Two critical genes (HLA-DRB1 and ABCF1) in the HLA region are associated with the susceptibility to autoimmune pancreatitis
Two critical genes (HLA-DRB1 and ABCF1) in the HLA region are associated with the susceptibility to autoimmune pancreatitis
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DOI：
10.1007/s00251-006-0178-2
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发表时间：
2007-01-01
期刊：
影响因子：
3.2
通讯作者：
Kawa, Shigeyuki
中科院分区：
文献类型：
--
作者：
Ota, Masao;Katsuyama, Yoshihiko;Kawa, Shigeyuki
我们以前曾报道过自身免疫性胰腺炎（AIP）是一种生物临床实体，其特征是高血清免疫球蛋白G4浓度和与HLA-DRB 1 *0405-DQB 1 *0401单倍型相关。然而，该单倍型中直接负责AIP发病机制的基因的精确身份尚未确定。为了剖析致病单倍型的遗传贡献，我们现在已经使用各种类型的多态性标记进行了人类白细胞抗原（HLA）区域内的关联分析。在这项分析中使用了来自43名AIP患者和213名无关的日本对照的基因组DNA。在每个DNA样本中，我们建立了分布在整个HLA区域的25个微卫星标记的基因型，TNFA和IkBLI（也称为NFKBIL 1）以及HLA I类和II类基因的5 '侧翼区域内的单核苷酸多态性。AIP的HLA-DRB 1基因片段与AIP的HLA-DRB 1基因片段有一定的相关性（* 0405; OR = 3.20，P = 0.00063，Pc = 0.0016）-DQB 1（* 0401; OR = 3.29，P = 0.00046，Pc = 0.0069），C3-2-11微卫星（等位基因219; OR = 2.96，P = 0.0076，Pc = 0.099）。分层分析后，在寻找协同效应的主要组织相容性复合体内广泛的连锁不平衡，它被确定为每个部分有助于疾病的发病机制。AIP易感性的两个关键HLA区域仅限于II类区域中的HLA-DRB 1 *0405-DQB 1 *0401和I类区域中靠近C3-2-11（HLA-E端粒）的ABCF 1。
We have previously reported that autoimmune pancreatitis (AIP) is a bioclinical entity characterized by high serum immunoglobulin G4 concentrations and association with the HLA-DRB1*0405-DQB1*0401 haplotype. However, the precise identity of gene(s) within this haplotype directly responsible for AIP pathogenesis is yet to be established. To dissect the genetic contribution of the incriminated haplotype, we have now performed an association analysis within the human leukocyte antigen (HLA) region using various types of polymorphic markers. Genomic DNAs from 43 AIP patients and 213 unrelated Japanese controls were used in this analysis. In each DNA sample, we established the genotype of 25 microsatellite markers distributed throughout the HLA region, that of single nucleotide polymorphism within the 5'-flanking regions of the TNFA and IkBLI (also known as NFKBIL1) as well as HLA class I and II genes. The HLA-linked susceptibility regions for AIP were localized to two segments: HLA-DRB1 (* 0405; OR = 3.20, P = 0.00063, Pc = 0.0016)-DQB1 (* 0401; OR = 3.29, P = 0.00046, Pc = 0.0069) in the HLA class II and C3-2-11 microsatellite ( allele 219; OR = 2.96, P = 0.0076, Pc = 0.099) in the HLA class I regions. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium within the major histocompatibility complex, it was established that each segment contributed to disease pathogenesis. The two critical HLA regions for susceptibility to AIP are limited to the HLA-DRB1*0405-DQB1*0401 in the class II and the ABCF1 proximal to C3-2-11, telomeric of HLA-E, in the class I regions.