Genotype-based phenotyping heralds a new taxonomy for inflammatory bowel disease.
ABSTRACT Inflammatory bowel disease (IBD) has traditionally been categorized as either ulcerative colitis or Crohn disease on the basis of clinical, radiologic, and histologic criteria. Within these diseases, however, significant heterogeneity is observed, suggesting the existence of phenotypic subtypes, based on features such as location and behavior of disease. Evidence for a possible genetic basis of these subgroups first emerged in the 1990s from epidemiologic studies in multiply affected families. Recent advances in our understanding of the genetics of IBD, in particular the identification of NOD2/CARD15, have provided the opportunity to explore the genetic basis for this heterogeneity. This article reviews recent studies investigating the contribution of genetics to IBD phenotype. Although many of the genes remain unidentified, the emerging data suggests that IBD comprises a heterogeneous family of oligogenic inflammatory disorders in which the specific clinical manifestations of disease in any individual are determined by the interaction of genetic and environmental factors. These data have validated the approach of classifying patients into accurately defined clinical subgroups, and they raise the possibility that a genetic basis for the observed disease heterogeneity may account for the discrepant findings from earlier genetic studies. A future molecular classification will provide the framework to understanding the different biologic mechanisms that underlie the clinical subgroups of IBD and, by patient stratification, permit the unraveling of the complex interaction between the genetic and environmental causes of disease.
Zeitschrift für Gastroenterologie 03/2007; 45(3):265-272. DOI:10.1055/s-2006-927283 · 1.67 Impact Factor
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ABSTRACT: Background and Aim: The diagnostic and therapeutic relevance of CARD15 genotyping in Crohn's disease (CD) for daily clinical practice has not been investigated so far. We therefore analyzed whether CARD15 variants are independent predictive factors for small bowel stenosis in CD evaluated by magnetic resonance enteroclysis (MRE). On the basis of these findings, the potential implications for patient management were investigated. Methods: Eighty CD patients with clinical symptoms suggestive of small bowel stenosis were included. All patients were genotyped for the CARD15 variants c.2104C > T (p.R702W), c.2722G > C (p.G908R), and c.3019_3020insC (p.Leu1007fsX1008) and examined by MRE of the small bowel. Results:CARD15 variants were found in 40 (50%) patients. MRE identified 31 (38%) patients with small bowel stenoses. Twenty-five of the 40 (62%) patients with at least one CARD15 variant were diagnosed of intestinal stenosis by MRE (odds ratio [OR] = 9.44; confidence interval [CI] 3.21–27.77; P = 0.00028, Bonferroni corrected). Particularly, the presence of the 1007fs variant was associated with an increased risk of an intestinal stenosis (OR = 12.00, CI 3.47–41.54, P = 0.00042, Bonferroni corrected). Twenty-one of 31 (68%) patients with stenoses required surgical intervention, with 13 of these 21 (62%) patients carrying the 1007fs variant. Conclusion: In the largest prospective study analyzing the diagnostic value of CARD15 variants in CD patients performed so far, we identified the 1007fs variant as strong predictor for intestinal stenoses with need for surgery in CD patients. Genotyping could therefore be an important diagnostic tool in clinical practice for identifying high-risk patients with specific diagnostic and therapeutic needs. Moreover, MRE is an excellent technique for diagnosing small bowel stenoses.Inflammatory Bowel Diseases 11/2006; 12(12):1114 - 1121. DOI:10.1097/01.mib.0000235836.32176.5e · 5.48 Impact Factor