Homozygosity for theCARD15frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis

Abstract

Patients homozygous for the 1007fs mutation had an early disease onset with long-segment ileal stenoses and entero-enteral fistulas. They frequently needed surgical intervention and had a high risk of re-stenosis. Genotyping therefore appears to be an important diagnostic tool in identifying severely affected patients requiring individualized treatment strategies at an early stage of the disease.

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].…”

The +1059G/C polymorphism in the C‐reactive protein (CRP) gene is associated with involvement of the terminal ileum and decreased serum CRP levels in patients with Crohn's disease

“…However, in univariate analysis, there was no significant association of this mutation with ileal disease location. Similar genotype frequencies were observed for the 1007fs CARD15 variant, for which we demonstrated ileal involvement, 28 in wildtype (17.8%) and heterozygous carriers (23.5%; P ¼ 0.522), thereby confirming that the observed association between the +1059 G/C polymorphism and ileal disease location is independent of the CARD15 1007fs variant. However, the overall prevalence of CARD15 variants was significantly higher in +1059G/C CRP heterozygous carriers (76.5%) compared with G/G wildtype carriers (39.7%, P ¼ 0.0043).…”

“…[28][29][30][31][32] We recently demonstrated an increased frequency of intestinal stenoses especially in the terminal ileum in homozygous carriers of the CARD15 variant L1007fsinsC (3020insC). 28 Therefore, we determined in all CD patients, whether the three common CD-associated CARD15 variants R702W, G908R, L1007fsinsC were present or not. The combined prevalence for these three variants in the CD cohort was 42.7%.…”