The Genetic Basis of Inflammatory Bowel Disease

Abstract

Twin studies and large-scale population studies have confirmed an increased sibling risk for both Crohn’s disease (CD) and ulcerative colitis (UC). Unlike single gene disorders, CD and UC are thought to result from a complex interplay of multiple genes and environmental factors. The confirmation of CARD15/NOD2 as a CD susceptibility gene in the late 1990s caused much excitement in the field of complex diseases in general and since then, the rapid rate of progress in molecular genetics, with the advent of large-scale affordable genotyping techniques, has resulted in large collaborations and the identification of over 30 inflammatory bowel disease (IBD)-associated genes. In particular, the importance of the innate immune system has been reaffirmed with the identification of IRGM and ATG16L1 genes in the autophagy pathway as CD susceptibility genes. Disturbance in the adaptive immune system, in particular the IL-23/Th17 axis, has also shown to be of importance for IBD overall. In this era of genome-wide association studies it may be possible to, at last, identify the multiple genes involved in IBD and thus improve our understanding of the genotype-phenotype correlation and improve treatment.

Crohn’s disease as an immunodeficiency

“…There has been a wealth of research to elucidate, in particular, the contributions of NOD2 and ATG16L1 to innate immune function [121], and recent research has elegantly demonstrated the potential for their interdependence [122,123]. However, mice deficient in either gene do not develop spontaneous enterocolitis [124][125][126][127].…”

“…It may be that improved or augmented genetic screening tools will be able to detect risk alleles of lower frequency than those currently described [116], and further study of epistasis (gene-gene interactions [139,140]) may be key to understanding the pathogenesis of complex phenotypes. There is potentially a wealth of knowledge contained within the known IBD loci [121], and fine mapping of the genes within these regions will identify novel genetic influences. Pharmacogenomics may play an increasing role, and has been introduced by advances in the understanding of thiopurine metabolism [141].…”

“…The relative frequencies of these polymorphisms in the general population, however, mean that for every CD patient homozygous or compound heterozygous for a NOD2 polymorphism, there would be approximately 20 individuals with the same genotype who do not develop disease. Despite conferring an odds ratio of 1.32 on disease risk, the influence of ATG16L1 disease-associated polymorphisms would be weaker still, particularly considering the similar frequencies in CD and control populations [119,120].There has been a wealth of research to elucidate, in particular, the contributions of NOD2 and ATG16L1 to innate immune function [121], and recent research has elegantly demonstrated the potential for their interdependence [122,123]. However, mice deficient in either gene do not develop spontaneous enterocolitis [124][125][126][127].…”

A Retrospective Study in 21 Shiba Dogs with Chronic Enteropathy

“…Based on response to treatment, chronic enteropathy can be classified into 3 main groups: food-responsive diarrhea (FRD), antibiotic-responsive diarrhea (ARD) and inflammatory bowel disease (IBD) [1,12,13,15]. Although the pathogenesis of the disease has not been completely clarified yet, some reports in human medicine and laboratory animals have demonstrated underlying genetic factors related to the disease [5]. In veterinary medicine, some breeds are known to be predisposed to specific types of chronic enteropathy, such as protein-losing enteropathy and nephropathy in the Soft Coated Wheaten Terrier [18], immunoproliferative enteropathy in the Basenji [3] and chronic enteropathy and ARD in the German Shepherd [2,11].…”

CARD15 Gene 3020insC Mutation with Inflammatory Bowel Diseases Patients in the Black Sea Region of Turkey

“…The incidence of these diseases is higher in developed countries such as USA, Japan and East European countries and it has increased about twofold in these countries from 1970s to date [13]. Although its etiology and pathogenesis have not been fully understood, result of epidemiological and genetic linkage studies have suggested that IBD is predisposed by certain genetic and environmental factors [14].…”