Predictive value of the CARD15 variant 1007fs for the diagnosis of intestinal stenoses and the need for surgery in Crohn's disease – results of a prospective study

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 9 T (p.R702W), c.2722G 9 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] 3.21Y27.77; 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 3.47Y41.54, 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.

NOD2 gene mutations in ulcerative colitis: useless or misunderstood?

“…Similar findings were reported in CD, where NOD2 carrier status has been associated not only with a more aggressive disease phenotype but also to an increased likelihood of steroid refractoriness and a higher need for surgery [5,9,10,[38][39][40][41][42][43][44][45][46][47][48][49].…”

“…In the past two decades, genetic variants identified as being [54,59] b No response to intravenous steroids and required salvage therapy with cyclosporine, infliximab, or colectomy c No response to cyclosporine and/or infliximab and required salvage colectomy associated with increased susceptibility to IBD were then subject to research in order to investigate whether they are also correlated with the disease phenotype. NOD2, the first gene linked with increased susceptibility to CD, has later been shown to be associated with ileal disease, early age of onset, stricturing, and/or penetrating phenotype and increased need for surgery [5,9,10,[38][39][40][41][42][43][44][45][46][47][48][49]. Among the UC susceptibility genes, HLA DRB1*0103 and the multidrug resistance gene 1 (MDR1/ABCB1) were also identified as being associated with extensive and severe disease [17,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”

“…Among the UC susceptibility genes, HLA DRB1*0103 and the multidrug resistance gene 1 (MDR1/ABCB1) also contribute to clinical phenotype and natural history, being associated with extensive and severe disease [17,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. In CD, NOD2 gene mutations have repeatedly been shown to be associated with ileal disease, early age of onset, stricturing, and/or penetrating phenotype and increased need for surgery [5,9,10,[38][39][40][41][42][43][44][45][46][47][48][49]. Surprisingly, there are no studies focusing on potential genotype-phenotype associations between NOD2 mutations and UC, perhaps because it is not commonly considered a susceptibility gene for UC [5,10,50].…”

CEACAM6 gene variants in inflammatory bowel disease

“…Therefore, one might speculate whether the role of CEACAM6 in ileal bacterial colonization is regulated via SOX9 expression implicating defective Paneth cell function in patients with small bowel CD. Given the association of defensin secretion with the NOD2 genotype [43] and the findings of numerous previous studies including studies from our IBD center demonstrating ileal disease localization in CD patients with NOD2 mutations [37,46,47], we also tested for potential gene-gene interaction of CEACAM6 and NOD2. However, we found no evidence for epistasis between these two genes regarding CD susceptibility.…”

Crohn’s Disease: a Role of Gut Microbiota and Nod2 Gene Polymorphisms in Disease Pathogenesis

“…They frequently need a surgical intervention and have a high risk of restenosis. This mutation is also associated with gastroduodenal involvement (26)(27)(28). In addition to CD, three missense mutations (R334W, R334QQ an L469F) in the nucleotide-binding domain of Nod2 confer susceptibility to another granulomatous disorder affecting the eyes, skin, and joints known as Blau syndrome (29) and early onset sarcoidosis (30).…”