Ota Masao, Katsuyama Yoshihiko, Hamano Hideaki, Umemura Takeji, Kimura Akinori, Yoshizawa Kaname, Kiyosawa Kendo, Fukushima Hirofumi, Bahram Seiamak, Inoko Hidetoshi, Kawa Shigeyuki
Department of Legal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
Immunogenetics. 2007 Jan;59(1):45-52. doi: 10.1007/s00251-006-0178-2. Epub 2006 Nov 21.
We have previously reported that autoimmune pancreatitis (AIP) is a bioclinical entity characterized by high serum immunoglobulin G4 concentrations and association with the HLA-DRB10405-DQB10401 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-DRB10405-DQB10401 in the class II and the ABCF1 proximal to C3-2-11, telomeric of HLA-E, in the class I regions.
我们之前曾报道，自身免疫性胰腺炎（AIP）是一种生物临床实体，其特征为血清免疫球蛋白G4浓度升高，并与HLA - DRB10405 - DQB10401单倍型相关。然而，该单倍型中直接导致AIP发病机制的基因的确切身份尚未确定。为了剖析该可疑单倍型的遗传贡献，我们现在使用各种类型的多态性标记在人类白细胞抗原（HLA）区域内进行了关联分析。本分析使用了43例AIP患者和213名无关日本对照的基因组DNA。在每个DNA样本中，我们确定了分布在整个HLA区域的25个微卫星标记的基因型、TNFA和IkBLI（也称为NFKBIL1）5'侧翼区域以及HLA I类和II类基因内的单核苷酸多态性基因型。AIP的HLA连锁易感区域定位于两个区段：HLA II类中的HLA - DRB1（0405；比值比[OR]=3.20，P = 0.00063，校正P值[Pc]=0.0016） - DQB1（0401；OR = 3.29, P = 0.00046, Pc = 0.0069）和HLA I类区域中的C3 - 2 - 11微卫星（等位基因219；OR = 2.96，P = 0.0076，Pc = 0.099）。鉴于主要组织相容性复合体内广泛的连锁不平衡，在分层分析中寻找协同效应时，确定每个区段都对疾病发病机制有贡献。AIP易感性的两个关键HLA区域局限于II类中的HLA - DRB10405 - DQB10401以及I类区域中HLA - E端粒附近C3 - 2 - 11近端的ABCF1。
