Division of Endocrinology, Department of Medicine, Mount Sinai Medical Center, New York, New York 10029, USA.
Thyroid. 2010 Jul;20(7):715-25. doi: 10.1089/thy.2010.1644.
Autoimmune thyroid diseases (AITD), including Graves' disease and Hashimoto's thyroiditis, arise due to complex interactions between environmental and genetic factors. There are sound data coming from epidemiological, family, and twin studies demonstrating a strong genetic influence on the development of AITD. In this review we summarize the new findings on the genetic susceptibility to AITD focusing on emerging mechanisms of susceptibility.
Candidate gene analysis, whole-genome linkage screening, genome-wide association studies, and whole-genome sequencing are the major technologies that have advanced this field, leading to the identification of at least seven genes whose variants have been associated with AITD. One of the major ones is the HLA-DR gene locus. Recently, it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide-binding pocket is key to the etiology of both Graves' disease and Hashimoto's thyroiditis. Several other genes have also been shown to confer susceptibility to AITD. These can be classified into two groups: (i) immune regulatory genes (cytotoxic T lymphocyte-associated protein 4, CD40, protein tyrosine phosphatase-22, and CD25) and (ii) thyroid-specific genes (thyroglobulin and thyrotropin receptor genes). The influence of individual genes on the development of AITD when assessed in a population appears to be weaker than would be expected from the data showing strong genetic susceptibility to AITD. Two possible mechanisms explaining this discrepancy are gene-gene interactions and subset effects.
Significant progress has been made in our understanding of the immunogenetic mechanisms leading to thyroid autoimmunity. For the first time we are beginning to unravel these mechanisms at the molecular level. It is hoped that these new data will be translated into novel therapies and prevention strategies in AITD, such as costimulatory blockade.
自身免疫性甲状腺疾病（AITD），包括格雷夫斯病和桥本甲状腺炎，是由于环境和遗传因素之间的复杂相互作用而产生的。流行病学、家族和双胞胎研究都有充分的数据表明，遗传因素对 AITD 的发生有很强的影响。在这篇综述中，我们总结了关于 AITD 遗传易感性的新发现，重点介绍了新兴的易感性机制。
候选基因分析、全基因组连锁筛选、全基因组关联研究和全基因组测序是推动这一领域发展的主要技术，这些技术导致至少 7 个基因的变异与 AITD 相关。其中一个主要的基因是 HLA-DR 基因座。最近，研究表明，HLA-DR 肽结合口袋β74 位的中性氨基酸 Ala 或 Gln 被精氨酸取代是格雷夫斯病和桥本甲状腺炎病因的关键。还有其他几个基因也被证明与 AITD 的易感性有关。这些基因可以分为两类：（i）免疫调节基因（细胞毒性 T 淋巴细胞相关蛋白 4、CD40、蛋白酪氨酸磷酸酶 22 和 CD25）和（ii）甲状腺特异性基因（甲状腺球蛋白和促甲状腺素受体基因）。当在人群中评估个体基因对 AITD 的发展的影响时，其影响似乎比表明对 AITD 有强烈遗传易感性的数据所预期的要弱。有两种可能的机制可以解释这种差异，即基因-基因相互作用和亚组效应。
我们对导致甲状腺自身免疫的免疫遗传机制的理解取得了重大进展。我们首次开始从分子水平上揭示这些机制。希望这些新数据能转化为 AITD 的新疗法和预防策略，如共刺激阻断。
