Altin G Jymishka, Sarah C Glover and Roxana M Coman*
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Received date: September 26, 2013; Accepted date: September 28, 2013; Published date: September 30, 2013
Citation: Jymishka AG, Glover SC, Coman RM (2013) IBD Associated Genetic Polymorphisms: Novel Insights into the Pathogenic Mechanisms. J Vaccines Vaccin 4:e121. doi: 10.4172/2157-7560.1000e121
Copyright: © 2013 Jymishka AG, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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There is a dramatic increase in the prevalence of inflammatory bowel disease (IBD), particularly in the western world . The etiology of IBD, which comprises two distinct entities Crohn’s disease (CD) and ulcerative colitis (UC), remains unknown. CD is a chronic, discontinuous, transmural inflammation of the bowel, but that can affect any part of gastrointestinal tract whereas, UC represents an intestinal inflammation limited to the colonic mucosa .
IBD pathogenesis it is thought to rely on genetic risk factors, environmental triggers (e.g., diet, gut microbiota) and immune response. Population based studies have shown familial aggregation of IBD with greater risk among first-degree relatives. Also, higher monozygotic concordance observed in CD relative to UC is indicative of a larger contribution of the genetic component in CD pathogenesis .
As a result of the genome wide association studies (GWAS) and meta–analyses performed, the number of identified common genetic polymorphism that are associated with IBD has continuously increased. These IBD associated genetic risk loci have implicated previously unknown pathogenic pathways. The most recent study on IBD genetics by Jostins et al. reported 163 IBD risk loci, many of which were found to be shared with host response pathways to mycobacterial infection and other immune mediated disorders such as ankylosing spondilitis, psoriasis and type 1 diabetes .
Specific mutations of the NOD2/CARD15 gene, which was the first CD susceptibility gene identified, have been associated with ileal disease and a decrease in alpha-defensins’ production [5,6]. NOD2/CARD15 is a cytoplasmic protein with a role in detection of intracellular bacterial peptidoglycan. NOD2/CARD15 gene mutations that predispose to ileal involvement in CD can lead to a dysfunction in antimicrobial activity of Paneth cells which are critical to the innate mucosal defense.
Whereas, SNPs of autophagy genes such as ATG16L1 and IRGM have been identified by GWAS to be associated with CD [7,8]. Autophagy is the process of degradation of intracellular components by lysosomes, and plays an important role in nutrient deprivation and infection (i.e., degradation of intracellular pathogens). As CD pathogenesis appears to rely heavily on the immune response to microbiota, a disruption in autophagic killing of intracellular bacteria (important for gut homeostasis), caused by mutations of ATG16L1 and IRGM genes, and consequent changes in gut microbiota can lead to the development of CD.
On the other hand, UC is specifically associated with the polymorphisms of genes such as ECM1, CDH1, HNF4a and LAMB1, which are involved in the regulation of gut epithelial barrier, indicating that mechanisms that enhance the permeability of the gut mucosa causing a “leaky gut” are important in UC pathogenesis .
Similarly, GWAS results of IBD patient cohorts reported by Kaser et al., showed that common SNPs located in the region of XBP1 gene, are associated with both forms of IBD (CD and UC) . XBP1 encodes for an important transcription factor (TF) in the endoplasmic reticulum (ER) stress response, otherwise known as unfolded protein response (UPR). The XBP1 protein, encoded by the unconventionally spliced XBP1 mRNA, is a potent transcription factor that mediates transcription of ER stress target genes such as those involved in protein folding and ER associated degradation (ERAD). In addition, Kaser et al. after performing deep resequencing of the XBP1 gene region, identified rare or private SNPs present only in IBD patients (and not in controls), and showed that two of these rare variants were hypomorphic.
Concomitant with the increased availability of new sequencing technologies (e.g., next generation sequencing, NGS) the deep resequencing of regions found by GWAS to be associated with the disease can be performed to identify low-frequency SNPs that are more likely to represent functional variants . The modern sequencing technologies combined with the decrease in sequencing costs is now making possible sequencing of whole genomes, exomes or transcriptomes. In addition, reference databases for human DNA variants, such as those provided by the 1000 Genomes Project, are now shaping a new era for human genetics to better understand how genotype influences phenotype . This progress in sequencing technologies will translate in discoveries that will open new avenues for the investigation of the pathogenesis of complex diseases such as IBD.
Department of Medicine, University of Florida and Gatorade fund; NIH grant RO1 CA113975-A2