HLA genes most likely account for only part of the genetic susceptibility to AITD. At least five additional non- HLA genes have been found to confer risk for AITD although each confers much less risk than HLA. Three immunoregulatory genes (CTLA- 4, CD40, and PTPN22) and two thyroid- specific genes (thyroglobulin, and the TSHR) have been reproducibly associated with these diseases. There are multiple other reports in the literature but many of these involve low risks and lack confirmation in different study populations. Such reproducibility is the hallmark of significance.
Cytotoxic T- lymphocyte antigen- 4 (CTLA- 4): CTLA- 4 is a costimulatory molecule that participates in the interaction between T cells and antigen presenting cells (APCs). APC’s activate T cells by presenting to the T- cell receptor an antigenic peptide bound to an HLA class II protein on the cell surface. For this activation to work, a second signal is required and these costimulatory signals are provided by a variety of proteins which are expressed on APCs (e.g. B7- 1, B7- 2, B7h, CD- 40) and interact with receptors (CD28, CTLA- 4, and CD- 40L) on the surface of CD 4+ T- lymphocytes during antigen presentation. Whereas, the binding of B7 to CD28 on T cells costimulates T- cell activation, the presence of CTLA- 4, which has a higher affinity for B7, downregulates T- cell activation by competing for the binding of B7 to CD28. The suppressive effects of CTLA- 4 on T- cell activation may be altered by polymorphisms reducing CTLA- 4 expression and/ or function resulting in exaggerated T- cell activation which may lead to the development of autoimmunity in susceptible individuals. Indeed, CTLA- 4 polymorphisms have been consistently shown to be associated with many different autoimmune conditions including both GD and HT and this association has been consistent across populations of different ethnic backgrounds.
Several CTLA- 4 variants have been reported as associated with AITD but three have shown the most consistent association including an (AT)n microsatellite within the 3’UTR region of the CTLA- 4 gene, a SNP at position 49 in the CTLA- 4 leader pep tide (designated A/ G49), resulting in an alanine/ threonine substitution, and a SNP (designated CT60) located near the 3’UTR of the CTLA- 4 gene. Interestingly the CTLA- 4 gene also appears to confer susceptibility to the production of thyroid anti bodies (TAbs) without clinically significant disease, thus substantiating its role as a general autoimmunity gene.
CD40: CD40 is a member of the tumour necrosis factor receptor (TNFR) family of molecules and is expressed primarily on B cells and other APCs including thyroid cells. CD40 plays a fundamental role in B- cell activation, inducing B- cell proliferation, immunoglobulin class switching, and antibody secretion.
Recently, using a combination of linkage and association studies, CD40 has been identified as a novel susceptibility gene for GD. A C/ T SNP at the 5’UTR of CD40 was associated with GD, with the CC genotype conferring the risk an observation replicated in several studies.
The protein tyrosine phosphatase- 22 (PTPN22) gene: The lymphoid tyrosine phosphatase (LYP), encoded by the protein tyro sine phosphatase- 22 (PTPN22) gene, is a 110 kDa protein tyrosine phosphatase that, like CTLA- 4, is a powerful inhibitor of T- cell activation. A tryptophan/ arginine substitution at codon 620 (R620W) of PTPN22 was found to be associated with AITD mostly with GD, as well as with other autoimmune diseases.
Thyroglobulin: Thyroglobulin represents one of the major tar gets of the immune response in AITD. The Tg gene has been shown consistently to also be an important AITD susceptibility gene with four Tg SNPs significantly associated with AITD. Moreover, three of the associated Tg SNPs were non- synonymous (i.e. they caused amino acid changes in the Tg protein). The association between Tg and AITD has been well replicated although the associated Tg poly morphism has not been consistent in different populations.
The thyrotropin receptor (TSHR): The presence of stimulating TSHR autoantibodies is the hallmark of GD indicating that the TSHR is a primary antigen. It is not surprising, therefore, that the TSHR gene is also reproducibly associated with GD and the most consistent studies have identified non- coding SNPs in intron 1 of the TSHR.
