Rheumatoid Arthritis
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.
What this condition connects to
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.
The variant, and the thing worth noticing about it
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.
How the study worked
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).
What actually matters clinically
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.
Positions joined since this page was written
What this is The text above discusses the variants this page was written around. Since then the catalogue has joined 54 more positions to it, by shared trait or shared paper. They are listed here by the paper each came from; the text does not describe them, and each variant page carries that study's own record.
Ishigaki K et al. 2022, Nature genetics rs73005423 (near COX7CP3), rs798000 (near NEFHP1), rs56750287 (GSDMB), rs16903108 (LINC00824), rs6681482 (TNFSF4), rs2141331 (CASP8), rs9826420 (STAG1), rs6831973 (near LINC02498), rs1234313 (TNFSF4), rs62097857 (PTPN2), rs34480360 (near ZNF629), rs113532504 (near JARID2-DT) and 15 more — PMID:36333501
Ha E et al. 2021, Annals of the rheumatic diseases rs7749323 (near LINC02865), rs7170107 (DRAIC), rs62422878 (ATG5), rs2841275 (near PLD4), rs6011186 (near C20orf181), rs502919 (PRKCQ), rs117605225 (CXCL13), rs11594656 (near RBM17), rs35576264 (RTKN2), rs10911902 (near PTGS2) — PMID:33310728
Saevarsdottir S et al. 2022, Annals of the rheumatic diseases rs10261758 (IKZF1), rs1538981 (LINC02664), rs7320598 (COG6), rs67574266 (REL), rs1471293 (RGS22), rs140675301 (STAT4) — PMID:35470158
Shigesi N et al. 2025, Human reproduction (Oxford, England) rs9603618 (near COG6), rs72727387 (RASGRP1), rs13026755 (near REL), rs11593907 (ARID5B) — PMID:40262193
Stahl EA et al. 2010, Nature genetics rs874040 (near LINC02357), rs6910071 (TSBP1) — PMID:20453842
Sakaue S et al. 2021, Nature genetics rs28362859 (NFKBIE), rs532322163 (near HLA-DQA1) — PMID:34594039
Ishigaki K et al. 2020, Nature genetics rs80202727 (TCTE1), rs56139217 (LINC02621) — PMID:32514122
Cai T et al. 2025, Clinical rheumatology rs539837 (near LINC01680) — PMID:40762897
In the news
2026-01-15 · Integrating human plasma proteomes with genome-wide association data implicates novel proteins and drug targets for rheumatoid arthritis. Clinical Proteomics. 2026. DOI:10.1186/s12014-026-09581-9
Over 100 GWAS loci are known for rheumatoid arthritis (RA), but a genetic locus doesn't say which protein actually drives disease. This study ran the first large-scale proteome-wide association study (PWAS) for RA, combining GWAS summary statistics (22,350 discovery cases, 31,313 replication cases) with plasma protein expression data from two large cohorts, using Mendelian randomization and colocalization to test causality. It identified 35 genetically regulated proteins associated with RA risk, 10 of them potentially causal. Six of these -- FCRL3, ICOSLG, MAPK3, WISP1, FAM213A and IL1RN -- were not implicated by the original GWAS at all, meaning they are genuinely new to RA biology despite RA's already-extensive genetic map. The druggability analysis found 160 drug-gene interactions, including AMG-557, an existing drug targeting ICOSLG with established anti-inflammatory and anti-rheumatic activity in other autoimmune diseases -- a direct, near-term repurposing candidate rather than a distant discovery. This site's rheumatoid arthritis page carries 62 variants; none of these 6 causal proteins are currently represented.
2026-02-19 · Schmidt A, et al., Nature 2026, PMID:41714741
Host control of persistent Epstein-Barr virus infection
Epstein-Barr virus infects roughly 90-95% of people and stays for life in B cells. This study read EBV out of ordinary blood-based genome sequencing: EBV reads turned up in 16.2% of 486,315 UK Biobank participants and 21.8% of 336,123 All of Us participants, tracking higher viral load in blood cells, and were more common with HIV infection, immunosuppressive drugs and current smoking. Genome-wide, the strongest signals were in the MHC — 54 independent HLA alleles across classes I and II — plus 27 regions outside it, with an interaction between HLA class I alleles and the ERAP2 locus. People with EBV-associated diseases carried a higher polygenic burden of the EBV-positive signal: at MHC class I in multiple sclerosis (driven by HLA-A*02:01) and at MHC class II in rheumatoid arthritis, with polygenic overlap also seen for inflammatory bowel disease, hypothyroidism and type 1 diabetes. Four of the study's non-MHC positions are already on this site — rs13098877 (LPP), rs884186 (KSR1), rs9828869 (near ILDR1) and rs34557412 (TNFRSF13B) — the last also linked here to lymphocyte count. PMID:41714741.
From our blog
Clinical detail
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.
Related variants MyGeneLog™ checks for
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. 117 positions are linked to this page; the ones this page's own text discusses are shown first.
Which ancestries this evidence comes from
The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 62 of 117 linked studies with a resolved discovery ancestry.
Sources
Quoting this page
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Rheumatoid Arthritis. MyGeneLog™. https://www.mygenelog.com/conditions/rheumatoid-arthritis
Questions about Rheumatoid Arthritis
What does "two independent signals" mean here?
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.
Does this variant predict whether I will develop rheumatoid arthritis?
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.
What actually helps?
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.
Free to reuse. This page's text is original writing from freely-available research, licensed CC BY 4.0 — reuse it, including commercially, with attribution to MyGeneLog™. It's general research-derived information, not medical advice or a diagnosis — see Terms of Use.