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Two critical genes (HLA-DRB1 and ABCF1)in the HLA region are associated with the susceptibility to autoimmune pancreatitis

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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.

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Acknowledgment

This work was supported in part by Grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (15659167 and 16390205), from the Japan Health Sciences Foundation (KH21022), and by a Research of Specific Diseases, Health and Labour Sciences Research Grant, Japan. S. Bahram wishes to thank INSERM/JSPS as well as the Agence de Biomedecine for support.

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Authors and Affiliations

  1. Department of Legal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan

    Masao Ota & Hirofumi Fukushima

  2. Department of Pharmacy, Shinshu University School of Medicine, Matsumoto, Japan

    Yoshihiko Katsuyama

  3. Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan

    Hideaki Hamano, Takeji Umemura, Kaname Yoshizawa & Kendo Kiyosawa

  4. Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan

    Akinori Kimura

  5. Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan

    Akinori Kimura

  6. Human Molecular Immunogenetics, Centre de Recherche d’Immunologie et d’Hematologie, Strasbourg, France

    Seiamak Bahram

  7. Department of Molecular Life Sciences, Division of Genetic Information, Tokai University School of Medicine, Isehara, Japan

    Hidetoshi Inoko

  8. Center for Health, Safety and Environmental Management, Shinshu University, Matsumoto, Japan

    Shigeyuki Kawa

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  1. Masao Ota
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  11. Shigeyuki Kawa
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Correspondence to Masao Ota.

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Ota, M., Katsuyama, Y., Hamano, H. et al. Two critical genes (HLA-DRB1 and ABCF1)in the HLA region are associated with the susceptibility to autoimmune pancreatitis. Immunogenetics 59, 45–52 (2007). https://doi.org/10.1007/s00251-006-0178-2

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  • DOI: https://doi.org/10.1007/s00251-006-0178-2

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