title: Identification of independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and their epistasis.
abstract: BACKGROUND
  Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto thyroiditis (HT), which partially share immunological features. Determining the genetic basis that distinguishes GD and HT is a key to understanding the differences between these 2 related diseases.
  
  
  OBJECTIVE
  The aims of this study were to identify HLA antigens that can explain the immunopathological difference between GD and HT and to elucidate epistatic interactions between protective and susceptible HLA alleles, which can delineate the distinct function of HLA in AITD etiology.
  
  
  METHODS
  We genotyped 991 patients with AITD (547 patients with GD and 444 patients with HT) and 481 control subjects at the HLA-A, HLA-C, HLA-B, DRB1, DQB1, and DPB1 loci. A direct comparison of HLA antigen frequencies between GD and HT was performed. We further analyzed an epistatic interaction between the susceptible and protective HLA alleles in the development of GD and HT.
  
  
  RESULTS
  We identified 4 and 2 susceptible HLA molecules primarily associated with GD and HT, respectively, HLA-B*35:01, HLA-B*46:01, HLA-DRB1*14:03, and HLA-DPB1*05:01 for GD and HLA-A*02:07 and HLA-DRB4 for HT. In a direct comparison between GD and HT, we identified GD-specific susceptible class II molecules, HLA-DP5 (HLA-DPB1*05:01; Pc = 1.0 × 10(-9)) and HLA-DR14 (HLA-DRB*14:03; Pc = .0018). In contrast, HLA components on 3 common haplotypes in Japanese showed significant protective effects against the development of GD and HT (HLA-A*24:02-C*12:02-B*52:01-DRB1*15:02-DQB1*06:01-DPB1*09:01 and HLA-A*24:02-C*07:02-B*07:02-DRB1*01:01-DQB1*05:01-DPB1*04:02 haplotypes for GD and HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01 haplotype for GD and HT). Interestingly, the representative protective HLA, HLA-DR13 (HLA-DRB1*13:02), was epistatic to susceptible HLA-DP5 in controlling the development of GD.
  
  
  CONCLUSIONS
  We show that HLA exerts a dual function, susceptibility and resistance, in controlling the development of GD and HT. We also show that the protective HLA allele is partially epistatic to the susceptible HLA allele in GD.
authors.affiliation: Institute for Advanced Study (S.U., D.O., T.S.), Division of Genome Analysis (K.Y.), Medical Institute of Bioregulation, Department of Medicine and Clinical Science (K.O.), Graduate School of Medicine, and Division of Host Defense (H.Y., A.O., Y.Y.), Medical Institute of Bioregulation, Kyushu University, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; Ito Hospital (J.Y.N., Y.K., K.S., K.I.), Shibuya-ku, Tokyo 150-8308, Japan; Department of Diabetes and Metabolic Medicine (M.N., K.I.), National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 16-8655, Japan; Department of Laboratory (K.K.), Japanese Red Cross Tokyo Blood Center, Koto-ku, Tokyo 135-8639, Japan; and Department of Immunogenetics (Y.N.), Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Ueda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Oryoji
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Jaeduk Yoshimura
authors.initials: JY
authors.lastname: Noh
authors.forename: Ken
authors.initials: K
authors.lastname: Okamura
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kosuga
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sekiya
authors.forename: Kaori
authors.initials: K
authors.lastname: Inoue
authors.forename: Hisakata
authors.initials: H
authors.lastname: Yamada
authors.forename: Akiko
authors.initials: A
authors.lastname: Oyamada
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
authors.forename: Koichi
authors.initials: K
authors.lastname: Ito
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D003937:Diagnosis, Differential; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007564:Japan; D013967:Thyroiditis, Autoimmune / Q000175:diagnosis* / Q000235:genetics
chemical_list: D006680:HLA Antigens