rs1805011 — IL4R IL4R Glu375Ala

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.