An autoimmune disease that attacks the lining of joints. The variant here sits in a small stretch of chromosome 6 that turned out to hold two independent signals 3.8 kb apart — a good picture of what it takes to say a region matters twice.
Rheumatoid arthritis is an autoimmune disease in which the immune system attacks the synovium, the lining of the joints. Untreated it damages cartilage and bone permanently, and it can affect the lungs, eyes, skin and blood vessels as well. Treated early it is a far better disease than it was thirty years ago.
rs10499194 sits at 6q23, about 150 kb from TNFAIP3 and OLIG3. TNFAIP3 encodes A20, a brake on inflammatory signalling — an unsurprising place for a rheumatoid arthritis gene to be.
What makes the finding instructive is what happened next. A concurrent study reported a different variant, rs6920220, 3.8 kb away. Two associations that close together usually mean one signal seen twice. Here they were shown to be statistically independent: the region carries two separate risk alleles, not one.
That is what careful fine-mapping looks like, and it is why this site tries not to write "the gene for" anything. A region can matter more than once, in ways that only careful analysis separates.
It is also a good example of doing a lot with a little. The scan genotyped just 397 people with rheumatoid arthritis for 116,204 SNPs and compared them against publicly available genotypes from 1,211 participants in the Framingham Heart Study — then replicated the finding in 5,541 further case-control samples (combined P = 10-9).
Two things, and neither is a common variant. Anti-CCP antibodies and rheumatoid factor separate the disease into forms that behave differently, and anti-CCP can be positive years before symptoms. And time: starting disease-modifying treatment early changes the long-term outcome more than anything else available.
The genetics that clinicians do use is HLA — the shared epitope alleles of HLA-DRB1 — and even that is a research and prognostic tool rather than a test that decides treatment.
Persistent joint swelling and stiffness lasting more than an hour in the morning deserves a prompt assessment. That sentence is worth more than this page.
The study. Plenge et al. genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and compared them with publicly available genotype data from 1,211 Framingham Heart Study participants, adjusting for technical and population bias. rs10499194 at 6q23 — approximately 150 kb from TNFAIP3 and OLIG3 — was associated in the scan (P = 10-3) and in 5,541 additional case-control samples (P < 10-6), giving a combined P = 10-9. The Wellcome Trust Case Control Consortium concurrently reported rs6920220, 3.8 kb away (P = 5 x 10-6); the two associations were shown to be statistically independent.
TNFAIP3. The gene encodes A20, a ubiquitin-editing enzyme that restrains NF-kB signalling downstream of TNF and Toll-like receptors. Variants in this region are associated with several autoimmune diseases — systemic lupus erythematosus among them — which is the recurring pattern across the autoimmune pages on this site: shared immune regulators, different diseases.
Clinical position. Diagnosis uses clinical criteria together with rheumatoid factor and anti-citrullinated protein antibodies, inflammatory markers and imaging. Anti-CCP positivity is both diagnostically useful and prognostic for erosive disease, and can precede symptoms by years. HLA-DRB1 shared epitope alleles carry the largest inherited effect and interact with smoking, particularly in anti-CCP-positive disease. Treatment is early disease-modifying therapy, escalated to targeted biologic or synthetic agents by response; no common variant on this page has a role in that decision.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Rheumatoid Arthritis comes down to these specific, well-studied positions — not a diagnosis.
Two variants 3.8 kb apart were each associated with the disease, and analysis showed neither explained the other. The region carries two separate risk alleles rather than one seen twice — which is why this site avoids the phrase "the gene for" anything.
No. It shifts risk slightly against a background where HLA-DRB1 carries far more weight, and where smoking interacts with that HLA effect. Nothing here is used for prediction, diagnosis or treatment.
Being seen early. Starting disease-modifying treatment promptly changes the long-term outcome more than anything else available, and joint swelling with morning stiffness lasting over an hour is the signal worth acting on. Not smoking matters here more than most places.
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