Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Clin Endocrinol Metab. 2014 Feb;99(2):E379-83. doi: 10.1210/jc.2013-2841. Epub 2013 Nov 27.

Identification of independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and their epistasis.

Author information

  • 1Institute 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.

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.

AIM:

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.

DESIGN:

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.

CONCLUSION:

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.

PMID:
24285682
[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Atypon
    Loading ...
    Write to the Help Desk