rs17561 — IL1A Ala114Ser

IL1A Ala114Ser — The IL-1α Hypomorph That Shapes Mucosal and Joint Immunity

Interleukin-1 alpha (IL-1α) is not just another pro-inflammatory cytokine — it is a unique alarmin¹¹ alarmin
An alarmin is a damage-associated molecular pattern (DAMP) that is released from dying or stressed cells to signal danger to the immune system before adaptive immunity activates. Unlike IL-1β, which must be actively processed by the inflammasome and secreted, IL-1α is constitutively produced as a precursor (pro-IL-1α) in virtually all nucleated cells and is released as an immediate alarm signal when cells are damaged. At rs17561, a single amino acid substitution at position 114 of the protein — alanine to serine — creates a very common hypomorphic form of IL-1α that releases roughly half as much cytokine into the extracellular space.

The Mechanism

Position 114 sits in the central linker region that joins the pro-domain to the mature cytokine domain of pro-IL-1α. Multi-species alignment shows this alanine is highly conserved across mammals, suggesting it is functionally important for protein handling. The A allele at rs17561 (on the plus strand) encodes serine at this position; the common C allele encodes alanine.

Wiggins et al. (2023, Immunology) characterised this variant functionally²² Wiggins et al. (2023, Immunology) characterised this variant functionally
The common IL1A single nucleotide polymorphism rs17561 is a hypomorphic mutation that significantly reduces interleukin-1α release from human blood cells. Immunology 168:459-472 using a recall-by-genotype design in the Cambridge BioResource. When whole blood from volunteers stratified by genotype was stimulated with LPS, AA homozygotes released approximately 50% less IL-1α than CC homozygotes, while IL-1β release was equivalent between groups. IL-1α transcript levels were identical across genotypes, ruling out a transcriptional mechanism. Protease cleavage assays with calpain, thrombin, elastase, and cathepsin B showed no difference between the Ala and Ser forms. The deficit appears to be post-translational: more Ser-form pro-IL-1α is retained within the cell rather than secreted. Transfected macrophage experiments confirmed that reduced secretion is caused directly by the amino acid substitution and not by confounding genetic variation in linkage disequilibrium.

The Evidence

Periodontitis. The Yin et al. (2016) meta-analysis of six case-control studies (336 cases, 366 controls)³³ Yin et al. (2016) meta-analysis of six case-control studies (336 cases, 366 controls)
Association between IL-1α rs17561 and IL-1β rs1143634 polymorphisms and periodontitis: a meta-analysis. Genet Mol Res 2016 found that the T allele (Ser form; called G/T in coding-strand notation, equivalent to C/A on the plus strand) is associated with significantly elevated periodontitis risk (OR = 1.50 per allele; OR = 1.57 for TC+TT carriers vs non-T carriers). The direction of effect — reduced IL-1α secretion correlating with worse periodontal disease — is counterintuitive at first glance but consistent with a model in which IL-1α provides essential mucosal barrier protection: insufficient IL-1α at gingival surfaces may impair bacterial sensing and the epithelial alarmin response, leaving subgingival biofilms inadequately controlled. It is worth noting that this meta-analysis was small (700 total participants) and findings across individual studies were not fully consistent.

Ankylosing spondylitis. The Sims et al. (2008) prospective meta-analysis, 2,675 AS cases and 2,592 controls across 12 centres in 10 countries⁴⁴ Sims et al. (2008) prospective meta-analysis, 2,675 AS cases and 2,592 controls across 12 centres in 10 countries
Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis. Ann Rheum Dis 67:1305-9 identified rs17561 as one of three IL1A SNPs with strong association with AS susceptibility (p = 0.000019), estimating the population-attributable risk in Caucasians at 4–6% for the IL1A locus overall. Whether this reflects direct causality through reduced IL-1α alarmin signalling or tagging of adjacent functional variation in the IL-1 gene cluster is not fully resolved.

Psoriatic arthritis. A subsequent Su et al. (2018) multi-disease meta-analysis⁵⁵ Su et al. (2018) multi-disease meta-analysis
Meta-analyses of IL1A polymorphisms and the risk of several autoimmune diseases published in databases. PLoS One 2018 found significant association of rs17561 with psoriatic arthritis (PA) specifically, while failing to find associations with RA, systemic sclerosis, SLE, or multiple sclerosis, suggesting a disease-specific rather than pan-autoimmune effect.

The Ser allele is substantially more common in Europeans (~30% allele frequency) and South Asians (~31%) compared to East Asians (~8%), which may partly explain why associations have primarily been documented in Caucasian cohorts.

Practical Actions

The A allele at rs17561 (Ser form, hypomorphic) is associated with reduced IL-1α alarmin signalling — meaning the variant's consequences manifest most prominently at barriers where this cytokine provides first-line surveillance: the periodontium and possibly the mucosal interfaces of the gut and joints. For carriers of one or two A alleles, the most actionable implications are: heightened attention to periodontal health (where the association is most directly supported) and awareness of the modest but significant IL1A locus contribution to ankylosing spondylitis susceptibility.

Anti-IL-1 biologic therapy (anakinra, canakinumab) is used in AS and certain autoinflammatory disorders. Carriers of the Ser hypomorph naturally have lower IL-1α output; this may be relevant to patient stratification in clinical trials of IL-1 pathway therapies, though personalised dosing based on rs17561 genotype is not yet established practice.

Interactions

IL1B rs1143634 and IL1RN rs2234663: IL-1α and IL-1β both signal through the IL-1 receptor (IL-1R1) and are co-expressed in inflamed tissues. IL-1 receptor antagonist (IL-1Ra, encoded by IL1RN) competitively inhibits both. Carriers of the IL1A Ser hypomorph (reduced IL-1α) combined with variants that increase IL-1β production or reduce IL-1Ra levels may have net IL-1 pathway activity that differs substantially from either variant alone — the overall alarmin balance is shaped by all three loci together.

IL1A rs1800587 (–889 C/T): A second functionally characterised IL1A variant in the proximal promoter (rs1800587) modulates IL1A transcription. The two variants are independent (rs17561 is exonic, rs1800587 is promoter) and potentially additive in their effects on IL-1α output. rs1800587 was associated with Graves' disease risk in the Su et al. meta-analysis. Carriers of risk alleles at both loci would have additive reductions in IL-1α availability.

IL1A rs6542095: A third IL1A variant with GWAS-level evidence for moderate-to-severe endometriosis susceptibility. rs6542095 and rs17561 are in different positions on chromosome 2q13 and likely independent.