rs10206753 — IL1RL1 IL1RL1 TIR Domain Risk Haplotype

IL1RL1 TIR Domain — When the IL-33 Receptor Amplifier Is Set Too High

The ST2 receptor encoded by IL1RL1 is the gateway through which IL-33¹¹ IL-33
Interleukin-33, a cytokine released by damaged airway and skin epithelial cells that acts as a danger signal for the type 2 immune system activates immune cells. When IL-33 docks onto ST2, the receptor's intracellular TIR domain²² TIR domain
Toll/IL-1 receptor homology domain — the intracellular signaling module that recruits adaptor proteins and fires downstream NF-kB and MAPK pathways relays the signal inside the cell. The rs10206753 missense variant sits directly in that TIR domain, changing amino acid 551 between leucine (Leu551, the risk haplotype) and serine (Ser551, the protective haplotype). This single amino acid difference meaningfully alters how hard the ST2 receptor fires when IL-33 arrives.

The Mechanism

rs10206753 is one of four coding changes that co-segregate in perfect linkage disequilibrium as a haplotype block in the IL1RL1 TIR domain. The risk haplotype (Ala433/Gln501/Thr549/Leu551, tagged by the T allele at rs10206753) produces a ST2 receptor that, when stimulated with IL-33, achieves a 2- to 3-fold induction of NF-kB signaling³³ 2- to 3-fold induction of NF-kB signaling
Measured in transfected cells stimulated with 10–50 ng/mL human recombinant IL-33; the protective Ser551 haplotype shows an attenuated response at equivalent stimulus concentrations. The protective haplotype (Thr433/Arg501/Ile549/Ser551, tagged by the C allele) shows a substantially attenuated signaling response to the same IL-33 stimulus. The Gln501Arg change within the haplotype is thought to be particularly important for this attenuated signaling, likely by altering adaptor protein recruitment to the TIR domain.

This is a distinct mechanism from the better-studied rs1420101 and rs11685480 eQTL variants, which affect how much sST2 decoy receptor is produced. rs10206753 instead changes the signal strength of the membrane-bound ST2L receptor itself — affecting IL-33 sensitivity at the receptor level rather than through decoy availability.

The Evidence

The IL1RL1 locus is among the most replicated asthma susceptibility loci in human genetics⁴⁴ IL1RL1 locus is among the most replicated asthma susceptibility loci in human genetics
Moffatt et al. NEJM 2010, GABRIEL GWAS of 10,365 cases and 16,110 controls across 10 populations; IL1RL1/IL18R1 locus p=3×10⁻⁹ for asthma. The TIR domain haplotype tagged by rs10206753 was functionally characterized by Portelli et al. JCI Insight 2020⁵⁵ Portelli et al. JCI Insight 2020
Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium, which showed that the risk haplotype ST2 protein produces significantly more NF-kB signaling per unit of IL-33 than the protective haplotype, while both haplotypes retain equivalent TNF-α responsiveness (confirming the effect is IL-33 pathway-specific).

Population evidence confirms the protective effect of the C allele. Bloodworth et al. JACI 2018⁶⁶ Bloodworth et al. JACI 2018
Association of ST2 polymorphisms with atopy, asthma, and leukemia reported an OR of 0.876 for asthma per C allele in a PheWAS of five ST2 SNPs including rs10206753, confirming the inverse relationship with asthma risk. The same study confirmed perfect linkage (r²=1) between rs10206753 and three other TIR domain coding variants (rs10192036, rs4988956, rs10192157), establishing that this is a haplotype effect rather than a single-SNP effect.

The C allele (protective Ser551 haplotype) appears protective against both asthma and chronic rhinosinusitis⁷⁷ chronic rhinosinusitis
Inflammation of the nasal sinuses persisting more than 12 weeks, frequently driven by the same IL-33/type-2 pathway as asthma. The same haplotype has been reported to modestly increase obesity risk, consistent with the role of IL-33/ST2 signaling in adipose tissue inflammation.

Practical Actions

For TT homozygotes — who carry two copies of the Leu551 risk haplotype and represent the most common genotype globally (~37% of Europeans) — the ST2 receptor is more reactive to IL-33. This means that when airway epithelium is damaged by allergens, viruses, or pollutants, IL-33 signaling reaches immune cells with greater intensity. The clinical translation is modestly elevated susceptibility to asthma and atopic disease, with the strongest actionability for those who already have asthma symptoms.

Given that rs10206753 and rs1420101 tag distinct mechanisms at the same gene, carriers of risk alleles at both loci may have synergistically elevated type-2-high asthma susceptibility: more reactive ST2 signaling (this variant) compounded with less sST2 decoy buffering (rs1420101 T allele).

Interactions

rs10206753 tags a haplotype that is independent of the primary sST2 eQTL signals (rs1420101 and rs11685480). Both mechanisms — receptor signaling amplitude (this variant) and decoy receptor availability (rs1420101 / rs11685480) — converge on the same IL-33/ST2 pathway. Carriers of risk genotypes at both loci face compounding effects: less IL-33 interception by circulating sST2 AND more IL-33-driven NF-kB activation once IL-33 reaches the membrane receptor.

Upstream IL33 variants (rs992969, rs1929992) further modulate the amount of IL-33 ligand produced by stressed epithelium. The full IL-33 axis risk can be assessed by genotyping the ligand (IL33), the decoy receptor (IL1RL1 eQTL signals), and the membrane receptor signaling amplitude (this TIR domain haplotype).