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      Las mutaciones del gen CARD15 presentan escasa relación con los fenotipos de la enfermedad de Crohn en Asturias Translated title: CARD15 mutations are poorly related to Crohn´s disease phenotypes in Asturias

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          Abstract

          Introducción: la asociación entre las mutaciones del gen CARD15 y la susceptibilidad genética para la enfermedad de Crohn (EC) se ha confirmado en diversos estudios, con amplias variaciones observadas a nivel mundial, tanto geográficas como étnicas. Objetivos: analizar la prevalencia de gen CARD 15 y sus polimorfismos en pacientes con EC en Asturias y su posible correlación con los diversos fenotipos de la enfermedad. Métodos: estudiamos la frecuencia de las tres mutaciones del gen CARD15 (R702W, G908R, L1007fs) usando cebadores específicos, en un total de 216 pacientes con EC y 86 controles procedentes del área de Oviedo. Los pacientes fueron clasificados de acuerdo con la edad al diagnóstico, localización la enfermedad y su comportamiento clínico (clasificación de Viena). Resultados: la frecuencia global de portadores de las mutaciones del gen CARD15 en los pacientes con EC fue del 17,3% frente a un 17,6% en controles (NS). Al analizar separadamente los polimorfismos R702, G908R y L1007fs los pacientes mostraban frecuencias del 8,8, 3 y 6% respectivamente, mientras que los controles las presentaban en el 11,6, 2,3 y 3,5%, sin encontrar diferencias significativas para ninguna de ellas (NS). Las frecuencias observadas en controles, fueron similares a las encontradas en otras regiones españolas. Conclusiones: la prevalencia de mutaciones en CARD15 en pacientes con EC en Asturias es menor a la reportada en otros trabajos publicados en población española. Otros factores ambientales, además de los genéticos, parecen tener mayor importancia en el desarrollo de EC en nuestra área.

          Translated abstract

          Background: the association between the three common CARD15 gene mutations (R702W, G908R, L1007fs) and the genetic susceptibility to Crohn's disease (CD) have been confirmed by several studies, with some differences found, in relation to geographic areas and ethnic groups. Objectives: To analyze the prevalence of CARD15 gen and its polymorphisms in patients with CD in Asturias and its possible correlation with the different genotypes of the disease. Methods: a total of 216 CD patients recruited from Asturias (North of Spain) and 86 ethnically matched healthy controls, were typed using Hybprobes on a LightCycler instrument for CARD15 mutations. Patients were subdivided according to Vienna classification. We have studied the frequency of these mutations in the different subgroups of CD patients and analyzed its contribution to the disease clinical characteristics and progression. Results: carrier frequencies for CARD15 mutations in our CD patients were similar to controls (17.8 vs. 17.4%) respectively (NS). CD patients exhibited frequencies of 8.8, 3.0 and 6.0% for the R702, G908R and L1007fs polymorphisms respectively, whereas our control population had allele frequencies of 11.6, 2.3 and 3.5% for the three mutations respectively (NS). We did not find any relationship between CARD15 mutations and the different phenotypes of Crohn's disease, according to Vienna classification. Conclusions: in our CD population, other factors (i.e. environmental), in addition to genetics, must be mainly involved in the development of the disease.

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          Most cited references 86

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          Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

           S Almer,  S Lesage,  J Hugot (2001)
          Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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            A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.

            Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.
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              Inflammatory bowel disease: cause and immunobiology.

              Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel disorders. In this paper, we discuss how environmental factors (eg, geography, cigarette smoking, sanitation and hygiene), infectious microbes, ethnic origin, genetic susceptibility, and a dysregulated immune system can result in mucosal inflammation. After describing the symbiotic interaction of the commensal microbiota with the host, oral tolerance, epithelial barrier function, antigen recognition, and immunoregulation by the innate and adaptive immune system, we examine the initiating and perpetuating events of mucosal inflammation. We pay special attention to pattern-recognition receptors, such as toll-like receptors and nucleotide-binding-oligomerisation-domains (NOD), NOD-like receptors and their mutual interaction on epithelial cells and antigen-presenting cells. We also discuss the important role of dendritic cells in directing tolerance and immunity by modulation of subpopulations of effector T cells, regulatory T cells, Th17 cells, natural killer T cells, natural killer cells, and monocyte-macrophages in mucosal inflammation. Implications for novel therapies, which are discussed in detail in the second paper in this Series, are covered briefly.
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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                diges
                Revista Española de Enfermedades Digestivas
                Rev. esp. enferm. dig.
                Sociedad Española de Patología Digestiva (Madrid, Madrid, Spain )
                1130-0108
                October 2007
                : 99
                : 10
                : 570-575
                Affiliations
                Oviedo orgnameHospital Universitario Central de Asturias orgdiv1Servicio de Inmunología
                orgnameHospital Clínico Universitario de Valladolid y Grupo de Estudio de Inmunología de las Mucosas orgdiv1Departamentos de Pediatría e Inmunología
                orgnameHospital Universitario Central de Asturias orgdiv1Servicio de Aparato Digestivo
                orgnameHospital Clínico Universitario de Santiago de Compostela orgdiv1Servicio de Aparato Digestivo
                orgnameHospital Clínico Universitario de Valladolid y Grupo de Estudio de Inmunología de las Mucosas orgdiv1Unidad de Investigación
                Article
                S1130-01082007001000002
                10.4321/s1130-01082007001000002

                This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 International License.

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                Product Information: SciELO Spain

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