A 28-year-old man presents with a 6-month history of chronic diarrhea, crampy right lower quadrant abdominal pain, and a 4 kg weight loss. Ileocolonoscopy with biopsies reveals the pathological pattern marked **A** in the diagram — discontinuous patches of inflammation separated by normal mucosa, with deep linear ulcers creating a cobblestone appearance and areas of luminal narrowing. Which of the following is the MOST important genetic risk factor and strongest predictor of disease susceptibility in this patient's condition?

Explanation

## Why NOD2/CARD15 mutations on chromosome 16 is right The clinical presentation and pathological findings marked **A** — skip lesions, cobblestone mucosa, and strictures — are diagnostic of Crohn disease. NOD2/CARD15 mutations on chromosome 16 are the STRONGEST and MOST IMPORTANT genetic risk factor for Crohn disease, increasing disease risk 2–4 fold in heterozygotes and 20–40 fold in homozygotes. This mutation impairs the innate immune recognition of bacterial lipopolysaccharides, leading to dysregulated mucosal immunity and transmural inflammation. The anchor fact directly states this is the strongest genetic predictor (Robbins Basic Pathology 11th Edition; ACG Crohn Disease Guidelines). ## Why each distractor is wrong - **HLA-B27 positivity**: While HLA-B27 is associated with extra-intestinal manifestations of inflammatory bowel disease (ankylosing spondylitis, sacroiliitis), it is NOT the primary genetic risk factor for Crohn disease susceptibility itself. It predicts complications, not disease onset. - **TPMT polymorphisms**: TPMT variants are relevant to PHARMACOGENETICS — they determine individual tolerance and metabolism of azathioprine and 6-mercaptopurine (maintenance immunomodulators used in Crohn disease management). They do NOT predict disease susceptibility. - **IL-23 receptor variants**: While IL-23 signaling is involved in Th17-mediated mucosal immunity and IL-23 antagonists (ustekinumab) are used therapeutically, IL-23 receptor variants are NOT the strongest genetic risk factor. NOD2/CARD15 remains the most robust and well-established predictor of Crohn disease susceptibility. **High-Yield:** NOD2/CARD15 mutations on chromosome 16 are the STRONGEST genetic risk factor for Crohn disease (20–40 fold risk increase in homozygotes); TPMT variants predict drug metabolism, not disease risk. [cite: Robbins Basic Pathology 11th Edition; ACG Crohn Disease Guidelines]