A rare autoimmune disease that hardens skin and internal organs. Both variants here sit in the interferon and T-cell signalling machinery that also turns up in lupus and rheumatoid arthritis — the same immune wiring, a different disease.
Solid lines are connections this site curates. Dashed lines mean the two ends share a research paper — worth knowing, and not a claim that one explains the other.
Systemic sclerosis, also called scleroderma, is an autoimmune disease with three things happening at once: blood vessels behave abnormally, the immune system is activated, and tissue lays down too much collagen. The result is thickened skin and, in many patients, fibrosis of internal organs — lungs, heart, kidneys, gut. It is uncommon, it is serious, and it varies enormously between patients.
Both come from the first genome-wide association study of the disease in people of European ancestry: 2,296 patients and 5,171 controls, with replication in an independent set of 2,753 patients and 4,569 controls.
The same study established the MHC region (P = 2.31 x 10-18) and found a new locus at CD247, part of the T cell receptor complex.
STAT4 and IRF5 are not specific to this disease. Both appear in lupus and rheumatoid arthritis as well. That is one of the most durable findings in autoimmune genetics: a shared set of immune switches, with the particular disease determined by other genetic and environmental context.
Which is worth knowing if you meet one of these genes in two different places and wonder whether something has gone wrong. It has not — the gene really is in both stories.
What actually guides care in systemic sclerosis is the pattern: how much skin is involved, which autoantibody a patient carries (anticentromere, anti-Scl-70, anti-RNA polymerase III), and organ screening — lung function tests, echocardiography, blood pressure and kidney monitoring. Those antibodies carry real prognostic information about which complications to watch for. Common variants do not, and are not tested for.
New Raynaud's phenomenon with skin tightening, difficulty swallowing, or breathlessness deserves prompt specialist assessment. Early detection of lung and kidney involvement changes outcomes; genotype does not.
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 8 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.
Ishikawa Y et al. 2024, Nature communications rs844663 (TNFSF4), rs10912594 (TNFSF4), rs11851053 (AHNAK2), rs10892286 (DDX6), rs5029949 (TNFAIP3), rs7355798 (FLNB), rs11177005 (IFNG-AS1), rs9074 (SLC12A5) — PMID:38296975
2026-04-15 · Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study. The Lancet Rheumatology. 2026. DOI:10.1016/s2665-9913(25)00376-5
First sex-specific genetic map of systemic sclerosis finds a male-only and two female-only risk loci
Systemic sclerosis affects far more women than men and tends to behave differently by sex, but genetic studies had rarely analyzed the sexes separately. This study, covering 10,653 systemic sclerosis patients (1,556 male, 9,097 female) and 18,043 controls, ran the first sex-stratified autosomal GWAS for the disease. It found 8 sex-specific loci in total: one newly reported male-specific locus in BCL11A (OR=1.32, 95% CI 1.20-1.45, P=8.39x10^-9), two newly reported female-specific loci in IRF4 (OR=0.78, 95% CI 0.71-0.85, P=2.36x10^-8, protective) and near RPL3-PDGFB (OR=1.19, 95% CI 1.12-1.26, P=3.18x10^-8), plus five previously known loci now shown to be specifically female-associated. Functional analysis implicated 39 candidate genes, 5 of which (IL12RB2, ARHGAP31, UBL7, CSK, MPI) showed measurably different expression between male and female patients, with IL12RB2 and interferon signaling highlighted as particularly relevant to the sex difference. The study's drug-repurposing analysis flagged two already-approved drugs, fostamatinib and dasatinib, as candidates worth investigating for sex-aware systemic sclerosis treatment. This site's systemic sclerosis page carries 10 variants; none of BCL11A, IRF4 or RPL3-PDGFB are currently among them, making this a genuine addition to what the page covers, and a concrete illustration of why sex-stratified genetic analysis can find real signal a combined analysis would average away.
2025-02-27 · Cross-Phenotype Genome-Wide Association Study on the Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis. Arthritis & Rheumatology. 2025. DOI:10.1002/art.43081
Patients with systemic sclerosis (SSc) have an elevated risk of primary biliary cholangitis (PBC), and this study quantified how much of that reflects shared genetics. It found a remarkably strong global genetic correlation between the two conditions (rg=0.84, P=1.7x10^-6) -- a very high value, indicating substantial overlap in genetic risk architecture, not just occasional clinical co-occurrence. Cross-phenotype meta-analysis identified 44 non-HLA loci reaching genome-wide significance, with 9 showing evidence of a shared causal variant between the two diseases, 5 of them newly reported. Integrating fine-mapping, colocalization with gene-expression and protein-expression data, and phenome-wide association analysis, the study prioritized 5 novel candidate causal genes: CD40, ERAP1, PLD4, SPPL3 and CCDC113. The CD40 risk locus specifically colocalized with trans-protein quantitative trait loci for multiple plasma proteins involved in B-cell function -- a coherent mechanistic thread, since both SSc and PBC involve autoantibody production driven by B cells. This site's systemic sclerosis page carries 10 variants and primary biliary cholangitis page carries 23; none of these five genes are currently on either.
The study. The first systemic sclerosis GWAS analysed 279,621 autosomal SNPs in 2,296 patients and 5,171 controls of European ancestry, with replication in 2,753 patients and 4,569 controls. It identified CD247 at 1q22-23 as a new susceptibility locus (rs2056626, P = 2.09 x 10-7 discovery, P = 3.39 x 10-9 combined) and firmly established the MHC (P = 2.31 x 10-18), IRF5 (P = 1.86 x 10-13) and STAT4 (P = 3.37 x 10-9) regions. rs10488631 sits in the IRF5/TNPO3 region and rs3821236 in STAT4.
Shared autoimmune architecture. STAT4 and the IRF5 region are established risk loci across several systemic autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis, consistent with shared dysregulation of type I interferon signalling and T-cell activation. Disease specificity appears to arise from combinations rather than from unique genes, which is why locus lists across these diseases overlap heavily.
Clinical stratification. Subsetting is by extent of skin involvement (limited versus diffuse cutaneous) and by autoantibody: anticentromere associates with limited disease and pulmonary hypertension risk, anti-topoisomerase I (Scl-70) with diffuse disease and interstitial lung disease, anti-RNA polymerase III with rapid skin progression and scleroderma renal crisis. Monitoring includes pulmonary function testing, echocardiography and blood pressure surveillance; ACE inhibitors transformed the outlook for renal crisis. No genotype from this page enters that assessment.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Systemic Sclerosis comes down to these specific, well-studied positions — not a diagnosis.
HLA-DPB1 · rs2021408
See detailed info →The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 10 of 19 linked studies with a resolved discovery ancestry.
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Systemic Sclerosis. MyGeneLog™. https://www.mygenelog.com/conditions/systemic-sclerosis
They shift risk slightly in a disease that is rare to begin with. Most people carrying them will never develop it, and the variants are not used to predict, screen for or diagnose it.
Because they are general immune switches — interferon regulation and cytokine signalling — rather than disease-specific genes. Sharing risk loci across lupus, rheumatoid arthritis and systemic sclerosis is one of the most consistent findings in autoimmune genetics.
The autoantibody pattern and the extent of skin involvement, not genotype. Anticentromere, anti-Scl-70 and anti-RNA polymerase III each associate with different complications, and that is what shapes monitoring.
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