PTPN22 and Autoimmune Diseases

The body continually balances between fighting off dangerous pathogens and keeping the immune response in check. The PTPN22 gene plays a pivotal role in that balance, and genetic variants (SNPs) in PTPN22 increase your risk of autoimmune conditions such as vitiligo, alopecia, RA, type 1 diabetes, and autoimmune thyroid diseases.

PTPN22: Genetics and Autoimmune Diseases

Genome-wide association studies allow researchers to cast a wide net, searching for genetic variations that increase susceptibility to diseases or conditions. One of the first autoimmune-related variants that genetic researchers discovered is in the PTPN22 gene (protein tyrosine phosphatase nonreceptor 22).

This unexpected discovery left researchers searching for the answer to ‘why PTPN22’?[ref][ref]

Subsequent research shows that PTPN22 regulates the immune system through impacting T cell activation and B cell auto-reactivity. It acts as a negative regulator, dampening T cell activation. Additionally, PTPN22 impacts innate immunity through promoting interferon I production.[ref][ref][ref]

A balancing act between killing invaders and not hurting your own cells.

The body produces T-cells and B-cells as part of the immune system. These are the cell types that recognize danger (e.g. bacteria, virus) and identify non-danger (e.g. your own cells).

B cells (aka B lymphocytes) are a type of white blood cell that secretes antibodies and also present antigens. T cells, similarly, are a type of white blood cell that matures in the thymus and controls immune response. Both B and T cells perform important immune system functions for determining invaders and keeping immune response in check against ‘self’.

Variants in the PTPN22 gene change the way that it functions, causing an increase in the inhibitory function on B-cells.[ref][ref]

The PTPN22 variants are linked to autoimmune diseases that affect connective tissues, thyroid, joints, muscle, blood, and the pancreas. But the variants don’t seem to increase the risk of autoimmune diseases that target the eyes, gastrointestinal tract, or brain. PTPN22 genetic changes are linked to:[ref][ref][ref]

  • Rheumatoid arthritis
  • Vitiligo
  • Alopecia areata
  • Vasculitis
  • Autoimmune Addison Disease
  • Graves’ Disease
  • Hashimoto thyroiditis
  • Idiopathic inflammatory myopathy
  • Juvenile arthritis
  • Lupus
  • Systemic scleroderma
  • Type 1 diabetes
  • Myasthenia gravis
  • Allergic rhinitis

What if you don’t have an autoimmune disease?

Research shows that even people without autoimmune diseases have a change from the PTPN22 R620W variant. People with even one copy of the variant have increased autoreactive B cells and autoantibodies.[ref]

Trade-offs:

Recent work using transgenic mice points to the PTPN22 variant that increases autoimmune risk as possibly decreasing skin cancer risk and improving survival in other cancers.[ref]

Additionally, research seems to show that people with the PTPN22 variants are at a decreased risk of Crohn’s disease and Behçet’s disease.[ref]

 


PTPN22 Genetic variants:


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The rs2476601 R620W variant is a well-studied link to autoimmune diseases with over 1,000 studies that reference it.

Check your genetic data for rs2476601 R620W (23andMe v4; AncestryDNA):

  • G/G: typical
  • A/G: increased risk of autoimmune diseases and endometriosis
  • A/A: increased risk of autoimmune diseases including: vitiligo[ref], Graves’ disease, type 1 diabetes[ref], Meniere’s disease[ref], juvenile arthritis[ref] psoriasis[ref] endometriosis[ref]

Members: Your genotype for rs2476601 is .

 

Check your genetic data for rs6679677 (23andMe v4, v5;):

  • A/A: Increased susceptibility to autoimmune diseases including: Hashimoto’s thyroiditis[ref], type 1 diabetes[ref], juvenile arthritis[ref]
  • A/C: increased risk of autoimmune diseases
  • C/C: typical

Members: Your genotype for rs6679677 is .

 

Check your genetic data for rs1310182 (23andMe v4; AncestryDNA):

  • G/G: Somewhat increased susceptibility to autoimmune diseases including: allergic rhinitis[ref] ulcerative colitis[ref] type 1 diabetes[ref]
  • A/G: typical risk
  • A/A: typical

Members: Your genotype for rs1310182 is .

 

 


Lifehacks:

What to do about PTPN22 variants in autoimmune diseases is the million-dollar question (or perhaps a billion-dollar answer…).

A 2019 study looked at PTPN22 in people with RA who were taking TNF-alpha inhibitors (etanercept, adalimumab, or tocilizumab).  The study participants were classified as responders if the TNF inhibitors worked or non-responders.  All of the responders had a significant increase in PTPN22 (2-fold), while the non-responders had no increase.[ref]

It may be that inhibiting TNF-alpha could help with autoimmune diseases for some people with the PTPN22 variants. Read more about TNF-alpha and natural inhibitors.

I don’t have any other ‘lifehacks’ that are specific to countering the effects of this PTPN22 variant. There is currently research going on to find allosteric inhibitors, but it would be premature to speculate at this point.

Instead, let me offer a few, more general autoimmune suggestions:

  • The fasting-mimicking diet or an intermittent fasting protocol also may be beneficial for keeping autoimmune flare-ups under control.[ref][ref][ref]
  • The autoimmune Paleo diet (AID) is a whole-foods based dietary approach that eliminates many foods that trigger inflammatory reactions.
  • For people with multiple sclerosis, the Wahls protocol diet is something to investigate and consider.

Related Articles and Genes:

Rheumatoid Arthritis Genes
Rheumatoid arthritis (RA) is a form of joint pain that is caused by an autoimmune response. About 1% of the population deals with the pain of RA. This article explains RA, the different genes that increase susceptibility to RA, and possible solutions based on the genetic variants.

Chronic Inflammation & Autoimmune Risk – IL17
Inflammation can be blamed for everything from heart disease to mood disorders to obesity. Yet, how does this somewhat nebulous idea of too much inflammation tie into our genes? It seems that some people have a more sensitive immune system and are more prone to inflammatory reactions.



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.