Levin Lara, Ban Yoshiyuki, Concepcion Erlinda, Davies Terry F, Greenberg David A, Tomer Yaron
Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Hum Immunol. 2004 Jun;65(6):640-7. doi: 10.1016/j.humimm.2004.02.026.
Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) are the most common autoimmune endocrine disorders. The similar pathogenesis of T1D and AITD and their tendency to occur together suggest that their etiology may involve common genetic factors. We hypothesized that the human leukocyte antigen (HLA) locus may contribute in part to the joint susceptibility to T1D and AITD. We therefore analyzed a data set of 40 multiplex families in which T1D and AITD clustered ("T1D-AITD families") for linkage and association with the HLA class II locus. We found evidence for linkage of the HLA region to T1D (maximum logarithm of odds score [MLS] = 7.3), to Hashimoto thyroiditis (HT) (MLS = 1.5), and to both (MLS = 3.8). Transmission disequilibrium test analysis revealed significant association of both T1D and AITD with HLA-DR3; however, only T1D was associated with HLA-DR4. We concluded that the finding of evidence for linkage of HLA with HT is in contrast to the strong evidence against linkage found in previous studies of AITD-only families; therefore, it is possible that the AITD phenotype seen in T1D families has a different genetic etiology than the AITD phenotype in AITD-only families; that HLA-DR3 was the major HLA allele contributing to the joint genetic susceptibility to T1D and AITD, whereas other alleles (e.g., DR4) are phenotype specific; and that because the logarithm of odds score for T1D + HT was lower than for T1D alone, additional non-HLA loci must contribute to the shared genetic susceptibility to T1D and AITD.
1型糖尿病（T1D）和自身免疫性甲状腺疾病（AITD）是最常见的自身免疫性内分泌疾病。T1D和AITD相似的发病机制以及它们共同出现的倾向表明，它们的病因可能涉及共同的遗传因素。我们推测人类白细胞抗原（HLA）基因座可能部分促成了对T1D和AITD的共同易感性。因此，我们分析了一个包含40个多重家庭的数据集（其中T1D和AITD聚集在一起，即“T1D - AITD家庭”），以研究与HLA II类基因座的连锁和关联情况。我们发现HLA区域与T1D存在连锁证据（最大优势对数评分[MLS]=7.3），与桥本甲状腺炎（HT）存在连锁证据（MLS = 1.5），与两者都存在连锁证据（MLS = 3.8）。传递不平衡检验分析显示，T1D和AITD均与HLA - DR3存在显著关联；然而，只有T1D与HLA - DR4相关联。我们得出结论，HLA与HT存在连锁证据这一发现与之前仅针对AITD家庭的研究中反对连锁的有力证据形成对比；因此，有可能T1D家庭中出现的AITD表型与仅患有AITD家庭中的AITD表型具有不同的遗传病因；HLA - DR3是导致对T1D和AITD共同遗传易感性的主要HLA等位基因，而其他等位基因（如DR4）具有表型特异性；并且由于T1D + HT的优势对数评分低于单独的T1D，所以其他非HLA基因座必定促成了对T1D和AITD的共同遗传易感性。
