rs2301436 — FGFR1OP

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 variant rs3093024, in strong LD with rs2301436, has been identified as a regulatory CCR6 variant affecting gene expression in immune cells.

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 and 7,532 controls; 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. The same locus was independently captured in McGovern et al. 2010⁵⁵ McGovern et al. 2010
2,693 UC cases and 6,791 controls; genome-wide significant for ulcerative colitis susceptibility, demonstrating that the autoimmune signal spans both major forms of IBD.

For rheumatoid arthritis, Stahl et al. 2010⁶⁶ Stahl et al. 2010
Meta-analysis of 5,539 RA cases and 20,169 controls; 7 new loci at genome-wide significance identified the CCR6 locus — overlapping with rs2301436 — among new RA susceptibility loci, establishing this region as a broad autoimmune risk locus not confined to IBD. A Korean Crohn's disease GWAS ⁷⁷ 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.

At the cellular level, a study of hematopoietic stem cell transplantation ⁸⁸ Broen et al. 2011; 180 matched-related transplant recipients found that CCR6 genotype at rs2301436 was associated with complications of immune reconstitution: donors homozygous for one allele showed markedly less chronic graft-versus- host disease, while the alternative homozygous genotype was associated with higher invasive fungal disease risk (OR 3.59, p=0.008) — a direct demonstration that this variant modulates clinically meaningful immune responses in vivo.

Practical Implications

Carrying the T allele at rs2301436 increases gut immune surveillance activity in ways that elevate Crohn's disease and IBD risk. The effect 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.