Can This Gene Contribute To Autoimmune Thyroid Disorders? (STAT3)

The STAT3 gene codes for one member of a family of proteins called signal transducer and activator of transcription, or just “STAT” for short. STAT proteins are activated by other proteins (such as JAK), which causes them to bind to DNA and turn certain genes “on” or “off” [R].

When it comes to STAT3 specifically, its main role is to control the expression of genes involved in the growth, development, and activation of immune system cells. This process is triggered by “messenger molecules” called cytokines. While STAT3 responds to many different cytokines, some of the main ones include IL-6, IL-10, IL-21, and  IL-23 [R, R, R].

The STAT3 gene encodes a protein that activates or blocks the expression of genes required for the function of immune cells.

Dual Role in Immunity Regulation

The immune system protects us from infections and cancer under normal circumstances, but also causes allergies and inflammatory/autoimmune disorders when imbalanced. STAT3 responds to cytokines that either activate or block the immune response — in other words, it is one of the mechanisms your body uses to fine-tune the immune system.

On the one hand, STAT3 contributes to the development and function of the cells that:

• Promote inflammation and kill microbes (neutrophils) [R, R]
• Present infectious particles to T-cells (dendritic cells) [R]
• Produce antibodies (B-cells) [R, R, R]
• Fight off infections, but which may cause autoimmune and inflammatory disorders if overactivated (Th17) [R, R, R]
• Quickly respond to repeated infections that the body has already developed immunity against (memory T-cells) [R, R]

STAT3 also blocks the immune response by reducing the production of immunosuppressive T-cells (also known as “Tregs”) [R].

On the other hand, STAT3 can also act as an immunosuppressant by:

• Increasing the expression of its own blocker (SOC3) [R, R, R]
• Preventing dendritic cell development [R]
• Blocking the production of pro-inflammatory cytokines by white blood cells (neutrophils, macrophages, and dendritic cells) [R, R, R]
• Producing the B-cells that suppress defense and autoimmunity (commonly known as “Bregs”) [R]
• Helping Tregs block Th17 development [R, R]

The STAT3 protein plays a fine-tuning role in the immune system, as it can both stimulate or suppress the immune response under different circumstances.

STAT3 and Autoimmune Thyroid Disorders

Autoimmune thyroid disorders are conditions in which the immune system targets the thyroid gland and alters its function, leading to abnormal levels of thyroid hormones. There are two main types [R]:

• Hashimoto’s disease: T-cells and antibodies target the thyroid gland and attack its tissues, resulting in thyroid hormone deficiency (hypothyroidism).
• Graves’ disease: antibodies bind to the thyroid gland causing it to be chronically stimulated, resulting in thyroid hormone overproduction (hyperthyroidism).

Despite having opposite symptoms, both conditions have been associated with T-cell imbalances in the immune system. Th1 cells are known to play a key role in Hashimoto’s symptoms, while Th2 cells prevail in the case of Graves’ disease [R, R, R].

More recently, studies in humans and mice have reported that Th17 cells contribute to the progression of both diseases — especially Hashimoto’s [R, R, R, R, R, R].

Given the well-known role of STAT3 in promoting the development of Th17 cells, several studies have suggested that over-active STAT3 variants may contribute to the progression of autoimmune thyroid disorders [R, R].

However, STAT3 also helps Tregs counteract the actions of Th17 cells, and promotes the production of its own blocker (SOC3) in thyroid cells. In this sense, over-active STAT3 variants may, actually be protective against autoimmune thyroid disorders [R, R, R].

All in all, it’s not yet clear whether STAT3 is better when it’s higher or lower, and more research will be needed to fully clarify its potential role in thyroid function and health. Nonetheless, some SNPs in the STAT3 gene have been associated with certain forms of thyroid disorders, which we’ll discuss in the next section.

The two main autoimmune thyroid disorders are Hashimoto’s and Graves’ disease. STAT3 may contribute to both of them by stimulating the development of Th17 cells, but may also help prevent them.

The most widely-studied STAT3 polymorphism is rs744166, whose ‘A’ allele is only slightly more common than the ‘G’ allele (51% vs 49%). Although its mechanism remains unknown, some researchers have suggested that certain alleles may alter the structure of the STAT3 protein, which changes how it responds to cytokines [R].

This could disrupt the normal way that the body regulates immune system activity, which may partially explain why this SNP has been associated with autoimmune disorders involving the thyroid.

For example, one study on over 100 people associated the ‘A’ allele with both Hashimoto’s and Graves’ disease in a Polish population [R].

However, other studies investigating this allele have reported conflicting results. One such study on almost 1,000 people found that this allele was only slightly associated with Hashimoto’s in a Chinese population, and was not associated with Graves’ disease at all. Similarly, another study on almost 400 Croatians failed to associate it with Hashimoto’s [R, R].

Therefore, it is possible that this allele’s effects only apply to certain ethnic groups, and more research will be needed to clarify this.

The major ‘T’ allele of another STAT3 polymorphism, rs3816769, was also associated with both Hashimoto’s and Graves’ disease in the Polish study. People with autoimmune thyroid disorders had ‘TT’ over 6 times more frequently than ‘CC’! [R].

Finally, the Chinese study also reported that the minor allele ‘C’ allele of rs1053005 was more common in people with either Hashimoto’s or Graves’ disease. This allele increases STAT3 production — and although its exact relationship to thyroid disorders hasn’t been directly studied, from what we know about this gene in general, it is possible that this increase in STAT3 could contribute to autoimmune thyroid issues by over-activating the immune system [R, R].

The major allele (‘A’) of rs744166 has been associated with autoimmune thyroid disorders in some studies, but not in others. The major ‘T’ allele of rs3816769 and the minor ‘C’ allele of rs1053005 were each associated with autoimmune thyroid disorders in one study.

You can see your genotype for several key STAT3 SNPs in the table below. However, keep in mind that these results are based on association studies, and more research will be needed to know what role (if any) these variants play in actually causing these disorders. Also, many different factors — including other genetic and environmental factors — can influence the risk of autoimmune conditions. Therefore, just because you have one of these genotypes does not necessarily mean you are at an increased risk of developing a thyroid-related autoimmune disorder!

Primary SNP: STAT3 rs744166:

• ‘A’ = Possibly more frequent in people with Hashimoto’s and Graves’ disease.
• ‘G’ = Possibly less frequent in people with Hashimoto’s and Graves’ disease.

Population Frequency:

• The ‘A’ allele is only slightly more common than ‘G’. Both homozygous genotypes are similarly frequent and roughly 44% of the world population has ‘AG’.
• In European descendants, the frequency of the ‘GG’ phenotype is reduced to 19%.

Other Important SNPs:

STAT3 rs3816769:

• ‘T’ = More frequent in people with Hashimoto’s and Graves’ disease.
• ‘C’ = Less frequent in people with Hashimoto’s and Graves’ disease.

Population Frequency:

• Almost 45% of the world population has ‘TC’.
• ‘T’ is only slightly more common than ‘C’ in South Asian descendants (51% vs 49%).

STAT3 rs1053005:

• ‘T’ = Less frequent in people with Hashimoto’s and Graves’ disease.
• ‘C’ = More frequent in people with Hashimoto’s and Graves’ disease.

Population Frequency:

• 50% of the world population has two copies of the ‘T’ allele and 40% has one.
• Less than 3% of American descendants have the ‘CC’ genotype.