Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands.
Endocr Rev. 2015 Apr;36(2):214-44. doi: 10.1210/er.2014-1081. Epub 2015 Mar 9.
For a long time it has been known that both hypo- and hyperthyroidism are associated with an increased risk of morbidity and mortality. In recent years, it has also become clear that minor variations in thyroid function, including subclinical dysfunction and variation in thyroid function within the reference range, can have important effects on clinical endpoints, such as bone mineral density, depression, metabolic syndrome, and cardiovascular mortality. Serum thyroid parameters show substantial interindividual variability, whereas the intraindividual variability lies within a narrow range. This suggests that every individual has a unique hypothalamus-pituitary-thyroid axis setpoint that is mainly determined by genetic factors, and this heritability has been estimated to be 40-60%. Various mutations in thyroid hormone pathway genes have been identified in persons with thyroid dysfunction or altered thyroid function tests. Because these causes are rare, many candidate gene and linkage studies have been performed over the years to identify more common variants (polymorphisms) associated with thyroid (dys)function, but only a limited number of consistent associations have been found. However, in the past 5 years, advances in genetic research have led to the identification of a large number of new candidate genes. In this review, we provide an overview of the current knowledge about the polygenic basis of thyroid (dys)function. This includes new candidate genes identified by genome-wide approaches, what insights these genes provide into the genetic basis of thyroid (dys)function, and which new techniques will help to further decipher the genetic basis of thyroid (dys)function in the near future.
长期以来，人们已经知道甲状腺功能减退症和甲状腺功能亢进症都会增加发病率和死亡率。近年来，人们也已经清楚，甲状腺功能的轻微变化，包括亚临床功能障碍和参考范围内甲状腺功能的变化，可能对临床终点有重要影响，如骨密度、抑郁、代谢综合征和心血管死亡率。血清甲状腺参数显示出显著的个体间变异性，而个体内的变异性则在狭窄范围内。这表明每个人都有一个独特的下丘脑-垂体-甲状腺轴设定点，主要由遗传因素决定，这种遗传性已被估计为 40-60%。在甲状腺功能障碍或甲状腺功能检查改变的人中，已经确定了甲状腺激素途径基因的各种突变。由于这些原因很少见，多年来已经进行了各种候选基因和连锁研究，以确定与甲状腺（功能障碍）相关的更常见变体（多态性），但只发现了有限数量的一致关联。然而，在过去的 5 年中，遗传研究的进展导致了大量新候选基因的鉴定。在这篇综述中，我们概述了目前关于甲状腺（功能障碍）多基因基础的知识。这包括全基因组方法鉴定的新候选基因，这些基因为甲状腺（功能障碍）的遗传基础提供了哪些见解，以及哪些新技术将有助于在不久的将来进一步解析甲状腺（功能障碍）的遗传基础。
