rs2301436 — FGFR1OP

Intronic variant in FGFR1OP (CEP43) at the RNASET2-FGFR1OP-CCR6 autoimmune susceptibility locus, with the T allele increasing risk for Crohn's disease

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FGFR1OP rs2301436 — A Gate in the Crohn's Disease Susceptibility Locus

Chromosome 6q27 hosts one of the most consistently replicated autoimmune susceptibility loci in the human genome. The region — spanning RNASET2, FGFR1OP (also called CEP43), and CCR6 — has been independently confirmed in genome-wide association studies for Crohn's disease11 Crohn's disease
A form of inflammatory bowel disease causing transmural inflammation anywhere in the gastrointestinal tract, ulcerative colitis, rheumatoid arthritis, vitiligo, and autoimmune thyroid disease. The rs2301436 variant sits within an intron of FGFR1OP and is one of the anchor SNPs that tags the autoimmune risk signal at this locus. Because the locus spans three genes, the precise causal variant and primary effector gene have not been fully resolved, but functional evidence points strongly to nearby CCR6 as the biological driver.

The Mechanism

FGFR1OP (fibroblast growth factor receptor 1 oncogene partner; gene symbol CEP43) encodes a centrosomal scaffolding protein involved in microtubule anchoring and ciliogenesis. It is the fusion partner in 8p11 myeloproliferative syndrome, where a t(6;8) chromosomal translocation creates a CEP43-FGFR1 oncogene. However, rs2301436 is an intronic variant with MODIFIER-level predicted functional impact — its disease relevance almost certainly derives from linkage disequilibrium22 linkage disequilibrium
Correlated inheritance of nearby variants due to limited recombination between them; an intronic FGFR1OP SNP can tag regulatory variants in neighboring CCR6 because both are inherited together in the same chromosomal block with functionally important variants in the adjacent CCR6 gene.

CCR6 (C-C chemokine receptor 6, CD196) is expressed on immature dendritic cells and memory T cells, where it governs migration in response to its ligand CCL20/MIP-3α. In the intestine, the CCL20-CCR6 axis controls dendritic cell homing to Peyer's patches33 Peyer's patches
Organized lymphoid follicles in the small intestine where immune surveillance of luminal contents occurs and regulates the balance between tolerogenic and inflammatory responses to gut bacteria. Dysregulation of this axis is a mechanistically plausible driver of both Crohn's disease and rheumatoid arthritis, two conditions where T-cell trafficking and mucosal immunity are central to pathogenesis.

The Evidence

The strongest GWAS evidence for rs2301436 comes from two IBD studies. Barrett et al. 2008 in Nature Genetics44 Barrett et al. 2008 in Nature Genetics
3,230 CD cases and 4,829 controls; replication in 3,664 cases; European populations mapped the RNASET2-FGFR1OP-CCR6 locus as one of more than 30 distinct Crohn's disease susceptibility loci, with rs2301436-T carrying an odds ratio of approximately 1.21 (p=1×10⁻¹²) — a robust, replicated association that has withstood numerous follow-up studies. A Korean Crohn's disease GWAS 55 Yang et al. Gut 2014; 1,001 Korean CD cases and 4,304 controls further replicated the RNASET2-FGFR1OP-CCR6 signal in a non-European population, supporting its status as a cross-ancestry IBD susceptibility locus.

Practical Implications

The effect of the T allele at rs2301436 is additive — each T allele copy contributes independently to risk. Practically, T allele carriers benefit most from being alert to early IBD symptoms (prolonged diarrhea, abdominal cramping, blood in stool, unintended weight loss, perianal symptoms), pursuing prompt investigation rather than watchful waiting, and understanding that smoking is a particularly potent environmental trigger in people with genetic Crohn's susceptibility. Dietary choices that support the mucosal barrier and reduce luminal antigenic load may also be relevant, though specific dietary prescriptions for this genotype remain an area of active research.

Interactions

The strongest documented interaction at this locus involves other CCR6- pathway variants. rs3093024, a CCR6 promoter-region regulatory variant in LD with rs2301436, was identified in Kochi et al. 2010 (PMID 20453841) as the primary rheumatoid arthritis signal at this locus, with rs2301436 serving as a secondary tag. Carriers of the T allele at rs2301436 who also carry risk alleles in IBD-associated genes such as NOD2 (rs2066844, rs2066845, rs2066847), IL23R (rs11209026), or ATG16L1 (rs2241880) may experience compounding susceptibility to Crohn's disease, consistent with the polygenic architecture of IBD risk.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

No FGFR1OP/CCR6 locus risk allele; baseline Crohn's disease and autoimmune susceptibility

You carry two copies of the C allele at rs2301436, meaning you do not carry the T risk allele at the RNASET2-FGFR1OP-CCR6 susceptibility locus. Your genetic contribution from this variant to Crohn's disease risk sits at the population baseline. Approximately 29% of people globally share this CC genotype; it is more common in South Asian populations (~45%) and less common among Europeans (~28%).

CT One Risk Allele Intermediate

One copy of the T risk allele; moderately elevated Crohn's disease and IBD susceptibility

The additive architecture of this locus means that CT carriers sit between CC (baseline) and TT (highest risk) in terms of Crohn's disease susceptibility. The per-allele OR of ~1.21 from large European IBD GWAS is modest individually, but it combines additively with risk alleles in other IBD-associated genes (NOD2, IL23R, ATG16L1) in the polygenic landscape of IBD risk.

TT Two Risk Alleles High Risk

Two copies of the T risk allele; elevated Crohn's disease and autoimmune IBD susceptibility

The CCR6 axis controls dendritic cell and memory T cell trafficking to intestinal Peyer's patches; dysregulation can shift mucosal immunity toward an inflammatory phenotype, increasing susceptibility to Crohn's-type transmural inflammation. Korean replication data from Yang et al. 2014 confirmed this locus is not population-specific — the signal holds across European and East Asian IBD cohorts, suggesting a conserved immune mechanism.