Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis
Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis
复制标题
DOI：
10.1002/hep.510300412
复制
发表时间：
1999-10-01
期刊：
影响因子：
13.5
通讯作者：
Donaldson, PT
中科院分区：
文献类型：
--
作者：
Cookson, S;Constantini, PK;Donaldson, PT
1型自身免疫性肝炎（AIH）的遗传参与表现为女性明显占优势，并与人类白细胞抗原（HLA）密切相关。然而，这些关联并不普遍，主要组织相容性复合体以外的一些基因也可能在1型AIH的易感性中起作用。目前的主要候选者是编码促炎和免疫调节细胞因子的多态性基因。本研究的目的是首次研究白细胞介素-1（IL-1）家族的2个成员，（IL-1B和IL-1 RN），白细胞介素-10（IL-10）基因启动子中的3个多态性位点（位置-1082、-819和-592），和肿瘤坏死因子-α中的2个多态性（TNF-α）启动子（位置-308和-238），该研究在2个独立收集的DNA库中进行，每个库都有适当的对照，并且在整个分析过程中，第一组中描述的关联在第二组中得到证实。采用标准的基于聚合酶链反应（PCR）的基因分型技术。总体而言，在两个研究集中，IL-1B和IL-10等位基因、基因型或单倍型的分布没有显著差异。相反，我们报告了1型AIH和TNF*2之间的显著相关性（第一组：34%的对照组对49%的患者，Pc = 0.014，第二组：26%对56%，P = 0.00008）。然而，发现TNF*2与HLA A1-B8-DR 3单倍型存在强连锁不平衡，分层分析表明与TNF*2的关联与HLA DRB 1 *0301相互依赖。这表明在染色体6p21.3上存在不止一个1型AIH的易感等位基因。
Genetic involvement in type 1 autoimmune hepatitis (AIH) is indicated by a marked female preponderance and strong, well-established, human leukocyte antigen (HLA) associations. These associations, however, are not universal and a number of genes outside the major histocompatibility complex may also play a role in susceptibility to type 1 AIH, Prime candidates at present are those polymorphic genes encoding the proinflammatory and immunoregulatory cytokines, The aim of this study was to investigate, for the first time, 2 members of the interleukin-1 (IL-1) family (IL-1B and IL-1RN), 3 polymorphic sites in the interleukin-10 (IL-10) gene promoter (positions -1082, -819, and -592), and 2 polymorphisms in the tumor necrosis factor-alpha (TNF-alpha) promoter (positions -308 and -238) in type 1 AIH, The study was performed on 2 independently collected DNA banks, each with appropriate controls, and throughout the analysis associations described in the first set were confirmed in the second set. Standard polymerase chain reaction (PCR)-based genotyping techniques were used. Overall there were no significant differences in the distributions of the IL-1B and IL-10 alleles, genotypes, or haplotypes in either study set. In contrast we report a significant association between type 1 AIH and TNF*2 (first set: 34% of controls vs. 49% of patients, Pc =.014 and second set: 26% vs. 56%, P =.00008). However, TNF*2 is found in strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype and stratification analysis indicates that the association with TNF*2 is interdependent with HLA DRB1*0301. This is an indication that there is more than one susceptibility allele for type 1 AIH on chromosome 6p21.3.