The Genetics of Autoimmune Thyroid Disease

Autoimmune thyroid disease (AITD) comprises a series of interrelated conditions including hyperthyroid Graves’ disease (GD), Hashimoto’s (goitrous) thyroiditis, atrophic autoimmune hypothyroidism, postpartum thyroiditis (PPT), and thyroid-associated orbitopathy (TAO). These different manifestations of AITD may occur synchronously, most frequently as the combination of GD and TAO. Different AITD phenotypes may also occur sequentially in the same individual, for instance, spontaneous hypothyroidism following an episode of GD or PPT. This clustering of different AITD phenotypes within an individual suggests that these conditions have a common pathophysiological basis. Together, AITDs are the commonest autoimmune disorders in the population, affecting between 2% and 4% of women and up to 1% of men (1–3). Furthermore, AITD prevalence increases with advancing age, with more than 10% of subjects over 75 yr of age having biochemical evidence of mild (subclinical) hypothyroidism, the majority of which is due to autoimmune disease (2, 3). A widely accepted model for the pathogenesis of AITD suggests that each subject has a background inherited predisposition to autoimmunity, with additional environmental and hormonal factors that trigger or contribute to the development of disease. In support of this model, there is good evidence that both cigarette smoking and adverse psychosocial events are associated with the development of GD (4– 6). Similarly, the female preponderance of human AITDs (1), the modulation of animal models of AITD with gonadal steroids (7), the amelioration of GD during pregnancy, and the occurrence of PPT all support the important role of sex steroids in these disorders. In contrast, there is little convincing evidence that infective agents, which are thought of as classical environmental precipitants for autoimmunity, trigger AITDs (8). A recent statistical model, based on data from a large twin study, found that 79% of the predisposition to GD is due to genetic factors, with only 21% due to nongenetic (environmental and hormonal) influences (9). This study has profound implications for the study of AITD and suggests that if we are to make progress in understanding the molecular basis for AITDs, the elucidation of the genetic factors is most likely to hold the key. Recent years have seen a flurry of activity in this research field, and in this article we will review these advances in understanding about the genetic basis of AITDs.