Allergy & Atopic Disease

Missense variant in IL1RL1 encoding the Leu551Ser amino acid change in the intracellular TIR signaling domain; the T (Leu551) allele tags a four-amino-acid risk haplotype that amplifies IL-33/ST2 receptor signaling, increasing susceptibility to asthma and chronic rhinosinusitis

Intronic IL1RL1 variant tagging an independent regulatory signal at the ST2 locus; A allele increases late-onset wheeze risk and affects sST2 (decoy receptor) expression independently of the primary rs1420101 signal

Upstream regulatory variant in the CHI3L1 YKL-40 quantitative trait locus; the common C allele is independently associated with higher circulating YKL-40 levels, elevated asthma susceptibility, and increased CHI3L1 mRNA expression

Missense variant in SLC22A4 encoding the organic cation/ergothioneine transporter OCTN1; the T allele (503F) increases ergothioneine transport efficiency and forms part of the IBD5 two-locus TC risk haplotype associated with Crohn's disease and other inflammatory conditions; strongly enriched in Europeans

Intronic variant in the PRG3 gene encoding eosinophil major basic protein homologue (MBPH/MBP-2) at chromosome 11q12.1; the rarer C allele tags variation in PRG3 expression and is associated with altered eosinophil granule protein activity implicated in allergic inflammation, IgE-mediated tissue damage, and atopic disease susceptibility

Intronic variant in the circadian clock regulator RORA; the T allele is protective against asthma in European cohorts with genome-wide significant replication

Intronic regulatory variant in TBX21 that influences T-bet expression and Th1/Th2 immune balance; the minor T allele is associated with elevated regulatory T-cell markers and reduced early-childhood atopic dermatitis risk, while the common C allele is linked to lower CD4+CD25+ Treg frequency and higher susceptibility to atopic disease

Regulatory tag SNP in the filaggrin (FLG) locus associated with reduced FLG expression and elevated atopic dermatitis risk — strongly enriched in East Asian populations where the G allele reaches 57% frequency

Intergenic tag SNP in the PRG2/PRG3 eosinophil major basic protein gene cluster at 11q12.1 whose C allele increases susceptibility to Crohn's disease, implicating eosinophil granule protein-mediated epithelial damage in IBD pathogenesis

Regulatory variant in a distal enhancer at 11q13.5 that controls GARP expression on regulatory T cells, impairing TGF-beta-mediated immune tolerance and increasing risk for asthma, allergic rhinitis, and inflammatory bowel disease

3'UTR variant in TSLP that acts as an eQTL driving higher TSLP mRNA expression in nasal epithelium; the A allele is a risk factor for asthma, atopic dermatitis, and elevated IgE, and co-defines the high-risk genotype together with rs2289277

Independent CTSS-locus GWAS signal for atopic dermatitis on chromosome 1q21.3; T allele associated with OR 1.18 for eczema risk through altered cathepsin S expression in antigen-presenting cells and PAR2-driven itch signalling

Intronic variant in ADH5 (GSNOR) in near-complete LD (r²=0.99) with adjacent promoter SNPs at a potential NF-κB binding site; the common A allele tags the asthma risk haplotype associated with elevated GSNOR transcription, GSNO depletion, and increased childhood asthma susceptibility, while the protective T allele is associated with reduced GSNOR expression and lower asthma risk

Intronic variant in TBX21 that forms a risk haplotype with rs16947078; the T allele is associated with increased susceptibility to allergic asthma through reduced T-bet-driven Th1 immune tone and excess Th2 polarization

Intronic regulatory variant in the ORMDL3 17q21 haploblock; the C allele drives elevated ORMDL3 expression in airway epithelial cells and immune cells, increasing asthma susceptibility and total IgE levels; the T allele is protective

A 3' UTR variant in TBX21 (c.*169T>C) that modulates T-bet expression; the C allele increases T-bet levels in immune cells and shifts the Th1/Th2 axis toward Th1, reducing classic atopic susceptibility while elevating risk for Th1-driven inflammatory conditions including ankylosing spondylitis

Common regulatory variant in the FLG locus associated with impaired skin barrier function and substantially elevated risk for atopic dermatitis (eczema)

Deep intronic IL6R variant associated with atopic dermatitis risk and systemic IL-6 signaling, with the G allele elevating eczema risk while reducing inflammatory cardiovascular markers through altered IL-6 receptor expression or splicing

Intronic variant in CHI3L1 (intron 6) independently associated with asthma severity and airway YKL-40 expression; the A allele drives higher circulating YKL-40 levels and worse airflow obstruction through a mechanism that is independent of the well-known promoter variant rs4950928

Intergenic variant 19 kb downstream of IL2RA associated with atopic dermatitis (OR 1.10), asthma, and type 1 diabetes risk — tags a regulatory locus controlling CD25 expression and T-regulatory cell homeostasis

Deep intronic variant in STAT6 that modulates IL-4/IL-13 signal transduction; the G allele is associated with eosinophilic esophagitis relapse on proton pump inhibitor therapy and with altered eosinophil recruitment in atopic inflammation, likely through effects on STAT6 expression or splicing in Th2-activated tissue

Intronic IL33 variant where the G allele is negatively associated with asthma (OR 0.71) in a Brazilian mixed-ancestry cohort; the G allele may dampen IL-33 alarmin output from damaged airway epithelium, reducing ILC2 and mast cell activation and blunting type 2 airway inflammation

Intronic IL33 variant where A-allele carriers showed a protective trend against childhood asthma in a Finnish birth cohort; may modulate IL-33 signalling by altering splice-site efficiency or regulatory element activity within the gene

Regulatory tagging SNP in the 17q21 asthma locus that is the strongest eQTL for ORMDL3 in whole blood; the C allele increases ORMDL3 expression and confers childhood asthma and early wheeze susceptibility

Regulatory variant in a FOXO1-binding enhancer element flanking the IKZF3 gene at 17q21; the C allele maintains FOXO1/MEF2A binding and is associated with elevated ORMDL3, GSDMB, and IKZF3 expression, higher asthma susceptibility, and risk for several autoimmune conditions; the T allele disrupts these binding sites, reducing expression of all three genes and is protective for asthma but associated with increased risk for multiple sclerosis and IBD

3'-UTR regulatory variant in IL13 that influences IL-13 mRNA stability and expression level; the minor A allele co-segregates with the rs20541 Q130 risk haplotype and is associated with elevated serum IgE and increased susceptibility to atopic dermatitis and allergic rhinitis through amplified IL-13 Th2 signaling

Intronic variant in IL13 that tags the atopic risk haplotype; the minor T allele co-segregates with rs20541 (R130Q) and rs1295685 on the same risk haplotype block and is consistently associated with elevated serum IgE, asthma susceptibility, atopic dermatitis, and food allergy through amplified IL-13 Th2 signaling

Intronic variant in IL1RL1 (encoding the ST2 receptor for IL-33) tagging haplotypes associated with lower soluble ST2 (sST2) levels; reduced sST2 decoy activity allows more unchecked IL-33 signaling, increasing type 2 inflammatory tone and susceptibility to asthma

Regulatory variant upstream of IL33; the C allele elevates IL-33 expression, amplifying the alarmin signal through the ST2 receptor and raising susceptibility to asthma, allergic rhinitis, hay fever, and eosinophilic airway inflammation

Intronic IL1RL1 variant in the 10th intron of the ST2 receptor gene; C allele is protective against late-onset wheeze and eosinophilic airway inflammation, reducing risk by approximately 26% per C allele copy in European birth cohorts

Intronic regulatory variant in IL1RL1 that lowers soluble ST2 (sST2) decoy receptor levels, amplifying IL-33 signaling and increasing susceptibility to asthma, hay fever, and atopic disease

Third independent CTSS-locus atopic dermatitis risk signal from the Budu-Aggrey 2023 GWAS; G allele associated with OR 1.25 for eczema risk through a distinct regulatory mechanism acting on cathepsin S expression in antigen-presenting cells

Rare splice acceptor variant that abolishes IL-33/ST2 signalling; the C allele produces a truncated, receptor-blind IL-33 protein that halves eosinophil counts and cuts asthma risk by more than half

Intronic variant in STAT6 (intron 2) that forms a functional haplotype with rs324011; the T allele increases STAT6 promoter activity and is associated with elevated serum IgE, atopic dermatitis, eczema herpeticum susceptibility, and eosinophilic esophagitis relapse through enhanced Th2 signaling

Intergenic regulatory variant near TBX21 associated with allergic asthma susceptibility; G allele homozygosity carries markedly elevated asthma risk through reduced T-bet-driven Th1 immune tone

Upstream promoter variant in TBX21 that reduces neonatal IL-5 and IL-13 secretion after innate immune stimulation; the minor C allele dampens Th2 cytokine output at birth, suggesting a role in early-life immune programming and atopic susceptibility through reduced TBX21 transcriptional drive

Intronic regulatory variant in SMAD3 that alters TGF-beta effector signaling in regulatory T cells, conferring pleiotropic risk for both allergic disease (asthma, hay fever, eczema) and Crohn's disease through impaired immune tolerance

Intronic tag SNP in HLA-DQA1 in strong LD with HLA-DQA1*01:02; the G allele increases peanut allergy susceptibility by tagging the DQA1*01:02 haplotype, raises HLA-DQB1 expression in CD4+ T cells, and drives protective peanut-specific IgG4 responses when peanut is consumed early in life

Intergenic variant 5 kb downstream of TBX21 (encoding the T-bet transcription factor) within the TBX21/OSBPL7 intergenic region; the G allele is associated with systemic sclerosis susceptibility and is thought to tag regulatory variation affecting the TBX21-IFNG transcriptional axis governing Th1 immune polarization.

Promoter variant that selectively increases IL-13 expression in Th2 lymphocytes, amplifying the central Th2 cytokine driving asthma, atopic dermatitis, elevated total IgE, and mucus hypersecretion; the T allele creates a Yin-Yang 1 binding site that attenuates STAT6-mediated repression of IL-13 transcription

Gain-of-function missense variant in the IL-4 receptor alpha chain that amplifies Th2 immune signaling, increasing susceptibility to asthma, atopic dermatitis, and allergic disease

Missense variant in the extracellular domain of the IL-4 receptor alpha chain that increases IL-4 signaling sensitivity; the Val75 (G) allele is found in 80% of allergic bronchopulmonary aspergillosis patients and elevates IgE-driven Th2 immune responses in asthma and atopic disease

Missense variant in the extracellular domain of the IL-4 receptor alpha chain that alters Th2 immune signaling, associated with atopic asthma, rhinitis, and altered IgE responsiveness

Upstream regulatory variant in TSLP reducing cytokine expression; the protective T allele lowers TSLP production 2.5-fold and is associated with reduced risk of asthma and allergic rhinitis

Intronic variant in the CTSS locus associated with elevated atopic dermatitis risk through altered cathepsin S expression in antigen-presenting cells

Intronic variant in RAD51B (RAD51 paralog B), a DNA double-strand break repair gene; the G allele is associated with increased susceptibility to asthma and atopic disease, while the A allele associates with rheumatoid arthritis risk, implicating RAD51B in shared immune dysregulation across inflammatory conditions

Intronic TSLP variant that modulates thymic stromal lymphopoietin activity, with T allele carriers showing milder, less persistent atopic dermatitis and reduced need for immunosuppressive treatment

Intronic variant in RAD51B on chromosome 14; the T allele is associated with increased rheumatoid arthritis risk (OR ~1.10 per allele) in trans-ethnic GWAS, likely through effects on lymphocyte genomic stability and immune cell development mediated by RAD51B's role in homologous recombination DNA repair

Intronic tag SNP near HLA-DQA1 that marks the DR3 (DRB1*0301-DQA1*0501-DQB1*0201) haplotype; the T allele tracks the highest-risk HLA genotype for type 1 diabetes and is associated with systemic lupus erythematosus, sarcoidosis, and HLA-mediated immune dysregulation relevant to atopic disease

Intronic variant in the RAD50/TH2LCRR region at 5q31.1 that tags an enhancer hub coordinating IL-4, IL-5, and IL-13 expression; the G allele is associated with elevated serum IgE and increased susceptibility to the atopic march (eczema → food allergy → asthma → allergic rhinitis) through amplified Th2 cytokine output

Missense variant in IL-13 that enhances Th2 cytokine signaling, elevating serum IgE and increasing risk for atopic dermatitis, allergic rhinitis, and eczema; the minor A allele (Q130) confers risk while the common G allele (R130) is protective for atopic disease

Upstream regulatory variant ~1,616 bp before the IFNG transcription start site that modulates IFN-gamma expression; the G allele (coding C) is associated with reduced Th1-mediated IFN-gamma output, favouring a Th2-skewed immune balance that increases susceptibility to atopic disease, while the A allele (coding T) supports robust STAT4-driven IFN-gamma transcription and a more Th1-balanced immune response.

5'-UTR variant 33 bases downstream of the IL-4 transcription start site; the T allele alters local RNA secondary structure and is associated with elevated IL-4 production, raised serum IgE, and increased susceptibility to allergic asthma, atopic dermatitis, and allergic rhinitis through amplified Th2-skewed immune responses

Intronic variant in TH2LCRR, a long noncoding RNA residing in the 5q31.1 RAD50/IL13 atopy susceptibility locus; the G allele is associated with elevated blood eosinophil counts, atopic dermatitis susceptibility in Chinese Han populations (OR 1.15), and asthma risk through amplified Th2 locus control region activity

Intronic regulatory variant in IL-4, the master Th2 cytokine; the T allele impairs IL-4 transcriptional regulation, elevating Th2-skewed inflammatory tone and increasing susceptibility to asthma, allergic rhinitis, and severe infections, while the G allele is associated with reduced atopic disease risk

Missense variant in the IL-6 receptor that increases receptor shedding and enhances IL-6 trans-signaling; the C allele (358Ala) is paradoxically protective for coronary heart disease but increases risk for asthma and allergic disease, and predicts differential response to tocilizumab

Intronic RAD50 variant in the Th2 locus control region (RHS7); T allele alters SMAD3 and SP1 transcription factor binding, shifts DNA methylation at the IL13 promoter in cord blood, and is associated with elevated total IgE levels and atopic disease risk.

Promoter polymorphism 589 bases upstream of the IL-4 transcription start site; the T allele enhances NFAT-1 binding, elevates IL-4 transcription, raises serum IgE, and amplifies Th2-skewed immune responses underlying allergic asthma, atopic dermatitis, and allergic rhinitis

Intronic IL4 variant that forms part of the protective C-G-C haplotype (rs2243250–rs2227284–rs2243290); the C allele is associated with reduced asthma susceptibility, while the A allele tracks with the high-Th2 haplotype and increased atopic disease risk

Intronic variant in RAD50 on chromosome 5q31.1 that was the top GWAS hit for asthma at this locus (P=3.04×10⁻⁷); the G allele tags a regulatory haplotype in the Th2 locus control region and is associated with elevated serum IgE and susceptibility to asthma and atopic disease through amplified IL-4/IL-13 output

Intronic variant in CHI3L1 associated with circulating YKL-40 levels and modulation of hypertension risk; the T allele is linked to lower YKL-40 output and a reduced risk of hypertension, extending the known allergy-relevant inflammatory axis of the CHI3L1 locus into cardiovascular biology

Synonymous variant in SPINK5 exon 13 that tags the same risk haplotype as the nearby functional Lys420Glu variant (rs2303067), associated with atopic dermatitis susceptibility through linkage disequilibrium rather than a direct protein-altering effect

Missense variant in SPINK5 encoding LEKTI domain 6 (p.Lys420Glu) that increases furin-mediated cleavage of the LEKTI precursor, impairing the strongest-activity inhibitory fragment D6–D9, elevating kallikrein protease activity, and increasing susceptibility to early-onset atopic dermatitis

Missense variant in gasdermin B that increases GSDMB expression and pyroptotic activity in airway epithelial cells, with the G (reference) allele conferring elevated childhood asthma risk through enhanced epithelial cell inflammatory death

Regulatory SNP in the ADH5 promoter at a potential NF-kB binding site; the protective T allele reduces GSNOR expression, preserving the bronchodilator S-nitrosoglutathione and lowering childhood asthma risk

Upstream promoter variant in ADH5 at a potential NF-kB binding site; the minor T allele is proposed to disrupt NF-kB-driven GSNOR transcription, reducing S-nitrosoglutathione catabolism and providing protection against childhood asthma

17q21 regulatory variant in the IKZF3-ORMDL3-GSDMB locus with opposite effects — risk for autoimmune diseases (RA, Crohn's, Graves') but protective for asthma

Intronic variant in ADH5 (GSNOR) associated with elevated childhood asthma risk; homozygotes carry ~60% higher relative risk, linked to impaired S-nitrosothiol homeostasis and airway hyperresponsiveness

A 3'UTR variant in the CERS4/NFILZ locus on chromosome 19 associated with atopic dermatitis risk (OR=1.06) in a large multi-ancestry GWAS meta-analysis; the T risk allele tags a ceramide-pathway locus where altered sphingolipid signaling impairs skin barrier function and amplifies IgE-mediated allergic inflammation.

Intronic variant in STAT6 near the 3' end of the gene that modulates STAT6 mRNA expression; the G allele is associated with atopic dermatitis risk and elevated Th2 immune tone through the same IL-4/IL-13 signaling pathway that drives allergic disease

Intronic variant in STAT6 (intron 2) that creates an NF-κB binding site, increasing STAT6 promoter activity; the T allele is associated with elevated total serum IgE and increased risk for atopic dermatitis, asthma, and allergic rhinitis through enhanced Th2 signaling

Promoter variant in STAT6 that alters transcription factor binding; the T allele is associated with reduced IFN-γ production in response to herpes simplex virus, forming a 6.87-kb haplotype with rs167769 that confers a 3.3-fold increased risk of eczema herpeticum in atopic dermatitis patients through enhanced Th2 signaling

Nonsense variant truncating ZNF77 at codon 100, impairing bronchial epithelial barrier integrity and increasing susceptibility to Aspergillus fumigatus airway colonization

GABRIEL Consortium lead GWAS SNP at the IL1RL1/IL18R1 locus on chromosome 2q12; G risk allele increases asthma susceptibility (OR 1.15, p=3×10⁻⁹) by tagging regulatory variation affecting IL-18 receptor and ST2 expression in type 2 immune responses

A 3'-UTR variant in IL1RL1 (the ST2 receptor gene); the A allele increases ST2 expression and is associated with reduced allergic rhinitis risk, making it a protective counterpart to the primary IL-33/ST2 signaling axis variants at this locus

Functional promoter variant in TSLP that creates an AP-1 transcription factor binding site; the T risk allele increases long-form TSLP expression in airway epithelial cells, raising susceptibility to asthma, allergic rhinitis, and atopic conditions (OR 1.29–1.32)

Regulatory variant ~5 kb upstream of IL33; the T allele is associated with increased asthma susceptibility, hay fever, nasal polyps, and chronic rhinosinusitis across large GWAS meta-analyses, colocalising with the IL-33 expression locus in airway epithelium

Intronic IL6R variant in perfect linkage disequilibrium with the functional Asp358Ala coding change; the T allele tags the receptor-shedding haplotype associated with increased asthma and allergic disease risk, reduced CRP, and lower coronary heart disease risk through enhanced IL-6 trans-signaling

Promoter variant ~1993 bp upstream of TBX21 (encoding the T-bet master transcription factor) that reduces TBX21 expression and blunts Th1-mediated immunity; the C allele is associated with altered Th1/Th2 balance, hypothyroidism susceptibility, and aspirin-induced asthma risk in Asian populations.

Promoter variant controlling YKL-40 (chitinase 3-like 1) expression; the common C allele drives higher circulating YKL-40 levels and increased susceptibility to asthma and airway inflammation

Intronic variant in RTEL1 (regulator of telomere elongation helicase 1) associated with atopic dermatitis risk; the A allele increases AD susceptibility through impaired telomere-dependent immune cell renewal

Intronic FLG-locus variant strongly associated with atopic dermatitis — the C allele marks filaggrin deficiency through a skin-specific mechanism with a larger effect size (OR 1.66) than the classical R501X null allele

Intergenic regulatory variant near the PRG2/PRG3 eosinophil granule protein cluster at chromosome 11; A allele may influence PRG2 expression and eosinophil major basic protein levels, implicated in eosinophil-mediated allergic inflammation and atopic disease susceptibility

Missense variant in the rhinovirus-C receptor CDHR3 that increases cell-surface receptor expression and viral binding ~10-fold, elevating risk of rhinovirus-C respiratory infections and childhood asthma exacerbations

Intronic EMSY variant that defines the high-risk haplotype at 11q13.5; the G allele is required for the rs7927894 T risk allele to exert its effect on atopic dermatitis and allergic rhinitis — without G at rs7125552, the rs7927894 T risk effect is abolished

Regulatory variant near LRRC32 (GARP) on chromosome 11q13.5; the G allele increases LRRC32 expression and is associated with elevated risk of atopic asthma, atopic dermatitis, and the eczema-to-asthma progression (atopic march)

Intronic SNX27 variant at the 1q21.3 GWAS locus that increases atopic dermatitis risk by disrupting T cell trafficking and immune synapse signalling; the locus also encompasses nearby RORC, the master Th17 transcription factor

Missense variant (Leu242Val) in the HLA-DRA alpha chain; the T allele tags HLA class II haplotypes associated with peanut allergy (OR ~1.6, p=5.5×10⁻⁸) and is a functionally confirmed risk allele for drug hypersensitivity via altered antigen presentation

Intronic GSDMB variant that acts as an eQTL for ORMDL3; the T allele elevates ORMDL3 expression in airway cells, increasing sphingolipid-pathway ER stress and childhood asthma susceptibility

Intronic variant in the IL1RL1/IL18R1 receptor gene cluster on chromosome 2q12 that modulates allergic disease susceptibility; carriers of the A allele show reduced risk for allergic rhinitis and atopic conditions

Regulatory variant near the EMSY/C11orf30 locus; T allele increases EMSY expression, suppressing filaggrin and ceramide production in skin, and is the broadest known allergic disease risk allele — associated with atopic dermatitis, asthma, hay fever, and the atopic march

Regulatory variant near C11orf30 (EMSY) on chromosome 11q13.5; the T allele reduces EMSY transcriptional repressor activity, releasing TSLP and CCL5 expression in epithelial cells and increasing susceptibility to eosinophilic inflammation, atopic dermatitis, eosinophilic esophagitis, asthma, poly-sensitization, and Crohn's disease

Intronic variant in MRPL4 on chromosome 19p13.2 that alters transcription factor binding (AREB6 loss, CREB2 gain), reducing mitochondrial ribosomal protein L4 expression and increasing susceptibility to atopy and allergic rhinitis via the HIF-1α signalling pathway

Third independent eQTL signal at the CHI3L1/YKL-40 locus on chromosome 1q32.1; the G allele modifies circulating YKL-40 levels independently of the two primary CHI3L1 regulatory variants and has been linked to altered inflammatory and cerebrovascular risk

3' untranslated region variant in the IL-4 receptor alpha chain gene; the G allele is associated with elevated type-2 inflammatory endotype in asthma and predicts exacerbation risk and pharmacogenetic response to IL-4 pathway blockade

A 3'UTR variant in IKZF3 that alters miR-326 binding affinity, reducing Aiolos transcription factor expression in a T-allele-dependent manner and increasing susceptibility to systemic autoimmune disease through impaired B-cell maturation and immune homeostasis

Intronic proxy variant in RAD51B associated with seropositive rheumatoid arthritis risk; the C allele is protective while the T allele tags a haplotype at the RAD51B locus that predisposes to anti-CCP-positive RA and more severe joint erosion

Intergenic tag SNP between HLA-DQB1 and HLA-DQA2 tagging the HLA-DQA1*01:02 risk haplotype; the C allele confers ~1.7-fold increased susceptibility to peanut allergy and is associated with multiple sclerosis risk

Intronic variant in the IL1RL1 gene on chromosome 2q12 encoding the ST2 receptor for IL-33; the T allele is associated with reduced allergic rhinitis risk, particularly in males, by modulating IL-33/ST2 signaling amplitude

A 3' UTR variant in RAD51B that alters miRNA-616 binding efficiency and is associated with increased risk of rheumatoid arthritis and impaired DNA double-strand break repair in immune cells

Regulatory variant upstream of IL33 encoding interleukin-33; the A allele increases IL33 expression in bronchial epithelium and raises risk for asthma, hay fever, and eczema across shared type-2 immune pathways