Triggers of autoimmune thyroiditis. Part 1. Genetics

 

The incidence of Hashimoto’s thyroiditis has been linked to risk factors  such as gender, age and heredity. While the exact mechanism of the autoimmune thyroiditis remains unknown, it is stated in current research that the genetic predisposition combined with environmental triggers initiate the autoimmune response to the thyroid gland. About 80% of the susceptibility to develop an autoimmune thyroid disease (AITD) is attributed to genetic factors, while environmental factors contribute to 20%.

Genetics

The family history of thyroid disorders is common and well documented in the literature. The epidemiological and population data, high sibling risk ratio, family and twin studies confirmed strong genetic involvement in the development of Hashimoto’s disease. 

Currently there are several known genes associated with Hashimoto’s thyroiditis: cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), human leukocyte antigens (HLA), protein tyrosine phosphatase 22 (PTPN22) and thyroglobulin receptor gene.

Some of these susceptibility genes are specific to Hashimoto’s thyroiditis, while others are common in Grave’s and Hashimoto’s diseases indicating that there is a shared genetic susceptibility to both. The interactions between the genes may influence the disease severity and favour the development of either Grave’s or Hashimoto’s.

The genes can be classified into two groups: 

  1. immune regulatory genes (CTLA-4, HLA and PTPN22)
  2. thyroid specific genes (thyroglobulin receptor gene)

Some of the genes vary in different ethnic groups. Hashimoto’s thyroiditis is associated with HLA-DR3, HLA-DR4 and HLA-DR5 genes in Caucasians. The HLA-DR3 is also responsible for the susceptibility for type 1 diabetes and Grave’s disease in families with a genetic predisposition. Furthermore, an association between Hashimoto’s and HLA-DQw7 has also been reported in Caucasians, while HLA-DRw53 was found in Japanese and HLA-DR9 in Chinese population.

Other autoimmune diseases are also associated with the same genes as a Hashimoto’s thyroiditis. Prevalence of celiac disease was noted to be in up to 19% of patients with type 1 diabetes mellitus, up to 4.5% in Grave’s and 13% in Hashimoto’s disease. The coexistence of celiac and autoimmune thyroid disease is partly due to a common genetic predisposition. Both celiac disease and Hashimoto’s thyroiditis are reported to be associated with the genes CTLA-4, HLA-DQ2 and HLA-DQ8 and share common trigger of the disease gluten.

If you have Hashimoto’s and/or celiac disease and worry that your children can also get these conditions you can order a HLA-DQ2 and HLA-DQ8 Gene Test that can evaluate their genetic predisposition.

Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4)

The CTLA-4 gene acts as a negative regulator and supressor of T-cell activation that could result in an exaggerated T cell activationand lead to the development of autoimmunity. CTLA-4 has been reported to be associated with Hashimoto’s thyroiditis in various populations including Caucasians and Japanese.

The CTLA-4 has a potential to affect many different tissues causing susceptibility to autoimmunity in general. The gene was found to be associated with a variety of autoimmune conditions such as type 1 diabetes, asthma, Addison’s disease, myasthenia gravis, Sjorgren’s syndrome, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis and all forms of AITD including Grave’s disease and Hashimoto’s thyroiditis.

According to genome scan studies, there is a link between the CTLA-4 gene and the production of thyroid antibodies (TAb’s) contributing to the development of thyroid autoimmunity. However, additional genetic and/or environmental factors are necessary for the development of either Grave’s or Hashimoto’s disease.

There are a number of studies which suggesting that CTLA-4 may influence the severity of the AITD. The gene was found to be associated with more severe thyrotoxicosis.

Thyroglobulin receptor genes

Thyroglobulin (Tg) is a molecule that builds the thyroid gland and is necessary for the production of the thyroid hormones T3 and T4 within it. The IgG anti-Tg and TPO antibodies are prevalent in patients with Hashimoto’s.

High levels of Tg antibodies were also found in the general population without ever causing autoimmune thyroid disease. According to studies of healthy individuals in the United States, the Tg antibodies differ from those seen in Hashimoto’s thyroididis patients, by being polyreactive, of lower affinity and of predominantly IgM isotype.

Protein tyrosine phosphatase 22

The protein tyrosine phosphatase 22 (PTPN22) like CTLA-4 is an inhibitor of T cell activation. It was found to be associated with multiple autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, Graves’ disease and Hashimoto’s thyroiditis.

Studies in certain geographic regions show different gene expressions depending on ethnic society. The PTPN22 gene is not found in the Japanese and, therefore, could not contribute to autoimmunity in this population group.

There is a lot more to discover about Hashimoto’s thyroiditis, so sign up for Outsmart Disease blog updates and get FREE e-mail course Nutritional guide for Hashimoto’s disease to learn more.

Triggers of autoimmune thyroiditis. Part 2. Environmental factors

References:

 The genetics of complex thyroid diseases. Takashi Akamizu, Masato Kasuga, Terry Francis Davies, Springer, 2002

Pathogenesis of autoimmune thyroid diseases. Arq Bras Endocrinol Metabol. 2009 Feb;53(1):5-14.

The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid autoimmunity: back to the future. J Autoimmun. 2007 Mar-May;28(2-3):85-98. Epub 2007 Mar 21.

The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology.J Autoimmun. 2008 Feb-Mar;30(1-2):58-62. Epub 2008 Jan 4.