TNF, NF-kB & Inflammatory Cytokines

Intergenic regulatory variant at 6q23 near TNFAIP3 whose T allele is protective against rheumatoid arthritis in Europeans, representing the second independent RA signal at this locus alongside risk variant rs6920220

Intergenic regulatory variant between TRAF1 and C5 on chromosome 9; the A allele reduces TRAF1 expression, amplifying NF-kB-driven inflammation and increasing rheumatoid arthritis risk in Europeans

Intronic variant in DBC1 (DBCCR1/BRINP1) at 9q33.1 associated with multiple sclerosis susceptibility; the common A allele increases MS risk, while the minor G allele is protective

Promoter variant that elevates IL-1β transcription, increasing risk of H. pylori-driven gastric cancer, chronic periodontitis, and inflammatory tissue damage

Synonymous exon 5 variant in IL-1β that increases IL-1β protein secretion despite no amino acid change, elevating chronic periodontitis risk and modulating inflammatory disease susceptibility

Intergenic protective variant near TNFAIP3 that tags a haplotype associated with enhanced A20-mediated NF-kB suppression, reducing rheumatoid arthritis and ankylosing spondylitis risk at the 6q23 locus

Missense variant in IL-1α (Ala114Ser) that acts as a common hypomorphic mutation — the minor Serine allele reduces IL-1α secretion by ~50% through post-translational retention; the Serine allele is associated with periodontitis susceptibility and ankylosing spondylitis in Europeans

Intronic STAT3 variant associated with increased atopic dermatitis risk (OR=1.09) via altered cytokine signaling in the JAK-STAT pathway

TNF promoter variant that disrupts an OCT-1 binding site, altering TNF-alpha transcription independently of the -308 variant; the T allele is associated with Crohn's disease susceptibility in Asian populations, psoriasis, and modified response to anti-TNF biologics

Promoter variant increasing TNF-alpha production approximately 2-fold, associated with autoimmune diseases and anti-TNF drug response

TNF promoter variant that disrupts NF-κB p50-p50 binding, reducing TNF-alpha production by ~31% and influencing susceptibility to autoimmune disease and biologic treatment response

X-linked intergenic variant near GPR174 (G protein-coupled receptor 174), a lysophosphatidylserine receptor expressed in lymphoid tissues; associated with modest rheumatoid arthritis risk, part of a GWAS signal at the GPR174/Xq21.1 locus

Truncating variant in the NLRP3 inflammasome brake that abolishes CARD8's caspase-1 inhibitory function, elevating IL-1β and IL-18 production and modifying susceptibility to autoimmune and inflammatory conditions

Intronic variant in LOC100506023 (PRDX6-AS1) and TNFSF4 at the 1q25.1 locus, where the common C allele is associated with modestly increased rheumatoid arthritis risk across diverse populations

Missense variant in PTPN13 (FAP-1) converting Ile to Met at position 1522; the G allele is associated with impaired tumor-suppressive Fas-mediated apoptosis and elevated squamous cell carcinoma risk

Missense variant in the A20 ubiquitin-editing enzyme that weakens NF-kB negative feedback, increasing susceptibility to autoimmune and inflammatory diseases

Missense variant in NFKBIE (IκBε) reducing the inhibitory capacity of the IκB-epsilon protein, leading to heightened NF-κB inflammatory signaling; the G allele is associated with rheumatoid arthritis susceptibility across multiple ancestries

Intron 2 VNTR polymorphism in IL1RN that alters IL-1Ra isoform balance and is associated with increased susceptibility to gastric cancer after H. pylori infection, severe chronic periodontitis, SLE, COPD, and post-traumatic osteomyelitis through dysregulated IL-1/IL-1Ra signaling

Promoter variant in the NFAT binding site that increases IL-17A transcription, elevating Th17-driven inflammation and autoimmune disease risk

Intronic variant in RTEL1 (Regulator of Telomere Elongation Helicase 1) on chromosome 20q13.33; the T allele is associated with increased glioma risk and reduced telomere maintenance capacity, linking impaired telomere biology to genomic instability and inflammatory aging

Intronic eQTL in CNR2 (cannabinoid receptor 2) that modulates receptor expression on immune cells; the minor A allele is associated with reduced CB2 expression, potentially impairing endocannabinoid-mediated immune regulation

Synonymous coding variant in the cannabinoid receptor 2 gene that tags a haplotype block influencing CB2 receptor expression in immune cells; the G allele (coding-strand C) is associated with elevated rheumatoid arthritis risk and altered endocannabinoid-mediated immune regulation

Exon 10 missense variant in the inflammasome regulator pyrin, converting methionine to isoleucine at codon 694; one of five founder FMF mutations, associated with mild-to-moderate familial Mediterranean fever, colchicine responsiveness, and lower amyloidosis risk than M694V — particularly prevalent in East Asian FMF patients and Lebanese founder lineages

Exon 10 missense variant in the inflammasome regulator pyrin; one of five founder FMF mutations, associated with moderate disease severity, high colchicine responsiveness, and lower amyloidosis risk compared to M694V — most clinically significant when homozygous or compound heterozygous with M694V

Exon 10 missense variant in the inflammasome regulator pyrin; one of five founder FMF mutations at codon 680 — a severity hotspot alongside codon 694. M680I homozygotes develop moderate-to-severe FMF, and M680I/M694V compound heterozygotes can have severe, colchicine- resistant disease comparable to M694V homozygosity.

Exon 2 missense variant in the inflammasome regulator pyrin; the most common and most debated MEFV variant, classified as likely benign by most clinical labs but associated with mild FMF-like symptoms in some homozygous carriers, especially in Middle Eastern and East/South Asian populations

3'UTR variant in IL-17A that alters post-transcriptional regulation via miRNA targeting, modulating IL-17A protein output and Th17-driven inflammatory disease susceptibility

Intronic GWAS variant in the TRAF1-C5 locus on chromosome 9 robustly associated with seropositive rheumatoid arthritis risk; the G allele tags a haplotype that upregulates TRAF1 expression and amplifies NF-kB-driven joint inflammation

Intronic STAT3 variant where the T allele (reference, ~66%) increases risk for autoimmune thyroid disease, Crohn's disease, and lung cancer while the protective C allele correlates with higher STAT3 expression

Intronic variant near MMEL1 and TNFRSF14 on chromosome 1p36; the C allele is associated with increased susceptibility to rheumatoid arthritis and other autoimmune conditions through disrupted immune costimulatory signaling at the HVEM/LIGHT/BTLA axis

Intronic IL6R variant associated with coronary artery disease risk, elevated inflammatory markers (CRP, LDL, ApoB), and altered response to IL-6 receptor-blocking biologics (tocilizumab, sarilumab); the T allele tags a haplotype with subtly enhanced classical IL-6 signaling

Intronic risk variant within TNFAIP3 intron 2 that independently increases susceptibility to rheumatoid arthritis and SLE through a distinct LD block from the nearby intergenic 6q23 signals, completing the three-signal risk model at the TNFAIP3 locus

Intronic variant near TNFAIP3 that tags a 6q23 haplotype strongly associated with SLE and Sjogren's syndrome through impaired A20 ubiquitin-editing activity and NF-kB dysregulation

The most common and clinically severe MEFV mutation, converting methionine to valine at codon 694 of pyrin; homozygous carriers typically develop full familial Mediterranean fever with early onset, frequent attacks, and high amyloidosis risk if untreated with colchicine

Regulatory variant upstream of TNFAIP3 that reduces A20 expression and impairs NF-kB negative feedback, increasing susceptibility to rheumatoid arthritis and multiple autoimmune diseases

Missense variant that reduces IL-17F bioactivity and acts as a natural IL-17F antagonist, protecting against Th17-driven autoimmune conditions while impairing antifungal mucosal defense

Intergenic tag SNP in the 6q23 regulatory region upstream of TNFAIP3 that co-tags haplotypes associated with altered A20 expression and susceptibility to multiple autoimmune and inflammatory conditions

Upstream regulatory variant of IL18R1 on chromosome 2q12; the T risk allele increases IL-18 receptor expression and Th1/NK inflammatory signaling, raising susceptibility to COPD and linking to the broader IL1RL1/IL18RAP autoimmune-inflammation locus