The Role of Genetic Factors

The etiology of autoimmune thyroid disease (AITD) is unclear. Similar to other autoimmune diseases, genetic, environmental, and other endogenous factors contribute to the initiation of the disease. Increased incidence of GD among members of a family and a higher degree of disease concordance among identical twins indicate that genetic factors may play an important role in determining susceptibility to GD [15-17]. As in most other autoimmune diseases, the strongest bias in developing GD is gender: women are 5-10 times more likely than men to develop the disease. Two recent reviews on genetic susceptibility to GD have summarized and discussed the implications of a large number of stud ies [18, 19]. The general conclusions one can draw from studies to date is that multiple genetic factors appear to contribute to the risk of developing GD. Some of the susceptibility gene(s) appear to be associated with the X chromosome, others seem to be specific to GD (e.g., GD-1, GD-2, and GD-3), and yet others such as MHC class II alleles and CTLA4 are involved in the generation of immune responses [20,21]. The CTLA4 protein exists in multiple isoforms due to genetic polymorphism of AT dimers at the 3'-untranslated region of the third exon. This is often linked with another polymorphism in the first exon [22]. A 106-base pair AT polymorphism is thought to be associated with increased risk of GD [20, 23]. Similarly, other associations with genetic polymorphism in CTLA4 have been reported [24-26]. Earlier studies have shown that patients with GD express HLA-B8 more often than control subjects without the disease [27]. Other studies have shown that the risk of developing the disease is higher among individuals with an MHC class II haplotype of HLA-DR3 [28, 29]. Similarly, the risk is increased in individuals with a DQA1-*0501 haplotype [30, 31]. In contrast, the expression of HLA DR /51*07 appears to confer protection [32]. There is also a racial variation in the association of MHC haplo-types with an increased risk for the development of GD [32]. However, it is no coincidence that the genetic associations with GD are related to genes involved in immune regulation. Although GD is an autoantibody-mediated disease, as discussed above, genetic factors such as linkage to MHC class II alleles and CTLA4 point to an essential T-cell role in its development. How the autoimmune response is initiated in genetically susceptible individuals is not fully understood, but environmental factors appear to play an important role.

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