Cookson S, Constantini P K, Clare M, Underhill J A, Bernal W, Czaja A J, Donaldson P T
Institute of Liver Studies, King's College Hospital, London, UK.
Hepatology. 1999 Oct;30(4):851-6. doi: 10.1002/hep.510300412.
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 TNF2 (first set: 34% of controls vs. 49% of patients, Pc =.014 and second set: 26% vs. 56%, P =.00008). However, TNF2 is found in strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype and stratification analysis indicates that the association with TNF2 is interdependent with HLA DRB10301. This is an indication that there is more than one susceptibility allele for type 1 AIH on chromosome 6p21.3.
1型自身免疫性肝炎（AIH）存在遗传因素参与，表现为明显的女性优势以及与人类白细胞抗原（HLA）的强关联且这种关联已得到充分证实。然而，这些关联并不普遍，主要组织相容性复合体之外的一些基因也可能在1型AIH的易感性中发挥作用。目前的主要候选基因是那些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对1型AIH患者白细胞介素-1（IL-1）家族的2个成员（IL-1B和IL-1RN）、白细胞介素-10（IL-10）基因启动子中的3个多态性位点（-1082、-819和-592位）以及肿瘤坏死因子-α（TNF-α）启动子中的2个多态性位点（-308和-238位）进行研究。该研究在2个独立收集的DNA库上进行，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了证实。使用了基于标准聚合酶链反应（PCR）的基因分型技术。总体而言，在任何一个研究组中，IL-1B和IL-10等位基因、基因型或单倍型的分布均无显著差异。相比之下，我们报告1型AIH与TNF2之间存在显著关联（第一组：对照组为34%，患者组为49%，Pc = 0.014；第二组：26% 对56%，P = 0.00008）。然而，TNF2与HLA A1-B8-DR3单倍型存在强连锁不平衡，分层分析表明与TNF2的关联与HLA DRB10301相互依赖。这表明在6号染色体p21.3上存在不止一个1型AIH的易感等位基因。
