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Graves' disease

From SNPedia

Wikipedia (as edited July 22, 2017) re Graves' disease: it is a form of autoimmune thyroid disease (AITD) in which the body produces antibodies to the receptor for thyroid-stimulating hormone. Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced. Graves' disease occurs in about 0.5% of people. It occurs about 7.5 times more often in women than men. Often it starts between the ages of 40 and 60. It is the most common cause of hyperthyroidism (overactive thyroid) and general thyroid enlargement in developed countries.

[PMID 30761086OA-icon.png]In a 2019 editorial, "TSH Receptor and Autoimmunity" it is now known that the TSH-Receptor antibodies (TRAb) have three variants with variable effects on thyroid status:

  • 1) TSAb - Stimulating (causing hyperthyroidism by mimicking TSH),
  • 2) TBAb - Blocking (causing hypothyroidism by blocking TSH activity to various degrees), and
  • 3) "Neutral" (neither blocking nor stimulating, "but may be involved in aberrant signal initiation and thyroid cell apoptosis")

Patients' sera may contain all three types of TRAbs; the clinical manifestation of hypo-, hyper-, or euthyroidism depends on the dominant antibody.

In Graves' disease, "TSHR-reactive T cells and B cells survive central and peripheral deletion and under appropriate circumstances the B cells secrete TSHR antibodies and also induce T cells to secrete pro-inflammatory cytokines." TSHR Antibodies interact with TSH receptors in the thyroid gland (causing thyroid stimulation, blocking and/or apoptosis), eye orbit tissues (causing Graves' eye disease), and skin (causing Graves' dermopathy).

[PMID 23025526OA-icon.png]Graves' disease patients can manifest with fluctuations between hyperthyroidism, hypothyroidism and euthyroidism over many years or decades, according to the 2013 article "Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa." They explain that "Switching between TBAb and TSAb (or vice versa) occurs in unusual patients after LT4 therapy for hypothyroidism or anti-thyroid drug treatment for Graves' disease. These changes involve differences in TSAb versus TBAb concentrations, affinities and/or potencies in individual patients. Thus, anti-thyroid drugs or suppression/hemodilution in pregnancy reduce initially low TSAb levels even further, leading to TBAb dominance. In contrast, TSAb emergence after LT4 administration may be sufficient to counteract TBAb inhibition. The occurrence of “switching” emphasizes the need for careful patient monitoring and management."

[PMID 28421036OA-icon.png] A 2017 review, "Genetics of Thyroid-Stimulating Hormone Receptor-Relevance for Autoimmune Thyroid Disease," reviews two decades of TSHR gene research on Graves' disease pathogenesis. Research has "narrowed the disease-susceptibility region to a 40 kb sequence in intron 1, where at least five GD-associated SNPs in tight linkage disequilibrium" exist. Table 1 lists multiple SNPs with Graves' disease risk. [These SNPs are included in the list below].

[PMID 17903292OA-icon.png] A 2012 article "Delineating the autoimmune mechanisms in Graves’ disease" responded to the oversimplified view that Graves' disease involves TSHR antibodies in a single pathway that necessarily leads to hyperthyroidism and orbitopathy. This is not the case. Authors outlined how three types of TSHR antibodies (stimulating, blocking and neutral) function differently in various phenotypes of GD patients, who vary from hyperthyroid to hypothyroid. TSHR blocking antibodies may prevent TSHR from binding to the receptor to such an extent that they may induce hypothyroidism. They also explored several immune mechanisms by which thyroid gland cell death (apoptosis) occurs, resulting in hypothyroidism. Therefore, GD involves genetic risk via multiple gene polymorphisms that interact with epigenetics and environmental factors, and may have a variety of disease pathways and outcomes.

SNPs reported to be associated with risk for Graves' disease include:

Additional SNPs reported in 2017 in [PMID 28421036OA-icon.png]

See SNPedia's Autoimmune thyroiditis page for more info and citations.