RESUMEN
Crohn disease and ulcerative colitis are two subphenotypes of inflammatory bowel disease (IBD), a complex disorder resulting from gene-environment interaction. We refined our previously defined linkage region for IBD on chromosome 10q23 and used positional cloning to identify genetic variants in DLG5 associated with IBD. DLG5 encodes a scaffolding protein involved in the maintenance of epithelial integrity. We identified two distinct haplotypes with a replicable distortion in transmission (P = 0.000023 and P = 0.004 for association with IBD, P = 0.00012 and P = 0.04 for association with Crohn disease). One of the risk-associated DLG5 haplotypes is distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism 113G-->A, resulting in the amino acid substitution R30Q in the DUF622 domain of DLG5. This mutation probably impedes scaffolding of DLG5. We stratified the study sample according to the presence of risk-associated CARD15 variants to study potential gene-gene interaction. We found a significant difference in association of the 113A DLG5 variant with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This is suggestive of a complex pattern of gene-gene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. Further functional studies will evaluate the biological significance of DLG5 variants.
Asunto(s)
Cromosomas Humanos Par 10/genética , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Variación Genética , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana/genética , Proteínas Supresoras de Tumor/genética , Alelos , Sustitución de Aminoácidos , Proteínas Portadoras/genética , Estudios de Casos y Controles , Niño , Mapeo Cromosómico , Clonación Molecular , Estudios de Cohortes , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/epidemiología , Europa (Continente)/epidemiología , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Proteína Adaptadora de Señalización NOD2 , Linaje , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Single nucleotide polymorphisms (SNPs) in the human genome are thought to be organised into blocks of high internal linkage disequilibrium (LD), separated by intermittent recombination hotspots. Since understanding haplotype structure is critical for an accurate assessment of inter-individual genetic differences, we investigated up to 968 SNPs from a 10-Mb region on chromosome 6p21, including the human major histocompatibility complex (MHC), in five different population samples (45-550 individuals). Regions of well-defined block structure were found to coexist alongside large areas lacking any clear structure; occasional long-range LD was observed in all five samples. The four white populations analysed were remarkably similar in terms of the extend and spatial distribution of local LD. In US African Americans, the distribution of LD was similar to that in the white populations but the observed haplotype diversity was higher. The existence of large regions without any clear block structure renders the systematic and thorough construction of SNP haplotype maps a crucial prerequisite for disease-association studies.