Inflammatory Bowel Disease: A Genomic Picture Predicts a Changing Response From the Laboratory–Part II

Abstract

IBD-1 Linkage Analysis Hugot and colleagues1 described the first genome screen for CD in 1996. The investigators initially screened 2 consecutive and independent panels of families comprising 40 affected sibling pairs using 270 markers throughout the genome. An analysis of allele sharing by affected sibling pairs showed that only 4 markers achieved statistical significance. Using data obtained from a second set of affected families localized the susceptibility locus to a pericentric region of chromosome 16. The initial work by Hugot was greeted with concern and mild skepticism. Prior to this time, susceptibility loci for other complex diseases had rarely been replicated. Examples of unimpressive attempts to duplicate these sorts of findings can be found in multiple sclerosis, affective disorders, and type II diabetes. At the same time, success had been achieved with high penetrance Mendelian syndromes, most notably the breast cancer-1 gene (BRCA1) which had been discovered using a similar linkage analysis process. The contrasting levels of success diverge according to inheritance patterns. Mendelian inheritance offers hope for finding susceptibility loci, while non-Mendelian (ie, complex) diseases usually failed critical reanalysis. Refinements in the localization of IBD1 proceeded immediately. By employing a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping and construction of bacterial artificial chromosomes, Hugot and colleagues identified 3 independent single nucleotide polymorphisms (SNPs) associated with CD.2 A frameshift polymorphism and 2 missense variants of NOD2 were found within the LRR domain encoded by the gene. Genotyping of patients with UC did not show an association with these SNPs. This observation agrees with earlier data showing the lack of linkage between UC and the IBD1 susceptibility locus.3 A connection to immune dysregulation is readily apparent. NOD2 belongs to the Apaf-1/Ced-4 superfamily After decades of stagnation, molecular discoveries have altered our view of inflammatory bowel disease (IBD). This recent change in our understanding of the IBD’s pathogenesis combined with emerging biologic therapeutics will benefit the laboratory, the clinician, and the patient. science [chemistry | molecular diagnostics] Inflammatory Bowel Disease: A Genomic Picture Predicts a Changing Response From the Laboratory–Part II