Ueda Sho, Oryoji Daisuke, Yamamoto Ken, Noh Jaeduk Yoshimura, Okamura Ken, Noda Mitsuhiko, Kashiwase Koichi, Kosuga Yuka, Sekiya Kenichi, Inoue Kaori, Yamada Hisakata, Oyamada Akiko, Nishimura Yasuharu, Yoshikai Yasunobu, Ito Koichi, Sasazuki Takehiko
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.
J Clin Endocrinol Metab. 2014 Feb;99(2):E379-83. doi: 10.1210/jc.2013-2841. Epub 2013 Nov 27.
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.
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.
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.
We identified 4 and 2 susceptible HLA molecules primarily associated with GD and HT, respectively, HLA-B35:01, HLA-B46:01, HLA-DRB114:03, and HLA-DPB105:01 for GD and HLA-A02:07 and HLA-DRB4 for HT. In a direct comparison between GD and HT, we identified GD-specific susceptible class II molecules, HLA-DP5 (HLA-DPB105:01; Pc = 1.0 × 10(-9)) and HLA-DR14 (HLA-DRB14:03; Pc = .0018). In contrast, HLA components on 3 common haplotypes in Japanese showed significant protective effects against the development of GD and HT (HLA-A24:02-C12:02-B52:01-DRB115:02-DQB106:01-DPB109:01 and HLA-A24:02-C07:02-B07:02-DRB101:01-DQB105:01-DPB104:02 haplotypes for GD and HLA-A33:03-C14:03-B44:03-DRB113:02-DQB106:04-DPB104:01 haplotype for GD and HT). Interestingly, the representative protective HLA, HLA-DR13 (HLA-DRB113:02), was epistatic to susceptible HLA-DP5 in controlling the development of GD.
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.
自身免疫性甲状腺疾病（AITD）包括格雷夫斯病（GD）和桥本甲状腺炎（HT），它们部分共享免疫特征。确定区分GD和HT的遗传基础是理解这两种相关疾病差异的关键。
本研究的目的是鉴定能够解释GD和HT之间免疫病理差异的HLA抗原，并阐明保护性和易感性HLA等位基因之间的上位相互作用，这可以描绘HLA在AITD病因学中的独特功能。
我们对991例AITD患者（547例GD患者和444例HT患者）和481例对照受试者进行了HLA-A、HLA-C、HLA-B、DRB1、DQB1和DPB1位点的基因分型。对GD和HT之间的HLA抗原频率进行了直接比较。我们进一步分析了易感性和保护性HLA等位基因在GD和HT发生过程中的上位相互作用。
我们分别鉴定出4种和2种主要与GD和HT相关的易感性HLA分子，GD的为HLA-B35:01、HLA-B46:01、HLA-DRB114:03和HLA-DPB105:01，HT的为HLA-A02:07和HLA-DRB4。在GD和HT的直接比较中，我们鉴定出GD特异性的易感性II类分子，HLA-DP5（HLA-DPB105:01；Pc = 1.0×10⁻⁹）和HLA-DR14（HLA-DRB14:03；Pc = 0.0018）。相比之下，日本人群中3种常见单倍型上的HLA成分对GD和HT的发生具有显著的保护作用（GD的HLA-A24:02-C12:02-B52:01-DRB115:02-DQB106:01-DPB109:01和HLA-A24:02-C07:02-B07:02-DRB101:01-DQB105:01-DPB104:02单倍型以及GD和HT的HLA-A33:03-C14:03-B44:03-DRB113:02-DQB106:04-DPB104:01单倍型）。有趣的是，代表性的保护性HLA，HLA-DR13（HLA-DRB113:02），在控制GD的发生方面对易感性HLA-DP5具有上位作用。
我们表明HLA在控制GD和HT的发生中发挥双重作用，即易感性和抗性。我们还表明，在GD中，保护性HLA等位基因对易感性HLA等位基因具有部分上位作用。
