Recent Insights Into the Genetics of Inflammatory Bowel Disease
Section snippets
Genetic Epidemiology
Population-based studies have provided compelling evidence that genetic factors contribute to the pathogenesis of inflammatory bowel disease (IBD); they demonstrated an 8- to 10-fold greater risk of IBD among relatives of ulcerative colitis (UC) and Crohn's disease (CD) probands1; that Ashkenazi Jews have an increased risk for IBD2; and, most importantly, that there is concordance between twins. Overall, rates of concordance between twins are more modest for CD (30.3% in monozygotic vs 3.6% in
Gene Mapping Approaches
Of the numerous candidate gene studies tested before linkage and genome-wide association studies (GWAS) were performed, only major histocompatibility complex class II alleles were consistently associated with IBD.11 Linkage mapping studies identified segments of human chromosomes shared among affected relatives, greater than expected by chance, and described the IBD1 CD locus on chromosome 16 in 1996, where the NOD2 gene was later identified. GWAS began in 2005, with a modest-sized Japanese
Genes That Affect Microbe Recognition by the Innate Immune System—NOD2
The most common mutations in NOD2 that are associated with CD (Arg702Trp [rs2066844], Gly908Arg [rs2066845], and Leu1007fsinsC [rs41450053]) lie either within or near the C-terminal, leucine-rich repeat domain, which is required for microbial sensing.16, 17 NOD2 is expressed by many leukocytes, including antigen presenting cells, macrophages, and lymphocytes, as well as ileal Paneth cells, fibroblasts, and epithelial cells. Activation of NOD2 by microbial ligands activates the transcription
Genes That Regulate Autophagy
Autophagy degrades damaged organelles and proteins, in homeostasis and as a response to starvation, and is important for the clearance of pathogens (xenophagy), which is required for immunity to multiple different types of bacteria. Autophagy 16-like 1 (ATG16L1) has been strongly associated with CD and encodes a protein component of the autophagy complex.27 ATG16L1 is broadly expressed, including in small intestinal Paneth cells28 where it mediates exocytosis of secretory granules that contain
Lymphocyte Activation, Survival, and Growth
HLA class II genes have been significantly associated with UC. HLA genes are frequently associated with chronic inflammatory genetic disorders, probably because of the enormous genetic and functional diversity contained within this region and its role in regulating interactions between host cells and pathogens. A comprehensive meta-analysis of HLA candidate gene studies reported that DRB1*0103 (odds ratio = 4.6) and DRB1*1502 (odds ratio = 3.3) conferred the greatest risk for UC, whereas
IL-23
After variants in NOD2, the variant most significantly associated with CD encodes the amino acid change Arg381Gln in the IL-23 receptor (IL23R). Glutamine 381, present in approximately 14% of healthy individuals of European ancestry, reduces risk for CD by nearly 3-fold and for UC by slightly less, compared with Arg381 carriers. Other uncommon alleles that reduce risk have been reported recently.44 Several more common polymorphisms in IL23R have independent contributions to IBD risk. IL23R is a
Comparing CD and UC Associations Identified by GWAS
The approximately 100 genomic loci that have been significantly associated with IBD contain candidate genes whose products mediate a variety of cell functions, including microbial recognition, lymphocyte activation, cytokine signaling, metabolism (FUT2, fucosytransferase),52 endoplasmic reticulum stress responses (eg, X box binding protein−1),53 physicochemical defense (eg, MUC1 and MUC19, mucins), and epithelial barrier function.33 Interestingly, a nonsense polymorphism in FUT2 that determines
Associations Across Chronic Inflammatory Diseases
The overlap between CD- and UC-associated genetic loci reflects the significant epidemiologic and clinical overlap. Extraintestinal manifestations of IBD include primary sclerosing cholangitis (PSC), uveitis, and ankylosing spondylitis, with frequencies of at most 2.4%, 4.5%, and 4.1%, respectively, based on data from a population-based study of IBD.66 Colitis is diagnosed in approximately 50% of patients with PSC, based on clinical evidence, and >80% on histopathology findings; it might be a
Future Directions—Uncommon Alleles, Population Differences, and Family Studies
The contributions of genetic factors to IBD are complex. Despite the success of GWAS in identifying significantly associated loci, they are estimated to account for <25% of predicted heritability.15 GWAS find common, human genetic variants associated with disease, but it is possible that uncommon polymorphisms also contribute to IBD; these may be identified through whole-genome sequencing approaches. Thus far, with the exception of the region of IRGM,35 large copy-number polymorphisms have not
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Conflicts of interest The authors disclose no conflicts.
Funding We gratefully acknowledge the following: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) U01 DK062429; U01 DK062422; RC1 DK086800; National Center for Research Resources: KL2RR024138, CCFA; R01 GM059507; David Wermuth; Bohmfalk Medical Foundation; PSC Partners for a Cure; 2P30 DK034989; U19 A1082713 (J.H.C.). NIDDK R01 DK83553; U01 DK062431; The W. Buford and Linda M. Lewis family, the Atran Foundation, and the Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center (S.R.B.).