AIM: Considerable attention is focused on polymorphisms in the gene encoding transforming growth factor-pi (TGF-β1), a multifunctional cytokine that is in turn a potent growth inhibitor involved in wound healing and ...AIM: Considerable attention is focused on polymorphisms in the gene encoding transforming growth factor-pi (TGF-β1), a multifunctional cytokine that is in turn a potent growth inhibitor involved in wound healing and differentiation. In humans, it promotes the pathogenesis of organ fibrosis, atherosclerosis, cancer, autoimmune and inflammatory diseases, keloid disease, and hypertrophic scarring. For this reason, much emphasis has been placed on studies elucidating the impact of TGF-β1 and its gene variations for the susceptibility and pathogenesis of these diseases. Unfortunately, some studies have serious limitations. METHODS: We have recently described a high-throughput method for investigation the Arg25Pro polymorphism of human TGF-β1 gene and showed that the frequency of the Pro25 allele is significantly associated with hepatic fibrogenesis. In this report, we describe two novel LightCyder (LC) techniques that facilitate the examination of the two other known alterations in the coding region of TGF-β1. We investigated whether these polymorphisms contribute to hepatitis-induced progression of fibrogenesis in Chinese and Caucasians. RESULTS: In the Chinese ancestry, the gene polymorphisms at codons 25 and 263 were not found and the genetic variant at codon 10 is unlikely to confer susceptibility to hepatic fibrosis. Contrarily, in Caucasians TGF-β1 allelic variations are more frequent and the presence of prolines either in codon 25 or 10 is associated with the interindividual variability in developing more severe fibrosis during chronic hepatitis C infection. CONCLUSION: In summary, these results confirm the hypothesis that TGF-β1 polymorphisms are associated with fibrosis progression in Caucasians chronically infected with hepatitis C.展开更多
目的通过研究乙型肝炎病毒(hepatitis B virus,HBV)长期感染与诱导性脱氨酶(activation induced deaminase,AID)表达水平的关系探讨肝癌发病机制。方法采用实时定量PCR法,测定乙肝病毒感染及转化生长因子β1(TGF-β1)和肿瘤坏死因子-α(...目的通过研究乙型肝炎病毒(hepatitis B virus,HBV)长期感染与诱导性脱氨酶(activation induced deaminase,AID)表达水平的关系探讨肝癌发病机制。方法采用实时定量PCR法,测定乙肝病毒感染及转化生长因子β1(TGF-β1)和肿瘤坏死因子-α(TNF-α)对Apobec蛋白家族AID和Apobec3G表达量的影响;采用3D-PCR法检测AID、Apobec3G表达组对乙肝病毒基因突变的影响;克隆测序PCR扩增乙肝病毒X基因产物,对比AID和Apobec3G对乙肝病毒基因组突变的影响,计算突变率;并用逆转录病毒携带AID组和对照组在肝脏细胞转染表达后,克隆测序PCR细胞部分基因扩增,对比测定对细胞基因组突变的影响,计算突变率。结果乙肝病毒感染或生长因子TGF-β1刺激使肝细胞中AID表达上调>10倍,TGFβ1刺激组较非刺激组引起乙肝病毒基因组高突变,分别为55个克隆中的16和4个。AID高表达使乙肝病毒基因组高度突变,突变率为55个克隆中的16个,显著高于对照组的1个,多为G到A突变;而且AID高表达使部分细胞基因组如p53和c-myc基因高度突变,突变率分别为8.2×10-5和7.3×10-5,高于对照组的突变率0。结论慢性肝炎病毒感染协同细胞因子诱导AID高表达,高表达的AID使肝炎病毒基因及细胞基因组突变,为肝细胞癌变的相关因素。展开更多
基金Supported by the Grants From the Federal Ministry of Education and Research of Germany (Network of Competence in Medicine HepNet)the Natural Science Foundation of China, No. 30270605
文摘AIM: Considerable attention is focused on polymorphisms in the gene encoding transforming growth factor-pi (TGF-β1), a multifunctional cytokine that is in turn a potent growth inhibitor involved in wound healing and differentiation. In humans, it promotes the pathogenesis of organ fibrosis, atherosclerosis, cancer, autoimmune and inflammatory diseases, keloid disease, and hypertrophic scarring. For this reason, much emphasis has been placed on studies elucidating the impact of TGF-β1 and its gene variations for the susceptibility and pathogenesis of these diseases. Unfortunately, some studies have serious limitations. METHODS: We have recently described a high-throughput method for investigation the Arg25Pro polymorphism of human TGF-β1 gene and showed that the frequency of the Pro25 allele is significantly associated with hepatic fibrogenesis. In this report, we describe two novel LightCyder (LC) techniques that facilitate the examination of the two other known alterations in the coding region of TGF-β1. We investigated whether these polymorphisms contribute to hepatitis-induced progression of fibrogenesis in Chinese and Caucasians. RESULTS: In the Chinese ancestry, the gene polymorphisms at codons 25 and 263 were not found and the genetic variant at codon 10 is unlikely to confer susceptibility to hepatic fibrosis. Contrarily, in Caucasians TGF-β1 allelic variations are more frequent and the presence of prolines either in codon 25 or 10 is associated with the interindividual variability in developing more severe fibrosis during chronic hepatitis C infection. CONCLUSION: In summary, these results confirm the hypothesis that TGF-β1 polymorphisms are associated with fibrosis progression in Caucasians chronically infected with hepatitis C.
文摘目的通过研究乙型肝炎病毒(hepatitis B virus,HBV)长期感染与诱导性脱氨酶(activation induced deaminase,AID)表达水平的关系探讨肝癌发病机制。方法采用实时定量PCR法,测定乙肝病毒感染及转化生长因子β1(TGF-β1)和肿瘤坏死因子-α(TNF-α)对Apobec蛋白家族AID和Apobec3G表达量的影响;采用3D-PCR法检测AID、Apobec3G表达组对乙肝病毒基因突变的影响;克隆测序PCR扩增乙肝病毒X基因产物,对比AID和Apobec3G对乙肝病毒基因组突变的影响,计算突变率;并用逆转录病毒携带AID组和对照组在肝脏细胞转染表达后,克隆测序PCR细胞部分基因扩增,对比测定对细胞基因组突变的影响,计算突变率。结果乙肝病毒感染或生长因子TGF-β1刺激使肝细胞中AID表达上调>10倍,TGFβ1刺激组较非刺激组引起乙肝病毒基因组高突变,分别为55个克隆中的16和4个。AID高表达使乙肝病毒基因组高度突变,突变率为55个克隆中的16个,显著高于对照组的1个,多为G到A突变;而且AID高表达使部分细胞基因组如p53和c-myc基因高度突变,突变率分别为8.2×10-5和7.3×10-5,高于对照组的突变率0。结论慢性肝炎病毒感染协同细胞因子诱导AID高表达,高表达的AID使肝炎病毒基因及细胞基因组突变,为肝细胞癌变的相关因素。
