Which genes are most strongly associated with risk of ileal Crohn's disease?

Genetic Risk Factors for Ileal Crohn's Disease

NOD2 (also known as CARD15) is the most strongly associated gene with ileal Crohn's disease, particularly the 1007fs frameshift mutation, which predicts ileal location, stricturing disease, and need for surgical intervention. 1, 2

Primary Genetic Association

NOD2/CARD15 represents the first and most replicated genetic risk factor specifically for ileal Crohn's disease 1, 2:

• The 1007fs (3020insC) frameshift mutation shows the strongest association with ileal disease location across multiple populations 3, 4, 5
• Patients homozygous for 1007fs develop early-onset disease with long-segment ileal stenoses, entero-enteral fistulas, and require surgery in 73.7% of cases with high re-stenosis rates (78.6%) 4
• Two additional NOD2 variants (R702W and G908R) also associate with ileal disease, though less consistently across populations 3, 5, 6

Mechanistic Basis

NOD2 functions as an intracellular pattern recognition receptor that:

• Recognizes muramyl dipeptide from both Gram-positive and Gram-negative bacteria 1
• Induces proinflammatory cytokines and stimulates defensin production specifically in the ileum 1
• Shows highest expression in Paneth cells of the terminal ileum, explaining the anatomic specificity 1
• Mice deficient in Nod2 demonstrate significantly higher Bacteroides and Firmicutes in the terminal ileum compared to wild-type littermates 1

Genotype-Phenotype Correlations

Carrying NOD2 variants predicts specific disease characteristics 3, 4, 5:

• Ileal involvement: 90% of NOD2 carriers versus 73% of non-carriers have ileal disease (p<0.05) 3
• Stricturing/penetrating phenotype: 88% of carriers versus 56% of non-carriers develop complicated disease (p<0.01) 3
• Increased surgical need: NOD2 carriers require bowel surgery more frequently than non-carriers 3
• Fibrostenotic disease: Presence of two CARD15 variants associates with fibrostenotic phenotype (OR 5.47,95% CI 1.61-18.58) 4

Additional Genetic Loci

While NOD2 remains the strongest single-gene association, over 60 genes have been linked to Crohn's disease overall 2:

• Other innate immunity genes mentioned in the context of ileal disease include genes involved in NOD-like receptor signaling and Toll-like receptor pathways 1
• Candidate genes from transcriptome-wide association studies in Crohn's disease include SLC22A4, SLC22A5, IRF1, CARD9, and STAT3, though these show tissue-specific expression patterns 1

Important Clinical Caveats

Population variation significantly affects NOD2 allele frequencies 5, 6:

• NOD2 variants explain only 20% of genetic susceptibility to Crohn's disease overall 5
• Remarkable heterogeneity exists across ethnicities—Finnish populations show lower frequencies (8.7% in CD patients) compared to Central European populations 3, 6
• In non-Caucasian populations, Crohn's disease incidence increases without NOD2 variation, indicating other genetic factors predominate 5
• Swedish studies found R702W and G908R associated with CD, but not 1007fs, demonstrating regional variation even within Scandinavia 6

Novel mutations continue to be identified 7:

• Five novel pathogenic CARD15 mutations (R38M, W355X, P727L, W907R, R1019X) were identified in Finnish patients, all presenting with complicated ileal or ileocolonic disease 7
• This suggests population-specific founder mutations may exist in genetically isolated populations 7

Practical Application

Routine genetic screening for NOD2 is not currently recommended for clinical management 5:

• Genotyping does not predict response to anti-TNF therapy 5
• The primary clinical utility remains identifying severely affected patients who may require individualized treatment strategies early in disease course 4
• Homozygosity or compound heterozygosity for CARD15 mutations should raise suspicion for complicated disease requiring aggressive management 7