rs1805011 — IL4R IL4R Glu375Ala

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

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IL-4 Receptor Glu375Ala — The Extracellular Signaling Modulator

The IL4R gene11 IL4R gene
Interleukin-4 receptor alpha chain, located at chromosome 16p12.1 encodes the alpha subunit of the IL-4 receptor, which sits at the heart of the body's allergic response circuitry. The rs1805011 variant (also called Glu375Ala in many publications, or Glu400Ala in the canonical full-length transcript) is a missense change in the extracellular domain of this receptor — the region that physically contacts the IL-4 cytokine during binding. Unlike the well-characterized intracellular Q576R variant (rs1801275), which amplifies downstream signaling, Glu375Ala sits upstream in the ligand-interaction zone, with the potential to subtly alter how efficiently IL-4 engages the receptor.

The Mechanism

The IL-4Rα extracellular domain folds into two immunoglobulin-like subdomains that form a binding cradle for [IL-4 | The cytokine interleukin-4, a key driver of Th2-type immune responses and IgE class switching in B cells]. Glutamic acid at position 375/400 sits within this ligand-binding region. Substituting glutamic acid (charged, negatively) for alanine (neutral, nonpolar) changes the local electrostatic environment near the binding interface.

When IL-4 binds IL-4Rα and the receptor complexes with either the common gamma chain (type I receptor)22 common gamma chain (type I receptor)
Forms on lymphocytes and drives Th2 differentiation or IL-13Rα1 (type II receptor)33 IL-13Rα1 (type II receptor)
Forms on non-hematopoietic cells and airway epithelium, drives mucus and airway remodeling, the intracellular JAK1/TYK2 kinases are activated, phosphorylating STAT644 STAT6
Signal transducer and activator of transcription 6, which moves to the nucleus to drive IgE class switching, Th2 differentiation, and mucin production. The Glu375Ala substitution is hypothesized to alter binding kinetics or receptor conformation in a way that modifies the threshold or magnitude of this signaling cascade — though the precise structural consequence has not been characterized in functional studies to the same degree as the intracellular variants.

The Evidence

Association evidence across several populations supports rs1805011 as a modest risk modifier for atopic disease.

Bottema et al. (2010), analyzing rhinitis and asthma in three cohorts totaling over 700 trios and case-control pairs55 Bottema et al. (2010), analyzing rhinitis and asthma in three cohorts totaling over 700 trios and case-control pairs
Family-based and case-control design; European-ancestry populations found that IL4R Glu375Ala (rs1805011) was associated with asthma. Critically, they also found a gene-gene interaction66 gene-gene interaction
When the effect of one genetic variant depends on the genotype at a second locus, producing a combined risk larger than either alone between rs1805011 and IL13 Arg130Gln — the two variants together conferred greater asthma risk than either alone, pointing to convergent Th2 pathway amplification.

A meta-analysis of case-control studies by Zhu et al. (2013)77 meta-analysis of case-control studies by Zhu et al. (2013)
Six studies examining IL-4 and IL-4R polymorphisms across Asian and European populations confirmed that individuals homozygous for the A allele at rs1805011 were significantly less likely to develop asthma, with the combined C-carrier genotypes (CC+AC) showing an overall OR of 0.39 versus AA (P=0.04), meaning the C allele roughly doubles asthma susceptibility in a dominant model.

In Polish children, Narożna et al. (2016)88 Narożna et al. (2016)
177 asthmatic children versus 194 healthy controls found rs1805011 to be the strongest IL4R association in their dataset, reaching genome-wide- suggestive significance for mild asthma (p=0.00005) and a significant signal for atopic dermatitis (p=0.0056).

A genome-wide pharmacogenomic analysis of asthma exacerbations Anderson et al. (2013)99 Anderson et al. (2013)
Data from four salmeterol clinical trials, 199 exacerbators vs 502 controls identified rs1805011 among a cluster of IL4R coding variants with consistent genetic effects across three independent studies (P<0.0006), suggesting this variant influences exacerbation biology in addition to initial susceptibility.

Evidence on atopic dermatitis and eczema is more nuanced. A Japanese women's cohort study (Miyake et al. 2013)1010 Japanese women's cohort study (Miyake et al. 2013)
188 eczema cases vs 635 controls found a protective association for the C allele in the context of eczema (OR 0.55, 95% CI 0.31-0.99), contrasting with asthma data. This divergence likely reflects condition-specific interactions with other immune loci, environmental exposures, and population differences.

Practical Actions

For carriers of the C allele, the core concern is modestly amplified IL-4 signaling leading to higher IgE class switching and Th2 immune polarization. Monitoring IgE levels quantifies the downstream consequence of altered receptor function. Screening for common aeroallergens and food allergens provides actionable information about which exposures are most likely to trigger clinical responses.

Quercetin directly targets the IL-4/STAT6 signaling axis. In vitro studies confirm that quercetin at 5 micromolar concentrations suppresses IL-4-induced STAT6 phosphorylation1111 In vitro studies confirm that quercetin at 5 micromolar concentrations suppresses IL-4-induced STAT6 phosphorylation
Achievable with oral doses of 1,000 mg reaching plasma levels of 5-12 micromolar, making it a molecularly targeted intervention for Th2 pathway overactivation.

Vitamin D modulates Th1/Th2 immune balance. Optimal levels support regulatory T cell function and suppress Th2-skewed cytokine production, directly counteracting the immune shift that this variant may facilitate.

Interactions

rs1805011 interacts functionally with IL13 Arg130Gln — together they yield greater asthma risk than either variant alone (Bottema et al. 2010), consistent with both variants affecting the same IL-4/IL-13 type II receptor complex.

Within the IL4R gene itself, rs1805011 forms haplotypes with [I75V (rs1805010) | Ile75Val, extracellular domain variant with independent atopy associations] and [Ser503Pro (rs1805015) | Extracellular domain variant also associated with atopic phenotypes in Japanese cohorts]. The combined haplotype across these three extracellular-domain positions may have additive effects on IL-4 binding efficiency. The intracellular variant Q576R (rs1801275) operates through a distinct gain-of-function mechanism; carrying risk alleles at both extracellular and intracellular positions would be expected to compound the overall shift toward amplified Th2 signaling.

Genotype Interpretations

What each possible genotype means for this variant.

AA Standard Receptor Normal

Normal IL-4 receptor extracellular domain — standard Th2 immune response threshold

You carry two copies of the ancestral A allele, encoding glutamic acid at position 375/400 of the IL-4 receptor alpha chain's extracellular domain. Your receptor retains its typical electrostatic environment in the IL-4 binding region. About 76% of people globally share this genotype, making it the clear majority worldwide — though the A allele is somewhat less dominant in populations of African descent (about 49% AA frequency).

AC Modified Receptor Intermediate

One copy of the Glu375Ala variant — mildly elevated atopic asthma susceptibility

The heterozygous state produces a mix of wild-type and Glu375Ala IL-4 receptors on your immune cells. Associations have been found with atopic asthma and atopic dermatitis across European and Asian cohorts. A notable gene-gene interaction has been documented between rs1805011 and the IL13 Arg130Gln variant — if you also carry an IL13 risk allele, your combined atopic disease risk may be higher than either variant predicts alone, as both affect the same type II receptor complex (IL-4Rα + IL-13Rα1).

The effect at this locus is more modest than the intracellular Q576R variant (rs1801275), and some studies show population- or condition-specific differences in direction of effect. Monitoring your actual IgE levels provides more personalized information than genotype alone.

CC Homozygous Variant High Risk

Two copies of the Glu375Ala variant — elevated atopic asthma and allergic disease risk

With both alleles encoding the Glu375Ala change, every IL-4 receptor alpha chain on your immune cells carries the modified extracellular domain. The extracellular change at this position is proposed to alter IL-4 ligand-binding kinetics, which could lower the activation threshold or modify the duration of receptor occupancy. While the precise functional mechanism has not been characterized to the same depth as the intracellular variants (Q576R), population data consistently places this genotype in a higher-risk category for atopic asthma.

The Bottema 2010 study showed that rs1805011 C-allele carriers interacting with IL13 risk variants had compounded asthma risk — a gene-gene interaction operating through the shared type II receptor complex (IL-4Rα + IL-13Rα1). If you also carry risk alleles at rs1805010 (I75V) or rs1801275 (Q576R), your cumulative IL-4 pathway burden may be substantially greater than any single variant suggests.

Monitoring IgE levels and specific allergen sensitization panels provides the most direct assessment of your functional Th2 activation state. If atopic conditions develop, awareness of your elevated genetic risk profile can help justify earlier specialist referral and more aggressive targeted management including biologic therapy if standard treatments are insufficient.