What is the gene associated with Crohn's disease in a young adult with a possible family history of inflammatory bowel disease?

Genes Associated with Crohn's Disease

NOD2 (also known as CARD15) is the most important and well-established gene associated with Crohn's disease, particularly in young adults with family history of inflammatory bowel disease. 1, 2

Primary Genetic Associations

NOD2/CARD15 Gene

• NOD2 is the first and most significant susceptibility gene identified for Crohn's disease, with variants (particularly the L1007fs variant) increasing disease risk and influencing clinical phenotype 1, 3, 2, 4
• NOD2 variants are associated with ileal disease location and stricturing (fibrotic) phenotype, which carries higher risk for surgical intervention 2
• Patients with NOD2 variants demonstrate increased steroid refractoriness and higher likelihood of requiring surgery, especially those carrying the L1007fs variant 2
• NOD2 functions in innate immunity and bacterial wall sensing, highlighting the role of microbial recognition in disease pathogenesis 3, 4

ATG16L1 Gene

• The T300A variant (rs2241880, G allele) in ATG16L1 confers strong risk for Crohn's disease and is the second most consistently replicated genetic association 5, 6
• This variant represents a threonine-to-alanine substitution at amino acid position 300, affecting the autophagy pathway 5
• ATG16L1 variants emphasize the critical role of autophagy in Crohn's disease pathogenesis 3, 5

IL23R Gene

• IL23R variants are among the most widely replicated genetic associations with Crohn's disease 3, 6
• This gene highlights the importance of TH-17 immune cell differentiation in inflammatory bowel disease pathophysiology 3

Additional Confirmed Genetic Loci

At least 163 genetic loci have been identified in association with inflammatory bowel disease, with over 60 genes specifically linked to Crohn's disease 1

Key additional genes include:

• IRGM - involved in autophagy mechanisms 3
• TNFSF15 - related to inflammatory pathways 3
• PTGER4 region - prostaglandin signaling 3
• PTPN2 and PTPN22 - immune regulation 3
• NKX2-3 - transcription factor 3

Clinical Applications of Genetic Testing

When to Consider Genetic Testing

Comprehensive genomic testing (gene panel or whole exome sequencing) should be pursued in three specific clinical scenarios 1:

1. Very early onset inflammatory bowel disease (VEOIBD) - defined as IBD onset by age 6 years, where monogenic disorders may masquerade as typical IBD and require different therapeutic approaches 1

2. Severe, refractory disease - children and adults with IBD unresponsive to conventional therapies, where identifying specific genetic causes may guide targeted treatment 1

3. Strong family history suggesting Mendelian inheritance - families with multiple affected members where single-gene disorders are more likely 1

Limitations of Genetic Risk Prediction

Despite identifying numerous susceptibility genes, most risk alleles are very frequent in healthy populations and provide limited predictive value for individual risk stratification 1

• Common polymorphisms identified through genome-wide association studies explain only a fraction of the heritable risk for Crohn's disease 1
• Single alleles or even allele combinations have failed to facilitate clear risk prediction in clinical practice 1
• The major alleles sometimes confer susceptibility, making interpretation complex 1

Current Clinical Utility

The main clinical use of genetic testing in routine IBD practice remains limited to pharmacogenomics (such as thiopurine methyltransferase testing before thiopurine use) and potentially predicting disease behavior 1

NOD2 variants may emerge as candidates for precision medicine if ongoing trials confirm their role in predicting treatment response to biologics and small molecules 2

Familial Risk Assessment

First-degree relatives of patients with ulcerative colitis have a 4-fold increased risk (incidence rate ratio 4.08), while second-degree relatives have 85% increased risk and third-degree relatives have 51% increased risk 7

Family history of colorectal cancer in a first-degree relative diagnosed before age 50 years confers a 9.2-fold increased risk of developing IBD-associated colorectal cancer 1

Key Clinical Pitfalls

• Do not rely on genetic testing for routine risk stratification in typical adult-onset Crohn's disease, as the predictive value remains insufficient for clinical decision-making 1
• Negative gene panel testing does not exclude genetic contribution to disease; consider whole exome sequencing in appropriate clinical contexts 1
• Genetic testing requires multidisciplinary expertise beyond typical gastroenterology practice and should be coordinated through specialized inflammatory bowel disease centers 1