The Role of Genes in Thyroid Autoimmunity (PTPN22)

The PTPN22 (or LYP) gene encodes a protein from the PTP (protein tyrosine phosphatases) family. This protein regulates the development and function of T cells, B cells, and other immune system components [R].

More precisely, it controls the antiviral immune response and prevents excessive inflammation that can harm the healthy tissue and trigger autoimmunity [R].

Mutations in the PTPN22 gene can cause defective protein synthesis and uncontrolled immune response; they are associated with a range of autoimmune disorders [R].

The PTPN22 gene encodes a protein that controls the antiviral immune response and prevents excessive inflammation. Mutations in this gene are associated with various autoimmune disorders.

Hashimoto’s Disease

According to a study conducted on almost 40,000 people, two PTPN22 variations—rs2476601 and rs6679677—have the strongest correlation with hypothyroidism. Carriers of minor “A” alleles on these variations had 36% higher rates of hypothyroidism, compared with people who carry major alleles (G and C, respectively) [R].

Given the well-known role of PTPN22 in the immune response and inflammation, this link likely stems from Hashimoto’s disease, the leading cause of hypothyroidism in the west [R].

Graves’ Disease

The above variant, rs2476601, also showed a significant connection with Graves’ disease or autoimmune hyperthyroidism. In two British studies of 2,700 total participants, the “A” allele was associated with 43-88% higher GD rates [R, R].

Two studies of over 900 Polish subjects confirmed this link. They also found that people with the “A” allele get diagnosed younger [R, R].

The same allele correlated with 85% higher rates of Graves’ disease in a Chinese meta-analysis of three clinical trials [R].

Minor “A” alleles on two PTPN22 variants—rs2476601 and rs6679677—correlate with higher rates of autoimmune thyroid disorders.

How It Works

As mentioned, mutations in the PTPN22 gene often lead to an overactive immune response, which may harm healthy tissue. One of the possible outcomes autoimmune thyroid inflammation (thyroiditis).

Scientists haven’t figured out the exact mechanism by which these variations cause harm. The key may lie in defective PTP (protein tyrosine phosphatase) production, which disables the protein and prevents the removal of self-attacking lymphocytes (T and B cells) [R, R].

Additionally, PTPN22 variants may [R, R, R, R]: 

• Hinder an antimicrobial immune response
• Increase the activity of Th1 and Th17 cells
• Suppress regulatory T cells (Tregs)

As a result, the immune system creates antibodies to different structures in the thyroid gland, thus suppressing its functions and lowering thyroid hormones.

The underlying mechanism of PTPN22-associated autoimmunity probably includes inflammation from overactive T-cells, B-cells, and cytokines. The suppression of regulatory T-cells allows for a self-destructive immune response.

Other Autoimmune Conditions

Conditions associated with risk variants of PTPN22 (rs2476601-A) include but are not limited to [R, R, R, R, R, R]:

1. Rheumatoid arthritis
2. Juvenile idiopathic arthritis (a chronic joint disorder in children)
3. Type 1 diabetes
4. Lupus
5. Vitiligo (autoimmune skin discoloration)
6. Myasthenia Gravis (a type of muscle weakness)
7. Alopecia Areata (autoimmune bald spots)
8. Drug-induced liver injury 
9. Addison’s Disease

Luckily, the problematic allele “A” on rs2476601 is present in 2.7% of the world population and 9.4% of the people of European ancestry. It’s nearly nonexistent in African and Asian populations.

Autoimmune diseases of the skin, gut, brain, and eyes showed a less significant association with this gene [R].

In the case of Crohn’s disease, the “A” allele actually showed an inverse correlation (around 16% lower odds) [R].

Besides thyroiditis, PTPN22 is associated with other autoimmune conditions such as rheumatoid arthritis, type 1 diabetes, and lupus. Luckily, only 2.7% of the world population carries the risk allele.

You can see your genotype for key PTPN22 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 thyroid disorders. Also, many different factors — including other genetic and environmental factors — can influence thyroid health. Just because you have one of these genotypes does not necessarily mean you are at an increased risk of developing a thyroid disorder!

Primary SNPs: 

PTPN22 rs2476601 [R]

• “A” allele correlates with autoimmune thyroid disorders
• “G” allele doesn’t correlate with autoimmune thyroid disorders

PTPN22 rs6679677 [R]

• “A” allele correlates with autoimmune hypothyroidism
• “C” allele doesn’t correlate with autoimmune hypothyroidism