rs1805010 — IL4R Ile75Val

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.