rs72823628 — IL1RL1

IL1RL1/IL18R1 — The Allergy Receptor Locus That Sets Your Immune Dial

When the immune system encounters a harmless pollen grain or a cat hair, the difference between a calm non-reaction and a full allergic cascade often begins at the cell surface, where receptor proteins decide whether to escalate or stand down. The IL1RL1/IL18R1 gene cluster on chromosome 2q12 encodes two closely related interleukin receptors — IL1RL1 (also called ST2)¹¹ IL1RL1 (also called ST2)
ST2 is the receptor for IL-33, a cytokine released by barrier epithelium during physical stress or allergen exposure. IL-33 signals through ST2 to activate type 2 immune responses, mast cells, and ILC2 cells and IL18R1 (the IL-18 receptor)²² IL18R1 (the IL-18 receptor)
IL-18 is an inflammasome-derived cytokine with context-dependent roles: it promotes Th1 anti-viral immunity but can amplify Th2-driven allergy when chronically elevated; IL18R1 is expressed on T cells, NK cells, and innate lymphoid cells — that together calibrate how strongly the immune system responds to inhaled and ingested allergens. The rs72823628 variant sits within an intron of IL1RL1 at position 102,312,157 on GRCh38, roughly 43 kb upstream of IL18R1. As a regulatory intronic variant, it most likely influences gene expression or mRNA processing rather than protein structure.

The Mechanism

IL1RL1 (ST2) is the surface receptor for IL-33, an alarmin cytokine rapidly released by airway epithelial cells and skin keratinocytes when damaged by allergens, pollutants, or mechanical stress. IL-33/ST2 signaling activates type 2 innate lymphoid cells (ILC2s)³³ type 2 innate lymphoid cells (ILC2s)
ILC2s are tissue-resident immune cells that amplify allergic inflammation without requiring prior antigen sensitization; they produce IL-4, IL-5, and IL-13, driving eosinophil recruitment and IgE production, mast cells, and basophils, producing the cytokines (IL-4, IL-5, IL-13) that define allergic inflammation. The intronic rs72823628 variant likely modifies IL1RL1 expression levels in these immune cells, altering the magnitude of IL-33-triggered responses. Variants in this locus have been shown to affect the ratio of soluble (sST2, a decoy receptor that quenches IL-33 signaling) to membrane-bound ST2, with regulatory alleles shifting this balance. Carriers of the A allele appear to have a configuration that reduces net IL-33 signaling amplitude, dampening the immune response to allergens.

The adjacent IL18R1 gene encodes the receptor for IL-18, an inflammasome-derived cytokine that bridges innate and adaptive immunity. In the context of allergic disease, IL-18 modulates both Th1-suppressive and Th2-amplifying pathways depending on the cytokine milieu. Genetic variation across the IL1RL1/IL18R1 cluster influences both arms of this response; rs72823628 may tag regulatory variation that affects the expression of one or both receptors in airway-relevant tissues.

The Evidence

The IL1RL1/IL18R1 locus on chromosome 2q12 is one of the most robustly replicated genetic associations with allergic and atopic disease. The GABRIEL Consortium GWAS⁴⁴ GABRIEL Consortium GWAS
Moffatt et al. 2010 — 10,365 asthma cases and 16,110 controls; rs3771166 at the IL1RL1/IL18R1 locus reached P=3×10⁻⁹ for asthma established this locus at genome-wide significance for asthma. The Ferreira 2017 analysis⁵⁵ Ferreira 2017 analysis
360,838 participants; 136 independent risk variants identified for asthma, hay fever, and eczema combined; the IL1RL1/IL18R1 region among the most consistently replicated loci across all three allergic conditions extended the association to all three major atopic diseases — asthma, allergic rhinitis (hay fever), and eczema — confirming shared genetic architecture.

For rs72823628 specifically, a 2022 case-control study in the Chinese Han population⁶⁶ 2022 case-control study in the Chinese Han population
Li et al. 2022 — 1,000 allergic rhinitis patients and 1,000 controls; genotyping by Agena MassARRAY; stratified analysis by sex found that the A allele was significantly associated with reduced allergic rhinitis risk. The protective effect was most pronounced in male participants. The IL33–IL1RL1 pathway analysis by Savenije et al. 2014⁷⁷ Savenije et al. 2014
PIAMA cohort (n=2,007) and ALSPAC cohort (n=7,247); intermediate-onset wheeze showed strongest IL33/IL1RL1 pathway associations, suggesting these variants influence the timing of allergic sensitization further refined the picture, showing that IL1RL1/IL18R1 variants particularly influence intermediate-onset wheezing — the phenotype most closely linked to allergic sensitization — rather than early transient or late non-atopic wheeze. This pattern supports the interpretation that rs72823628 modifies not simply whether allergic disease occurs but when sensitization first takes hold.

The A allele frequency shows striking population variation: ~21% in Africans, ~14% in Europeans, ~13% in East Asians, and only ~3% in South Asians. This variation means protection is distributed very unevenly across ancestries, with South Asian populations carrying the highest prevalence of the susceptibility (GG) genotype.

Practical Actions

The G allele (standard genotype) does not indicate disease — the majority of people carry GG and do not develop clinical allergic disease. However, the GG genotype lacks the reduced IL-33 signaling associated with the A allele, meaning the allergic response threshold is set at the population-average level. For people who do develop allergic symptoms, this knowledge supports earlier evaluation rather than watchful waiting, since genetic susceptibility at this locus predates sensitization.

Carriers of at least one A allele (AG or AA) carry a partial or full protective effect against allergen sensitization through dampened IL-33/ST2 signaling. This does not confer immunity to allergic disease but shifts the threshold upward — a meaningful difference in high-allergen environments or in families with strong atopic history.

Interactions

The IL1RL1/IL18R1 locus works in concert with the upstream IL-33 ligand gene. The variant rs1342326 near IL33 (identified at P=9×10⁻¹⁰ in the GABRIEL asthma GWAS) represents the other end of the signaling axis: IL-33 as the danger signal, IL1RL1/ST2 as the receptor. Individuals who carry both higher IL-33 production alleles (IL33 locus) and standard-susceptibility alleles at IL1RL1 (GG at rs72823628) may experience amplified allergic signaling from both ends of the pathway — a compound effect worth considering if allergy history is strong. The interaction between IL33 and IL1RL1 variant combinations has been examined in the Savenije 2014 study, which identified SNP pair interactions for childhood asthma phenotypes.