What’s the Link Between This Gene and Thyroid Autoimmunity? (TSHR)

The pituitary gland makes TSH (thyroid-stimulating hormone, or “thyrotropin“), whose primary purpose is to stimulate the thyroid gland to produce several important thyroid hormones [R, R].

The TSHR gene codes for TSH receptors (“TSHRs”) on thyroid cells, enabling them to be stimulated by the pituitary gland. Thus, TSHR is one of the key players in thyroid health [R].

Image source: [R]

The Role of TSHR in Graves’ Disease

Graves’ disease (GD) is an autoimmune condition in which antibodies from the immune system mimic TSH and activate TSH receptors, resulting in the overproduction of thyroid hormones. This can lead to enlargement of the thyroid gland, as well as symptoms such as [R, R]:

• Fatigue
• Anxiety
• Weight Loss
• Eye pain, redness, and swelling
• Increased heart rate
• Shaky hands

These TSHR-stimulating antibodies (TSAbs) are the hallmark sign of Graves’ disease, which are present in nearly all cases. Their levels often correlate with the severity of the disease. Since the TSHR gene determines the number and structure of TSH receptors, it essentially controls how sensitive the thyroid gland is to (over-)stimulation. Therefore, experts consider this gene to be among the main genetic factors involved in GD [R, R].

The role of TSHR in Graves’ disease has been a hot topic for several decades, but it wasn’t until 2016 that researchers established a firm connection. A meta-analysis of eight clinical trials with over 14,000 participants confirmed two major variants that are associated with the development of GD [R]:

• rs179247 (A/G): The major “A” allele is associated with 42% higher rates of GD
• rs12101255 (C/T): The minor “T” allele is associated with 50% higher rates of GD

Another group of authors also conducted a meta-analysis that further confirmed these findings [R].

According to one clinical study, GD patients with the “AA” genotype for rs179247 get Graves’ disease on average 9.2 years earlier, compared with carriers of the “GG” genotype [R].

A recent trial of 1,200 participants identified two more TSHR variants with a significant impact: the major ‘G’ allele of rs4903964 and the major ‘C’ allele of rs12101261 have each been associated with lower rates of Graves’ disease [R].

Specific TSHR variants — such as rs179247-A, rs12101255-T, and rs12101261-T — have been associated with Graves’ disease and other thyroid disorders.

How It Works

Scientists are still figuring out the exact mechanisms responsible for the associations between these TSHR variants and thyroid disorders. According to some researchers, one part of the answer may lie in the potential of these variants to change the TSH receptor structure and stimulate an autoimmune response against it [R, R].

For example, several researchers have suggested that these variants may reduce the length of one part of the TSH receptor (called the alpha subunit), which tricks the immune system into “attacking” the receptor [R, R, R].

Different studies have analyzed blood samples of GD patients, and have identified two changes in the immune system that may mediate this “self-attack” [R, R, R, R]:

• Increased Th17 cells and IL-17 production
• Lowered T-regs (regulatory T cells)

According to some authors, another possibility is that the variants prevent immune cells from building tolerance to TSHRs, which could result in autoimmunity [R, R].

TSHR variants probably change the structure of TSH receptors and prevent immune cells from building tolerance to them. This effect may increase Th17 cells and decrease T-regs, leading to an autoimmune response.

You can see your genotype for several TSHR SNPs in the table below. However, it is important to keep in mind that these results are based on association studies suggesting that certain genetic variants are relatively more common in people with thyroid conditions. More research will be needed to know what role, if any, these variants play in directly causing thyroid issues. Therefore, just because you have one of these genotypes does not necessarily mean you are at increased risk of developing any of these health conditions!

Primary SNPs:

TSHR rs179247:

• ‘A’ = Associated with higher rates of Graves’ disease
• ‘G’ = Not associated with Graves’ disease

TSHR rs12101255:

• ‘T’ = Associated with higher rates of Graves’ disease
• ‘C’ = Not associated with Graves’ disease

TSHR rs12101261:

• ‘C’ = Associated with lower rates of Graves’ disease
• ‘T’ = Not associated with Graves’ disease

TSHR rs4903964:

• ‘G’ = Associated with lower rates of Graves’ disease
• ‘A’ = Not associated with Graves’ disease

Population Frequency

These four SNPs are almost always inherited together, so they act as a single genetic factor. This means most people either have no “problematic” alleles or all of them. About 45% of European descendants carry one and 10% carry both copies of problematic alleles. In East Asian populations, about 35% of people have both copies. 

The “problematic” allele at rs179247 is a bit more common in Europeans, with both copies present in 25% of people.