title: Two critical genes (HLA-DRB1 and ABCF1)in the HLA region are associated with the susceptibility to autoimmune pancreatitis.
abstract: 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.
authors.affiliation: Department of Legal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. otamasao@sch.md.shinshu-u.ac.jp
authors.forename: Masao
authors.initials: M
authors.lastname: Ota
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Katsuyama
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hamano
authors.forename: Takeji
authors.initials: T
authors.lastname: Umemura
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Kaname
authors.initials: K
authors.lastname: Yoshizawa
authors.forename: Kendo
authors.initials: K
authors.lastname: Kiyosawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Seiamak
authors.initials: S
authors.lastname: Bahram
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kawa
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing; D044466:Asian People / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics*; D016022:Case-Control Studies; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D010195:Pancreatitis / Q000235:genetics*; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: C115776:ABCF1 protein, human; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C120111:NFKBIL1 protein, human; D014409:Tumor Necrosis Factor-alpha