method. The association between these polymorphisms and disease status was evaluated while controlling for confounding factors. However, we found no evidence for significant association between the C677T and A1298C polymorphism and risk of HCC and NPC. When the analyses were stratified by age, sex, status of smoking and drinking, and pack-years of smoking, the association remained negative. Our findings therefore suggest that the MTHFR C677T and A1298C polymorphisms may not play a major role in mediating susceptibility to HCC and NPC.
引文
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