TY - JOUR
T1 - CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease
AU - EPWG-IBD group
AU - EPIMAD group
AU - GETAID group
AU - Lesage, Suzanne
AU - Zouali, Habib
AU - Cézard, Jean Pierre
AU - Colombel, Jean Frédéric
AU - Belaiche, Jacques
AU - Almer, Sven
AU - Tysk, Curt
AU - OéMorain, Colm
AU - Gassull, Miquel
AU - Binder, Vibeke
AU - Finkel, Yigael
AU - Modigliani, Robert
AU - Gower-Rousseau, Corinne
AU - Macry, Jeanne
AU - Merlin, Françoise
AU - Chamaillard, Mathias
AU - Jannot, Anne Sophie
AU - Thomas, Gilles
AU - Hugot, Jean Pierre
N1 - Funding Information:
We are grateful to the patients and their families for their participation in this study. Drs. J. Balanzo, B. Bonaz, Y. Bouhnik, G. Cadiot, A. Cortot, S. Cucchiara, B. Crusius, J. J. Delchier, B. Duclos, J. L. Dupas, J. P. Galmiche, J. P. Gendre, D. Golfain, C. Grännö, D. Heresbach, A. Lachaux, H. Lautraite, C. Lenaerts, E. Lerebours, V. Levy, R. Löfberg, H. Malchow, P. Marteau, A. Morali, F. Pallone, S. Pena, A. Rotenberg, I. Rousseau, J. Schmitz, F. Shanahan, I. Sobhani, H. Svensson, A. Van Gossum, M. Van Winckel, and M. Veyrac, as well as gastroenterologists from Nord, Pas de Calais, Somme, and Seine Maritime, generously assisted in the recruitment of families for the study. We are grateful to Dr. C. Bellanné-Chantelot, J. C. Beaudoin, C. Billon, O. Bluteau, T. H. Bui, L. Cazes, C. Guidicelli, P. Legoix, M. Legrand, C. Massart, C. Merlin, P. Pasturaud, S. Martin-Blanc, A. Martins, J. M. Sebaoun, C. de Toma, M. Sahbatou, C. Vaury, and Dr. J. Zucman for their expert technical assistance. We thank Dr. L. Pascoe for critically reading the manuscript. This project received support from the following organizations: the European Union (BIOMED BMH4-97-2098), the Ministère de l'Enseignement National de la Recherche et de la Technologie, the Institut National de la Santé et de la Recherche Médicale, the Direction Générale de la Santé, Association François Aupetit, the Institut de Recherche sur les Maladies de l'Appareil Digestif, and the Swedish Society of Medicine.
PY - 2002
Y1 - 2002
N2 - CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P =. 01), a more frequent stricturing phenotype (53% vs. 28%; P =. 00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P =. 003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.
AB - CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P =. 01), a more frequent stricturing phenotype (53% vs. 28%; P =. 00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P =. 003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.
UR - https://www.scopus.com/pages/publications/0036201577
U2 - 10.1086/339432
DO - 10.1086/339432
M3 - Article
C2 - 11875755
AN - SCOPUS:0036201577
SN - 0002-9297
VL - 70
SP - 845
EP - 857
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -