Transforming growth factor-beta (TGF-β1) genotype and lung allograft fibrosis
Transforming growth factor-beta (TGF-β1) genotype and lung allograft fibrosis
复制标题
DOI：
10.1016/s1053-2498(98)00024-2
复制
发表时间：
1999-06-01
影响因子：
8.9
通讯作者：
Hutchinson, IV
中科院分区：
文献类型：
--
作者：
El-Gamel, A;Awad, MR;Hutchinson, IV
背景：TGF-β（1）是一种与纤维化过程有关的促硬化细胞因子。肺实质和气道的纤维化是肺移植受者在移植前后的常见表现。在编码TGF-β（1）蛋白前导序列的DNA序列中存在两种遗传多态性，位于密码子10（亮氨酸或脯氨酸）和密码子25（精氨酸或脯氨酸）。密码子25精氨酸等位基因与体外激活的细胞产生更高的TGF-β（1）相关。我们检验了这样的假设，即TGF-β 1基因的等位基因的遗传赋予更高的TGF-β 1的生产可能是负责TGF-β 1的过度表达，在移植受体导致肺同种异体纤维化。方法：我们从白细胞中提取DNA，这些白细胞收集自1990年5月至1995年9月在我们中心进行的91例肺移植和96例正常健康志愿者。PCR扩增第一外显子的部分片段。样本进行基因分型，通过使用序列特异性寡核苷酸probes.Results：密码子10等位基因的分布是相似的，在正常健康对照组和肺移植受者，无论他们的移植前肺病理。相比之下，对照组和移植组之间密码子25等位基因的频率有显著差异。在正常对照组中，第25位密码子精氨酸/精氨酸（A/A）纯合子占81%，精氨酸/脯氨酸（A/P）杂合子占19%，脯氨酸/脯氨酸（P/P）纯合子占0%。在肺移植受者中，密码子25等位基因的分布是相似的，这些受者在移植前病理学中没有显著的纤维化，但是在移植受者中，98%（42例患者中的41例）的密码子25 A/A等位基因是纯合的（p <0.05）。肺移植后，91例患者中有39例发生了肺移植物纤维化，其中92.3%（36/39例受者）是纯合密码子25 A/A高TGF-β 1生产基因型（p <0.001）。与所有其他TGF-β 1基因型相比，密码子10 L/L和密码子25 AIA均为纯合子的肺移植受者的生存率较低结论：TGF-β前导序列第25位密码子精氨酸的纯合性（1），与体外较高的TGF-β产量相关，与肺移植前的纤维化肺病理学和移植物中纤维化的发展有关。与密码子10亮氨酸等位基因组合，密码子25精氨酸等位基因的纯合性是移植后预后和受体存活不良的标志。
Background: TGF-beta(1) is a prosclerotic cytokine implicated in fibrotic processes. Fibrosis of the pulmonary parenchyma and airways is a frequent presentation in lung transplant recipients before and after transplantation. There are two genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta(1) protein, located at codon 10 (either leucine or proline) and at codon 25 (either arginine or proline). The codon 25 arginine allele is associated with higher TGF-beta(1) production by cells activated in vitro. We tested the hypothesis that inheritance of alleles of the TGF-beta(1) gene conferring higher production of TGF-beta(1) may be responsible for over-expression of TGF-beta(1) in transplant recipients resulting in lung allograft fibrosis.Methods: We extracted DNA from leukocytes collected from 91 pulmonary transplants performed at our centre and 96 normal healthy volunteers between May 1990 and September 1995. Part of the first exon was amplified by PCR. Samples were genotyped by using sequence specific oligonucleotide probes.Results: The distribution of codon 10 alleles was similar in a normal healthy control group and in lung transplant recipients, regardless of their pretransplant lung pathology. By contrast, there was a significant difference in the frequency of codon 25 alleles between the control and transplant groups. In the normal control group 81% were codon 25 arginine/arginine (A/A) homozygotes, 19% were arginine/proline (A/P) heterozygotes and none were proline/proline (P/P) homozygotes. The distribution of codon 25 alleles was similar in lung transplant recipients who did not have a significant fibrosis in pretransplant pathology, but in transplant recipients who came to transplantation with lung fibrosis 98% (41 of 42 patients) were homozygous for the codon 25 A/A allele (p < .05). After lung transplantation 39 of 91 patients developed lung allograft fibrosis, and of these 92.3% (36 of 39 recipients) were of homozygous codon 25 A/A high TGF-beta(1) producer genotype (p < .001). Lung transplant recipients who were homozygous for both codon 10 L/L and codon 25 AIA showed poor survival compared with all other TGF-beta(1) genotypes (p < .03).Conclusions: Homozygosity for arginine at codon 25 of the leader sequence of TGF-beta(1), that correlates with higher TGF-b production in vitro, is associated with fibrotic lung pathology before lung transplantation and with the development of fibrosis in the graft. In combination with the codon 10 leucine allele, homozygosity for the codon 25 arginine allele is a marker for poor post-transplant prognosis and recipient survival.