Ratanachaiyavong S, Lloyd L, Darke C, McGregor A M
Department of Medicine, King's College School of Medicine, London, UK.
Hum Immunol. 1993 Feb;36(2):99-111. doi: 10.1016/0198-8859(93)90112-e.
MHC-extended haplotypes were investigated in multiplex families of patients with hyperthyroid GD. Using a combination of both phenotypic (serology and protein electrophoresis) and genotypic (DNA-RFLP) markers, 159 MHC-extended haplotypes extending from HLA-A across the MHC class III (C2, Bf, C4A, and C4B) toward the HLA-DR/DQ complex were deduced from 217 (51 and 166 affected and unaffected) members of 21 families of patients with GD. Thyroid autoantibodies were measured and found positive in 27.1% of 166 clinically euthyroid unaffected members. Extended haplotypes were classified into four categories--affected (n = 40), Aff/Ab + ve (shared haplotype between affected and Ab + ve members, n = 31), Ab + ve (n = 29), and Ab - ve (n = 59)--based on the presence and absence of these haplotypes in 51 affected members with GD and 45 and 121 unaffected members who were respectively positive and negative for thyroid autoantibodies. Five recombinations were detected: three were found between HLA-A and B and two between HLA-B and the MHC class III. No recombination was found between or within the MHC class III and class II complex. Though the HLA-DR17 (DR beta 17(1) and DR beta 17(2)) allele was found to be significantly increased in both the affected and the Aff/Ab + ve when compared with the Ab - ve haplotypes (p < 0.042 and p < 0.018), the frequency of the HLA-B8, 2.7-kb SstI-4.5-kb TaqI/C2 BfS, 6.4-kb TaqI/C4AQ0C4B1, HLA-DR beta 17(1)/DQ alpha 2-DQ beta 2a extended haplotype was found to be significantly increased only in the affected haplotype (p < 0.05). These results suggest that while HLA-DR17 is a susceptibility allele shared between GD and individuals with positive thyroid autoantibodies, the HLA-B8, 2.7-kb SstI-4.5-kb TaqI/5'-3'C2 BfS, 6.4-kb TaqI/C4AQ0B1, DR beta 17(1)/DQ alpha 2-DQ beta 2a is a disease susceptibility-extended haplotype for Graves' disease.
在甲状腺功能亢进型格雷夫斯病（GD）患者的多个家庭中研究了MHC扩展单倍型。使用表型（血清学和蛋白质电泳）和基因型（DNA - RFLP）标记相结合的方法，从21个GD患者家庭的217名成员（51名患者和166名未患病成员）中推导出来自HLA - A横跨MHCⅢ类（C2、Bf、C4A和C4B）直至HLA - DR/DQ复合体的159个MHC扩展单倍型。检测了甲状腺自身抗体，发现166名临床甲状腺功能正常的未患病成员中有27.1%呈阳性。根据这些单倍型在51名患有GD的患者以及45名和121名分别甲状腺自身抗体呈阳性和阴性的未患病成员中的有无情况，将扩展单倍型分为四类：患病（n = 40）、患病/抗体阳性（患病成员与抗体阳性成员之间的共享单倍型，n = 31）、抗体阳性（n = 29）和抗体阴性（n = 59）。检测到5次重组：3次发生在HLA - A和B之间，2次发生在HLA - B与MHCⅢ类之间。在MHCⅢ类和Ⅱ类复合体内或之间未发现重组。尽管与抗体阴性单倍型相比，发现HLA - DR17（DRβ17(1)和DRβ17(2)）等位基因在患病和患病/抗体阳性单倍型中均显著增加（p < 0.042和p < 0.018），但HLA - B8、2.7kb SstI - 4.5kb TaqI/C2 BfS、6.4kb TaqI/C4AQ0C4B1、HLA - DRβ17(1)/DQα2 - DQβ2a扩展单倍型仅在患病单倍型中显著增加（p < 0.05）。这些结果表明，虽然HLA - DR17是GD与甲状腺自身抗体阳性个体共有的易感等位基因，但HLA - B8、2.7kb SstI - 4.5kb TaqI/5'-3'C2 BfS、6.4kb TaqI/C4AQ0B1、DRβ17(1)/DQα2 - DQβ2a是格雷夫斯病的疾病易感扩展单倍型。
