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Betegségjelentés · Gastrointestinal

Crohn's Disease

Whole genome sequencing reveals the full landscape of genetic susceptibility to inflammatory bowel disease, identifying NOD2 and IL23R variants that predict disease severity and therapeutic response.

A betegségjelentés olyan ritka variánsokat keres, amelyekről ismert, hogy okozzák az általa lefedett betegségeket.

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A(z) condition ismertetése

A chronic inflammatory bowel disease that can affect any part of the digestive tract, causing symptoms like abdominal pain, severe diarrhea, fatigue, and weight loss.

Inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis is characterized by chronic intestinal inflammation leading to abdominal pain, diarrhea, blood in stool, weight loss, and potential complications including strictures, fistulas, and colorectal cancer. Prevalence of Crohn's disease is approximately 1 in 1,000 in developed countries, with higher incidence in younger patients (peak onset 15-35 years). Genetic contribution is substantial: heritability is estimated at 50-80%, and the field has identified more than 200 GWAS loci associated with IBD. The first Crohn's disease susceptibility gene identified was NOD2/CARD15 in 2001, a landmark discovery that opened the field to understanding innate immune dysfunction in CD. NOD2 encodes an intracellular pattern recognition receptor that detects bacterial muramyl dipeptide (MDP), triggering NF-κB signaling and inflammatory response. Three common NOD2 variants (R702W, G908R, 1007fs) account for approximately 15-20% of population attributable risk in European ancestry CD patients.

Homozygous or compound heterozygous NOD2 variants confer approximately 20-40-fold increased Crohn's disease risk compared to non-carriers. NOD2 loss-of-function variants impair MDP sensing and reduce inflammatory responses to bacteria, paradoxically increasing disease risk through failure of appropriate bacterial containment and dysbiotic expansion of pathogenic flora. This counterintuitive mechanism (why would reduced immune response cause inflammation?) is now understood in the context of dysbiosis and barrier dysfunction. IL23R encodes interleukin-23 receptor, involved in Th17 lineage differentiation; the protective variant rs11209026 (R381Q) actually reduces Th17 polarization, suggesting IL-23/Th17 axis hyperactivation drives IBD. This discovery led directly to therapeutic development: IL-23 pathway inhibitors (ustekinumab, risankizumab, guselkumab) are now approved for CD and UC, producing dramatic clinical responses in subgroups of patients.

NOD2 genotyping provides prognostic insight into disease course: homozygous NOD2 carriers typically develop earlier-onset disease, more extensive colonic involvement, and higher rates of complications including strictures and fistulas. IL23R protective variant carriers predict better response to IL-23 inhibitors, suggesting that future pharmacogenomic prediction could guide therapy selection. Genetic understanding of IBD has principally driven drug development rather than altering individual patient management; the landmark discovery that IL23R variants were protective led directly to ustekinumab, risankizumab, and guselkumab, now approved therapies that benefit the broader IBD population. Understanding the genetic basis of IBD is shifting clinical perspective from viewing it as primarily a gastrointestinal disorder to recognizing its deep immunological underpinnings.

A vizsgált betegség

A gastrointestinal disorder characterized by chronic inflammation involving all layers of the intestinal wall, noncaseating granulomas affecting the intestinal wall and regional lymph nodes, and transmural fibrosis. Crohn disease most commonly involves the terminal ileum; the colon is the second most common site of involvement.

Mit változtat a diagnózis

TNF-α inhibitors (biologics), IL-23 inhibitors, immunosuppressants, mesalamine, dietary modification, surgery (resection for complications)

Más néven

Crohn's disease of large bowel; paediatric Crohn's disease; pediatric Crohn's disease; regional enteritis

11 kapcsolódó altípust tartalmaz ↓
  • Crohn disease of the esophagus
  • Crohn ileitis
  • Crohn jejunitis
  • Crohn jejunoileitis
  • Crohn's colitis
  • gastroduodenal Crohn disease
  • ileocolitis
  • oral Crohn disease
  • pediatric Crohn disease
  • perianal Crohn disease
  • small bowel Crohn disease
MONDO:0005011Orphanet 206MedGen 3664

Miért a teljes genom szekvenálás

Genetic testing is not standard for IBD diagnosis, howevr WGS captures all 200+ loci relevant to comprehensive genetic risk profiling and disease course estimation.

IBD involves 200+ genetic loci, each with small individual effect

Genetic contribution to IBD is distributed across more than 200 GWAS loci, each with small individual effect sizes. Standard genetic panels do not test for this polygenic architecture. NOD2 genotyping is sometimes performed for prognostic assessment but is not routine in IBD diagnosis, which relies on endoscopy, histology, and radiography. Genetic testing does not replace clinical diagnosis. However, whole genome sequencing provides the comprehensive GWAS variant data necessary for future polygenic risk score calculation, enabling individualized genetic risk assessment that may eventually guide therapy intensity, predict disease severity, and inform family screening.

NOD2 variants predict disease course and therapeutic opportunity

NOD2 genotyping identifies high-risk patients destined for early-onset, extensive disease with complications. These patients benefit from more aggressive upfront therapy and closer surveillance for stricture and fistula formation. IL23R genetic variants identify patients likely to respond to IL-23 inhibitors; ustekinumab, risankizumab, and guselkumab are now approved for CD and produce dramatic responses in genetically susceptible subgroups. A comprehensive genetic assessment through WGS establishes a baseline for future clinical utility: as polygenic risk models mature and are clinically validated, patients with genetic data on file can benefit from new therapeutic recommendations based on their individual genetic profile.

További gastrointestinal conditions

Minden feltétel →

Egy teszt. Egy életen át tartó válaszok.

Egy csomag, házhoz szállítva. Az egész genomját a diagnosztikai döntésekhez használt klinikai színvonalon szekvenáljuk. Orvos számára is használható jelentéseit 6–8 héten belül küldjük el a Genome Manager-be. Ezek tartósan érvényesek, és a tudomány fejlődésével frissülnek.

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