Genetics of Graves' Disease

Abstract

Graves' disease (GD) is a common autoimmune condition characterised by autoantibody attack against components of the thyroid gland which leads to hyperthyroidism. Both genetic and environmental factors have been implicated in disease onset. Uncovering the genetic contribution to GD has revealed that the disease is caused by a variety of factors encompassing both immunological and thyroid specific pathways. Recent advancements in genetic screening technologies, including the success of genome‐wide association studies, have provided further insights into GD susceptibility loci. The challenge now is to determine how these newly found susceptibility loci play a role in disease while simultaneously identifying the remainder of the genetic contribution to GD. This will, in turn, piece together the complex pathogenic pathways associated with GD, painting a clearer picture of disease development and with it the provision of new opportunities for improved therapeutics and treatment strategies.

Key Concepts:

  • In Graves' disease (GD) autoantibodies are produced which bind to and constitutively activate the thyroid‐stimulating hormone receptor usually resulting in the overproduction of the thyroid hormones, triiodothyronine and thryoxine.

  • GD is a complex disease caused by a variety of genetic and environmental factors.

  • A variety of different genetic approaches have been used to detect the genetic contribution to GD, including case‐control studies and genome‐wide association scans.

  • GD susceptibility loci are likely to alter both immunological and thyroid specific pathways.

  • Many of the GD susceptibility loci are also found to contribute to other autoimmune diseases suggesting the presence of shared autoimmune disease pathways.

  • Confirmed GD susceptible loci, detected to date, only account for a small amount of the observed genetic effect, with a large degree of genetic heritability still unaccounted for.

  • Fine mapping of known gene effects, screening of low frequency and rare variants and investigating gene–gene and gene–environment interactions are currently being undertaken to locate the remaining missing genetic heritability for GD.

Keywords: Graves' disease; genome‐wide association studies; autoimmunity; genetics; susceptibility loci; human leucocyte antigen; thyroid; case‐control studies; linkage disequilibrium; autoimmune thyroid disease

Figure 1.

How thyroid function is disrupted in Graves’ disease (GD). Diagrammatic representation of how thyroid function and control of thyroid signalling is altered in GD by the production of autoantibodies directed against the thyroid‐stimulating hormone receptor (TSHR). (1) The hypothalamus senses when thyroid hormone levels are low and releases thyrotropin releasing hormone (TRH) which stimulates thyroid‐stimulating hormone (TSH) production in the pituitary gland. (2) TSH binds to the TSHR on thyroid follicular cells. (3) This activates signalling pathways stimulating gene expression. (4) Gene expression leads to the synthesis of thyroglobulin (Tg) which is exocytosed into the follicular lumen. (5) Thyroid peroxidase (TPO) adds iodine to Tg. (6) These chains then conjugate and the Tg is endocytosed back into the thyroid follicular cell. (7) Proteases degrade the protein chain leaving thyroid hormone molecules triiodothyronine (T3) and thyroxine (T4) which are subsequently exocytosed into the bloodstream. Although both are produced by the thyroid, the majority of T3 comes from the conversion of T4 by iodothyronine deiodinases (IYH) in peripheral tissues (shown by the curved arrow). (8) Excess T3 and T4 hormones negatively feedback through inhibition of TRH and as a consequence TSH expression. This reduces TSH production and in turn T3 and T4 production. (9) TSHRAbs which are produced during GD effectively block this negative feedback mechanism by binding to and constitutively activating the receptor, driving forward autonomous T3 and T4 production. High levels of T3 and T4 suppress TSH levels accordingly.

Figure 2.

Timeline of notable GD associated genes. Case‐control studies initially led to the identification of HLA class II region, CTLA‐4 and PTPN22 yet stagnated until the use of Tag SNPs and fluorescent genotyping came in the early 2000s leading to the identification of additional susceptibility loci. GWAS confirmed many of the results from case‐control studies while also identifying other potential modulators of GD. Δ denotes gene found in region identified through linkage studies and confirmed by case‐control studies. * denotes gene originally found in case‐control studies and confirmed by GWAS.

Figure 3.

Inhibition at the immunological synapse. HLA class II molecules on the surface of antigen‐presenting cells (APCs) interact with the T cell receptor (TCR) of the CD4+ Th cells. If the TCR recognises the antigen as nonself, a primary signal is transduced. A secondary signal is then required via CD80/CD86 coreceptors on the APC interacting with CD28 on the T cell. CTLA‐4 acts to inhibit this second signal via binding to CD80/CD86 preventing CD28 signal transduction. CTLA‐4 is also proposed to directly inhibit the TCR or inhibit other signalling molecules including ITAM kinases, Fyn, Lck and Zap‐70. CTLA‐4 could also interact with the LYP–Grb2 complex to inhibit T cell activation by a currently unknown mechanism. LYP interacts with further adaptor molecules involved in controlling downstream T cell signalling including Csk and c‐Cbl. The LYP–Csk complex associates with the Fyn and Lck kinases, allowing LYP to dephosphorylate and inactivate the kinases. The LYP–c‐Cbl complex also inhibits T cell signalling through dephosphorylation of Zap‐70 while it interacts with the ITAM domains of the TCR (Brand et al., ).

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Further Reading

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Hamilton, Alexander, Gough, Stephen CL, and Simmonds, Matthew J(Sep 2013) Genetics of Graves' Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024977]