rs1805010 — IL4R Ile75Val

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

See your personal result for IL4R

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

IL-4 Receptor Ile75Val — The Gateway to ABPA Susceptibility

Interleukin-411 Interleukin-4
IL-4 is the master switch cytokine for Th2 immune responses — it drives IgE class switching in B cells, mast cell activation, and alternative macrophage polarization acts through a dimeric receptor on the surface of immune cells. The alpha chain of this receptor (IL-4Rα, encoded by IL4R on chromosome 16) is the critical ligand-binding component shared by both the type I receptor (IL-4Rα + γc, on lymphocytes) and the type II receptor (IL-4Rα + IL-13Rα1, on non-hematopoietic cells). The rs1805010 variant changes the amino acid at position 75 in the receptor's extracellular IL-4–binding domain from isoleucine (Ile, the common form) to valine (Val), subtly reshaping the interface where IL-4 engages its receptor. In large patient studies, this variant is found in 80% of allergic bronchopulmonary aspergillosis patients22 80% of allergic bronchopulmonary aspergillosis patients
Knutsen et al. Clin Mol Allergy 2006; 62 ABPA patients (40 cystic fibrosis + 22 asthmatic) vs 56 non-ABPA controls; IL-4Rα SNPs overall found in 95% of ABPA cases, making it the most prevalent genetic risk marker for this severe fungal allergy syndrome.

The Mechanism

The Val75 substitution is located in the extracellular domain of IL-4Rα, within the region that contacts the IL-4 cytokine directly. Although the amino acid change is chemically conservative (isoleucine and valine differ only by a single methylene group), functional studies consistently find that Val75 cells show heightened responsiveness to IL-4 stimulation — producing more surface CD23 (the low-affinity IgE receptor) per B cell at equivalent IL-4 concentrations compared to Ile75 B cells. Khan et al. 200033 Khan et al. 2000
International Archives of Allergy and Immunology 2000; 10 ABPA patients, 9 atopic controls, 8 non-atopic controls; ABPA patients showed significantly greater CD23 and CD86 upregulation after IL-4 stimulation at 5 and 10 ng/mL (p<0.001) established that IL-4 hypersensitivity is a defining immunological feature of ABPA, and the Ile75Val variant provides the structural basis for this amplified receptor output. Through the JAK-STAT6 signaling cascade downstream of IL-4Rα, Val75 carriers experience enhanced STAT6 phosphorylation, greater transcription of IgE switch factors (AID, germline ε transcript), and higher steady-state serum IgE — exactly the physiological conditions that predispose to ABPA and severe asthma.

The Evidence

The most direct evidence linking rs1805010 to ABPA comes from Knutsen et al. (2006), who found ile75val present in 80% of ABPA patients44 ile75val present in 80% of ABPA patients
Clin Mol Allergy 2006; n=62 ABPA, n=56 non-ABPA controls; CD23 expression significantly elevated after IL-4 stimulation in ABPA patients at 5 and 10 ng/mL, p<0.02 — a prevalence far exceeding population background frequencies. In asthma more broadly, Al-Muhsen et al. 201455 Al-Muhsen et al. 2014
case-control study, 190 severe asthmatics vs 194 controls, Saudi Arabia; G allele OR=1.6 (95% CI 1.01–2.53) for asthma susceptibility; combined G-G haplotype with rs1801275 OR=2.43 confirmed rs1805010 G allele as a significant asthma susceptibility factor, with notably stronger effects in females (OR=3.73). Chinese pediatric data from Chen et al. 201466 Chen et al. 2014
160 asthmatic children vs 143 healthy controls; I75V variant allele carriers had significantly higher serum IgE vs non-carriers in the asthma group (p=0.036) confirmed that carrying the Val75 allele associates with higher IgE production, providing a direct biological link between the genotype and the IgE-mediated pathology in both asthma and ABPA. Occupational allergen studies reinforce this: in 373 bakery workers77 373 bakery workers
Omae et al. 2013; G allele carriers had 16.0% prevalence of work-related lower respiratory symptoms vs 2.9% in AA carriers, p=0.004, the Val75 allele significantly amplified the response to inhaled allergens.

Practical Implications

Carriers of the Val75 (G) allele — particularly GG homozygotes — have an inherently lower threshold for IL-4–driven immune activation. In clinical practice this means: monitoring serum total IgE as a direct readout of IL-4Rα activity; heightened vigilance for fungal sensitization (especially Aspergillus fumigatus) in asthmatics, given the 80% ABPA prevalence of this allele; and recognition that the JAK-STAT6 pathway downstream of IL-4Rα is the pharmacological target of dupilumab (anti-IL-4Rα). Val75 carriers with moderate-severe asthma or atopic dermatitis unresponsive to inhaled corticosteroids are biologically well-aligned with dupilumab therapy, since the drug targets the exact receptor whose activity is enhanced by this variant.

Interactions

rs1805010 (Ile75Val) and rs1801275 (Gln576Arg, Q576R) are the two most clinically studied IL4R variants and act synergistically. Ile75Val sits in the extracellular IL-4–binding domain and increases ligand-binding sensitivity; Q576R sits in the cytoplasmic signaling domain and amplifies downstream JAK1-STAT6 phosphorylation (the Hershey 1997 NEJM gain-of-function variant). Carriers of both risk alleles simultaneously — the G-G haplotype — face compounding IL-4 pathway amplification at two mechanistically distinct levels: enhanced IL-4 capture at the extracellular surface AND amplified intracellular signal transduction. The G-G haplotype is more frequent in severe asthmatics than either variant alone (OR=2.43). The combination also appears at increased frequency in ABPA patients alongside IL-13 polymorphisms (rs20541 Arg130Gln), since IL-13 shares the IL-4Rα subunit in the type II receptor — making the rs1805010 × rs1801275 × rs20541 triad the most biologically coherent gene-gene interaction in ABPA genetics.

Genotype Interpretations

What each possible genotype means for this variant.

AA Standard IL-4 Receptor Sensitivity Normal

Common Ile75 form with typical IL-4 receptor sensitivity and population-average ABPA and asthma risk

The Ile75 form of IL-4Rα is the ancestral configuration, with the bulkier isoleucine side chain at position 75 in the extracellular ligand-binding domain. Structural and functional studies suggest this amino acid position contributes subtly to the geometry of the IL-4/IL-4Rα contact interface. AA homozygotes show baseline CD23 upregulation kinetics after IL-4 stimulation — neither the enhanced sensitivity seen in Val75 carriers nor any impairment. Given that ABPA patients show this variant in 80% of cases, the absence of the G allele meaningfully reduces individual genetic susceptibility to ABPA compared to G carriers, though other genetic (HLA-DR2/DR5, IL-13 polymorphisms) and environmental factors remain relevant.

AG Elevated IL-4 Sensitivity (Heterozygous) Intermediate

One copy of the Val75 risk allele with moderately increased IL-4 receptor sensitivity and elevated ABPA/asthma susceptibility

The IL-4Rα Ile75Val substitution is in the extracellular domain at the IL-4 contact surface. Heterozygotes produce a mixture of Ile75 and Val75 receptor chains on their immune cell surfaces — roughly half of receptor complexes carry the enhanced-sensitivity Val75 configuration. This intermediate receptor pool produces intermediate IL-4 signaling tone: serum IgE tends to be modestly elevated relative to AA carriers, and the threshold for allergen-driven IgE class switching is somewhat lower. In the context of occupational allergen exposure, heterozygotes show measurably higher rates of respiratory sensitization than AA individuals (Omae 2013). For ABPA risk specifically, the Val75 allele at any copy number is a risk marker given its 80% prevalence in ABPA cases.

GG High IL-4 Sensitivity (Homozygous) High Risk

Two copies of the Val75 risk allele with substantially elevated IL-4 receptor sensitivity and the highest genetic susceptibility to ABPA and IgE-driven allergic asthma

As a GG homozygote at rs1805010, every IL-4Rα chain you produce carries the Val75 substitution in the extracellular IL-4–binding domain. Val75/Val75 B cells show the strongest CD23 upregulation after IL-4 stimulation — the highest IL-4 receptor output of any genotype at this locus. The JAK-STAT6 cascade downstream is maximally activated at lower IL-4 concentrations, driving the most pronounced IgE class switching, mast cell activation, and Th2 polarization. In the ABPA study population (n=62), IL-4Rα SNPs overall were found in 95% of cases and ile75val specifically in 80% — predominantly driven by heterozygotes and homozygotes combined. For GG homozygotes, every IL-4–driven immune event — from initial allergen sensitization to ongoing IgE production — operates with an amplified gain setting. For asthmatic GG carriers specifically, the pharmaceutical target dupilumab (anti-IL-4Rα) directly inhibits the receptor whose extracellular domain this variant amplifies, making this genotype the mechanistic basis for a biologic therapy decision.