How This Autoimmunity Gene Impacts Thyroid Health (CTLA4)

Your body works 24/7 to keep the immune system in balance. Weak immunity would make you prone to cancer, chronic diseases, and microbes, while overactive immunity opens the door for allergies and autoimmune conditions. CTLA4 is one of your main tools for fine-tuning defense mechanisms.

The CTLA4 (cytotoxic T-lymphocyte associated protein 4) gene encodes for a protein that keeps the immune response in check by suppressing T-cells. Another regulatory protein, CD28, stimulates T-cells, while CTLA4 inhibits them: these two work in balance to ensure optimal immune reaction [R, R].

Animal models have confirmed the inhibitory effect of CTLA4 on the immune system. CTLA4-blocking antibodies enhance antitumor and antimicrobial protection but also trigger allergic reactions and autoimmunity. In other words, the immune system becomes overactive in the absence of this “checkpoint” [R].

Not surprisingly, scientists have associated specific CTLA4 gene variations with [R, R, R]:

• Autoimmune thyroid disorders
• Type 1 diabetes
• Celiac disease
• Lupus
• Ulcerative colitis
• Multiple sclerosis

CTLA-4 encodes for a protein that keeps the immune response in check. The lack of this controller causes an enhanced immune response but also contributes to allergic reactions and autoimmunity.

In the absence of CTLA4, cell-damaging (cytotoxic) T-cells become much more active and overproduce cytokines such as IFN-gamma. They can infiltrate healthy tissue and stimulate the production of self-harming antibodies, which are the hallmark of autoimmunity [R]. 

People with a rare genetic condition, CTLA4 deficiency, have enlarged lymph nodes and spleen,  due to overproduction of immune cells, and a wide range of autoimmune problems [R].

Blocking CTLA4 with specific antibodies stimulates T-cells and IL-2 production. Mice without this protein die due to overactive T lymphocytes that attack and destroy healthy tissue. On the other hand, the administration of CTLA4 can suppress an autoimmune response in lupus, arthritis, and diabetes models [R, R].

The exact mechanisms by which CTLA4 suppresses T-cell immune response are still being studied. A part of the answer lies in regulatory T cells, which are known to prevent autoimmune reactions. CTLA4 likely stimulates while CD28 suppresses Treg function and survival [R, R].

CTLA4 prevents an autoimmune response by suppressing cytotoxic T cells and overproduction of cytokines such as IFN-gamma and IL-2. Regulatory T cells likely mediate this effect.

Many thyroid disorders have an autoimmune background. Autoimmune thyroid disorders are conditions in which the immune system targets the thyroid gland and alters its function; the two main types are [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 excess thyroid hormones (hyperthyroidism).

Besides other autoimmune conditions, studies have identified significant roles of CTLA4 variants in the above thyroid disorders. Here we’ll discuss the three most important variations (SNPs) [R].

rs231775 (‘A49G’)

Multiple studies have investigated the connection between rs231775 and autoimmune thyroid condition. On average, carriers of the “G” allele had 40-60% higher rates of Graves’ disease, compared with the “A” allele. The association with Hashimoto’s disease is similar, but there’s less clinical data to back it up [R].

A meta-analysis of 44 clinical trials and 15,000 subjects have confirmed and summarized the above findings: those with at least one copy of the “G” allele had 49% and 29% higher rates of Graves’ and Hashimoto’s disease, respectively. The results were consistent among European and Asian participants [R].

Disease Severity and Complications

In a study of nearly 1,000 European (Caucasian) subjects with Graves’ disease (GD), the ‘G’ allele on rs231775 was associated with higher thyroxine levels and a more severe disease form [R].

In one Japanese study, the ‘G’ allele (and the ‘GG’ genotype) were more common among GD patients who didn’t fully recover after five years of treatment [R].

Some authors have reported an association between this variant and eye disease in GD patients (Graves’ orbitopathy, GO). However, others have failed to confirm this and suggested that the association stems from a more severe disease in “G” allele carriers [R, R, R].

The ‘G’ allele on rs231775 is associated with Graves’ and Hashimoto’s disease. Carriers of this allele may also have more severe, treatment-resistant forms of Graves’ disease.

rs3087243 (‘CT60’)

In a meta-analysis of 21 clinical trials (over 10,300 Asian and European participants), the ‘G’ allele on rs3087243 was associated with 45% and 64% higher rates of Graves’ and Hashimoto’s disease, respectively [R].

A Japanese study of 1,800 participants confirmed the association between this variant and autoimmune thyroid disorders (AITD). Additionally, type 1 diabetes patients with the ‘G’ allele were more likely to have AITD as a complication [R].

The ‘G’ allele of rs3087243 was also associated with 84% higher rates of Graves’ disease, according to a more recent Chinese study of 578 subjects [R].

Carriers of the ‘G’ allele on rs3087243 are more likely to have an autoimmune thyroid disorder as a primary condition or as a complication of type 1 diabetes.

rs231779

In one of the largest studies investigating genetic factors of hypothyroidism in nearly 40K participants, rs231779 showed a weak association. Those with the ‘T’ allele had 13% higher rates of hypothyroidism, compared with the ‘C’ allele [R].

The authors emphasized the well-known connection between this gene and thyroid autoimmunity, which was likely responsible for low thyroid hormones. 

This variant may also be associated with Graves’ disease, according to a Chinese study of 4,800 subjects. Those with the ‘T’ allele had 35% higher rates of GD [R].

Key Mechanisms at Play

As mentioned, reduced expression of CTLA4 may lead to an overactive and self-destructive immune response. A couple of studies have confirmed that the rs231775 variant reduces CTLA4 gene expression and the number of CTLA4 proteins expressed on immune cells [R, R].

According to other research, this variant changes the structure of the CTLA4 peptide and prevents its inhibitory effect on T-cell activation [R, R].

Scientists are still figuring out the exact mechanisms, but the end result is the same: uncontrolled immune response and the production of antibodies to thyroid components such as thyroglobulin and thyroid peroxidase [R, R].

Although the mechanisms behind other variants haven’t been studied in-depth, they likely follow similar patterns.

The above variants have been reported to reduce CTLA4 expression, and suppress its inhibitory effect on T-cells. This leads to an overactive immune response and the production of autoantibodies to different thyroid structures.

You can see your genotype for several CTLA4 SNPs in the table below. However, note that these variants are just associated with some aspects of thyroid health. That does not mean they will necessarily make you more prone to thyroid disorders! More research will be needed to determine whether and how much they contribute to the actual development of thyroid autoimmunity.

SNP Table:

Primary SNPs:

CTLA-4 rs231775

• ‘A’ doesn’t correlate with autoimmune thyroid disorders (AITD)
• ‘G’ correlates with higher rates of AITD

CTLA-4 rs231779

• ‘C’ doesn’t correlate with AITD
• ‘T’ correlates with higher rates of AITD

CTLA-4 rs3087243

• ‘A’ doesn’t correlate with AITD
• ‘G’ correlates with higher rates of AITD

Population Frequency

The first two SNPs, rs231775 and rs231779, are almost always inherited together, which means they essentially act as a single genetic factor. Around 60% of European descendants carry at least one copy of the “problematic” alleles (G and T, respectively). 

The frequency of these alleles is much higher in East Asian populations (China, Japan), where around 40% of people carry both copies (‘GG’ and ‘TT’, respectively).

When it comes to rs3087243, approximately 27% of European descendants carry both copies of the “problematic” G allele (GG). This combination is more common in East Asian (55%) and African (67%) populations.