rs9807989 — IL18R1

IL18R1 Upstream Variant — The IL-18 Receptor Expression Dial on Chromosome 2q12

The chromosome 2q12 region is one of the most densely connected immune susceptibility loci in the human genome. Packed into a span of less than 300 kilobases are several interleukin-1 receptor family members — IL1RL1 (encoding the IL-33 receptor ST2), IL18R1, and IL18RAP — all of which form a tightly co-regulated signaling hub that links innate immune sensing to Th1 and type-2 inflammatory cascades. rs9807989 sits approximately 1 kilobase upstream of the IL18R1 transcription start site, in a position to influence how much IL-18 receptor is available on immune cell surfaces.

The Mechanism

IL-18¹¹ IL-18
Interleukin-18; an inflammasome-activated cytokine that drives IFN-γ production from T helper 1 cells, NK cells, and NKT cells — a key bridge between innate detection and adaptive Th1 amplification binds a two-chain receptor complex composed of IL-18R1 (the ligand-binding α chain) and IL18RAP (the signal-transducing β chain). When IL-18 binds this complex, it activates NF-κB and MAPK pathways, driving IFN-γ secretion and amplifying macrophage and NK cell activity. The upstream position of rs9807989 places it in the gene's regulatory region, where T/C variation in transcription factor binding sites can affect IL18R1 transcript levels — altering how efficiently immune cells respond when IL-18 is released from activated inflammasomes.

The locus is in partial linkage disequilibrium with the adjacent rs2287037 promoter SNP and the IL18RAP variant rs917997, both of which have been shown to have large cis-effects on receptor expression. Trynka et al. (J Immunology, 2014)²² Trynka et al. (J Immunology, 2014)
IL18RAP region disease polymorphism decreases IL-18RAP/IL-18R1/IL-1R1 surface expression and downstream signaling capacity demonstrated that risk alleles in this region reduce receptor surface availability on monocyte-derived macrophages, impairing MAPK, NF-κB, and calcium-flux responses to both IL-18 and NOD2 stimulation. The haplotype structure of this locus means rs9807989 acts as a tag for cumulative regulatory variation across IL18R1 and its flanking partners.

The Evidence

The most direct evidence for rs9807989 comes from a 2025 case-control study of chronic obstructive pulmonary disease. Ren et al. (Annals of Medicine, 2025)³³ Ren et al. (Annals of Medicine, 2025)
Identification of genetic variants of the IL18R1 gene in association with COPD susceptibility genotyped rs9807989 in 996 subjects (498 COPD cases, 498 healthy controls). The C allele showed strongly protective association against COPD in all tested models — allele (OR 0.42, p<0.001), dominant (OR 0.39, p<0.001), and recessive (OR 0.20, p=0.014). Haplotype analysis placed rs9807989 in Block 1 with the promoter SNP rs2287037; the T(rs9807989)/T(rs2287037) haplotype was associated with increased COPD risk (OR 2.32, p<0.001), confirming additive effects within the LD block.

The broader 2q12 locus is one of the most replicated signals in inflammatory disease genetics. Parkes et al. (Am J Hum Genet, 2008)⁴⁴ Parkes et al. (Am J Hum Genet, 2008)
Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies susceptibility loci harboring IL18RAP demonstrated that variants in the IL1RL1-IL18R1-IL18RAP cluster reach genome-wide significance for both Crohn's disease and ulcerative colitis combined (OR 1.35, p=1.9×10⁻⁸) in 1,851 IBD patients and 1,936 controls. Festen et al. (PLoS Genetics, 2011)⁵⁵ Festen et al. (PLoS Genetics, 2011)
Meta-analysis of GWAS identifies IL18RAP as shared risk locus for Crohn's disease and celiac disease extended these findings, showing shared 2q12 genetic risk across two distinct autoimmune diseases, with the IL18RAP signal reaching p=8.37×10⁻⁸ in combined analysis.

Functionally, the risk alleles at this locus — including the T allele at rs9807989 — are associated with dysregulated IFN-γ responses. Myhr et al. (J Autoimmunity, 2013)⁶⁶ Myhr et al. (J Autoimmunity, 2013)
The autoimmune disease-associated SNP rs917997 of IL18RAP controls IFN-γ production by PBMC showed that cells carrying the susceptibility genotype produce significantly more IFN-γ after IL-12 and IL-18 stimulation (P=0.0296), along with reduced IL-18RAP and IL-18R1 surface protein expression on NK cells — a pattern consistent with compensatory upregulation of remaining receptor complexes or autocrine amplification loops.

Practical Actions

The T risk allele at rs9807989 operates through heightened inflammatory signaling at the IL-18 receptor axis. Relevant actions focus on monitoring biomarkers of IL-18-driven inflammation and managing modifiable factors that activate inflammasomes — the cellular machinery that cleaves IL-18 into its active form.

Interactions

rs9807989 is in linkage disequilibrium with the IL18R1 promoter SNP rs2287037 (same Block 1 haplotype). The adjacent locus tags rs3771166 (IL18R1 intron, GABRIEL asthma GWAS lead) and rs1420101 (IL1RL1 intron, IL-33 pathway sST2 eQTL) represent partially independent signals within the same chromosomal region. Individuals carrying risk alleles at multiple 2q12 nodes accumulate additive susceptibility across the IL-33 and IL-18 receptor arms simultaneously. The IL18RAP variant rs917997 (in LD with the region) is the most studied functional variant at this locus and the primary GWAS signal for IBD and celiac disease association.