What is the role of genetic markers, such as NOD2/CARD15 variants, in diagnosing and managing Crohn's disease?

Genetic Markers in Crohn's Disease: Limited Role in Routine Clinical Practice

Genetic testing for NOD2/CARD15 variants should not be used for diagnosing Crohn's disease, as more than 250 IBD-associated genetic variants have been identified but do not allow diagnosis of IBD. 1

Diagnostic Role: Not Recommended

• No single reference standard exists for diagnosing Crohn's disease; diagnosis requires a combination of clinical, biochemical, endoscopic, cross-sectional imaging, and histological investigations 1, 2
• Although NOD2/CARD15 mutations on chromosome 16 are associated with small intestinal Crohn's disease in white populations (but not Asian populations), genetic testing for common variants does not allow diagnosis of IBD 1
• The diagnostic accuracy of genetic markers is insufficient for clinical use, as they explain only up to 20% of total genetic predisposition for Crohn's disease 3
• Ileocolonoscopy with biopsies from inflamed and uninflamed segments remains the gold standard for establishing diagnosis 1, 2

Prognostic Role: Emerging but Not Standard Practice

Disease Phenotype Associations

NOD2/CARD15 mutations are consistently associated with specific disease characteristics:

• Ileal disease location and younger age at diagnosis 4, 5, 6, 7
• Stricturing (fibrotic) phenotype rather than inflammatory or penetrating disease 7
• Small bowel involvement, particularly terminal ileum 1, 3

Surgical Risk Prediction

The strongest clinical correlation involves surgical outcomes:

• Patients with at least one NOD2/CARD15 mutation have 1.96 times higher risk of requiring surgical treatment 4
• Carriers of G908R or 1007fs mutations require surgery more frequently, particularly for ileal resection and fistula repair 5, 6
• Patients with two or more mutations have more aggressive disease course, earlier surgery, and higher reoperation rates 4, 6, 7
• The L1007fs variant specifically increases risk for surgical intervention 7

Current Clinical Applications

Pharmacogenomics: The Primary Use

• Genetic testing in routine IBD practice is currently limited to pharmacogenomics, specifically thiopurine methyltransferase (TPMT) polymorphisms before azathioprine therapy 1, 3
• TPMT screening identifies patients who will not tolerate standard azathioprine doses due to cytotoxic and immunosuppressive adverse effects 3
• Evidence for NOD2 variants predicting response to biologics or small molecules remains limited and inconclusive 3, 7
• NOD2 variants are associated with steroid refractoriness, though this has not translated into routine testing 7

Very Early Onset IBD: The Exception

Comprehensive genomic testing (gene panels or whole exome sequencing) should be considered in very early onset inflammatory bowel disease (onset by age 6 years), patients with family history suggesting Mendelian inheritance, or severe refractory disease 1

• The goal is to identify monogenic disorders mimicking IBD that require different therapeutic approaches 1
• This testing complements immunophenotyping and can lead to more effective individualized therapies in severely ill young children 1

Key Clinical Pitfalls

• Do not use NOD2/CARD15 testing to establish or exclude a diagnosis of Crohn's disease—the sensitivity and specificity are inadequate 1
• The frequency of NOD2/CARD15 mutations does not allow their use to predict disease course in individual patients 5
• Genetic associations identified in white populations may not apply to Asian or other ethnic populations 1
• In 5-15% of IBD cases, even comprehensive endoscopic and histological evaluation cannot distinguish Crohn's disease from ulcerative colitis, requiring classification as IBD-unclassified 2

Future Directions

• Studies confirming effectiveness of therapies designed for genetic subgroups will expand the role of genomic testing 1
• If further trials support initial evidence, NOD2 variants may emerge as candidates for precision medicine in Crohn's disease, particularly for surgical risk stratification 7
• Current research focuses on integrating genetic data with epigenome, microbiome, and metabolomics factors 1