title: Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation.
abstract: The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes mostly important for immunity and 50 noncoding RNAs (ncRNAs). Biological function of these ncRNAs remains unknown, becoming hot spot in the studies of HLA-associated diseases. The genomic diversity analysis in the HLA region facilitated by next-generation sequencing will pave the way to molecular understanding of linkage disequilibrium structure, population diversity, histocompatibility in transplantation, and associations with autoimmune diseases. The 4-digit DNA genotyping of HLA for six HLA loci, HLA-A through DP, in the patients with Graves' disease (GD) and Hashimoto thyroiditis (HT) identified six susceptible and three resistant HLA alleles. Their epistatic interactions in controlling the development of these diseases are shown. Four susceptible and one resistant HLA alleles are shared by GD and HT. Two HLA alleles associated with GD or HT control the titers of autoantibodies to thyroid antigens. All these observations led us to propose a new model for the development of GD and HT. Hematopoietic stem cell transplantation from unrelated donor (UR-HSCT) provides a natural experiment to elucidate the role of allogenic HLA molecules in immune response. Large cohort studies using HLA allele and clinical outcome data have elucidated that (1) HLA locus, allele, and haplotype mismatches between donor and patient, (2) specific amino acid substitution at specific positions of HLA molecules, and (3) ethnic background are all responsible for the immunological events related to UR-HSCT including acute graft-versus-host disease (GVHD), chronic GVHD, graft-versus-leukemia (GvL) effect, and graft failure.
authors.affiliation: Institute for Advanced Study, Kyushu University, Higashi-ku, Fukuoka, Japan. Electronic address: sasazuki@bioreg.kyushu-u.ac.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.affiliation: GenoDive Pharma Inc., Atsugi, Kanagawa, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.affiliation: Division of Hematology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Morishima
authors.affiliation: Division of Epidemiology and Prevention, Aiichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
mesh_terms: D000483:Alleles; D001323:Autoantibodies / Q000097:blood / Q000235:genetics / Q000276:immunology; D002874:Chromosome Mapping; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006086:Graft vs Host Disease / Q000235:genetics; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology; D006111:Graves Disease / Q000235:genetics*; D006239:Haplotypes; D050031:Hashimoto Disease / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D059014:High-Throughput Nucleotide Sequencing; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans
chemical_list: D001323:Autoantibodies; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II
keywords: Acute graft-versus-host disease; DNA typing; Epistatic interaction; Genome diversity; Graft-versus-leukemia effect; Graves’ disease; HLA allele; HLA class I and class II gene and molecule; HLA haplotype; Hashimoto thyroiditis; Linkage disequilibrium; Next-generation sequencing; Polymorphism; Regulatory T cell; Thyroglobulin antibody and serum level; Thyroid peroxidase antibody and serum level; Thyroid stimulating hormone receptor antibody and serum level; Unrelated hematopoietic stem cell transplantation