Autoimmune risk (PTPN22 R620W)

PTPN22 helps set how easily immune cells switch on. A common variant (R620W) makes the immune system a bit more trigger-happy and is one of the strongest common risk factors shared across several autoimmune diseases, like rheumatoid arthritis, type 1 diabetes and lupus.

What the PTPN22 R620W variant does

PTPN22 makes a phosphatase that acts as a brake on T-cell and B-cell receptor signalling, damping down immune cells that are being activated. This variant changes one amino acid in the region that binds a partner kinase, altering that braking function.

The consequence is a shift in how self-reactive lymphocytes are filtered out during development and controlled afterwards, which is why the same variant appears across several autoimmune diseases rather than one.

How strong the evidence is

It is one of the strongest and most reproducible non-HLA autoimmune variants known. The catalogued association here is with rheumatoid arthritis, at an odds ratio of 1.8 per copy in a study of up to 14,361 European-ancestry cases and 42,923 controls, with a p-value below 1e-169 and 39 supporting publications in this site's evidence file.

Similar associations are established for type 1 diabetes, systemic lupus erythematosus and autoimmune thyroid disease, while it is notably not associated with multiple sclerosis, which is a useful reminder that autoimmunity is not one thing.

An ancestry difference worth knowing

The risk allele is carried by roughly 9% of European-ancestry individuals and is essentially absent in East Asian populations. Rheumatoid arthritis and type 1 diabetes both occur in East Asia, so the variant cannot be a necessary cause of either, and its absence is a clean example of why autoimmune genetic risk has to be assessed within a population rather than across populations.

What this variant does not tell you

The largest genetic contribution to rheumatoid arthritis comes from specific HLA-DRB1 alleles, the shared epitope, which carry effects several times larger than this variant and which consumer genotyping chips cannot type reliably. Smoking interacts with those HLA alleles and is the strongest known environmental factor.

Because a single variant raises risk across several conditions modestly, it cannot tell you which condition, if any, and it is not used clinically for prediction. Persistent joint swelling with morning stiffness, or symptoms suggesting thyroid or blood sugar problems, are assessed on their own merits.

What each rs2476601 genotype means

rs2476601 has three possible genotypes: GG, AG and AA.

No PTPN22 risk variant (rs2476601 GG). You don't carry the PTPN22 R620W variant, so as far as this strong shared autoimmune-risk gene goes, your risk sits at the baseline. Autoimmune conditions depend on many genes and the environment, so this is just one piece.

Higher autoimmune risk (PTPN22) (rs2476601 AG). You carry one copy of the PTPN22 R620W variant, which makes your immune system a little more trigger-happy and modestly raises risk for several autoimmune conditions (such as rheumatoid arthritis, type 1 diabetes and lupus). Most carriers never develop any of them, so it's a shared risk factor, not a prediction.

High autoimmune risk (PTPN22) (rs2476601 AA). You have two copies of the PTPN22 R620W variant (uncommon), which raises your risk across several autoimmune diseases more than a single copy. Even so, most people with this genotype stay healthy. It's useful background if autoimmune symptoms ever come up or run in your family.

Evidence & sources

Across global populations, fewer than 1% of people carry two copies of this variant, and about 84% carry none.

This variant appears in 39 published genetic studies: PubMed 17554260 · PubMed 17632545 · PubMed 17804836 · PubMed 19430480 · PubMed 19503088 · PubMed 19838195 · PubMed 20410501 · PubMed 20453842 · PubMed 21156761 · PubMed 21829393 · PubMed 22922229 · PubMed 23143596 · PubMed 24390342 · PubMed 24449572 · PubMed 24532676 · PubMed 25751624 · PubMed 25936594 · PubMed 26502338 · PubMed 27193031 · PubMed 27399966 · PubMed 27723757 · PubMed 28714469 · PubMed 30254083 · PubMed 30423114 · PubMed 30572963 · PubMed 30573655 · PubMed 30595370 · PubMed 30891314 · PubMed 32581359 · PubMed 33686288 · PubMed 34594039 · PubMed 34737425 · PubMed 35470158 · PubMed 36333501 · PubMed 36750564 · PubMed 37002690 · PubMed 39024449 · PubMed 39749473 · PubMed 41748903.

Common questions

Does this variant mean I will develop an autoimmune disease? No. It raises the odds of several autoimmune conditions modestly, each of which is uncommon, so most carriers never develop any of them. It is not used for prediction or screening in clinical practice.

Which diseases is PTPN22 linked to? Rheumatoid arthritis most strongly, along with type 1 diabetes, lupus and autoimmune thyroid disease. It is not associated with multiple sclerosis, and the pattern of which conditions it affects is part of what makes it biologically interesting.

Related

Alzheimer's disease · Atrial fibrillation · Body mass (BMI) tendency · Breast cancer (female) · Coronary artery disease risk (9p21) · Rheumatoid arthritis · Type 2 diabetes