Inflammatory Bowel Disease (Crohn Disease) 1

A number sign (#) is used with this entry because of evidence that mutations in the NOD2/CARD15 gene (605956) are associated with susceptibility to Crohn disease in families linked to chromosome 16. A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to Crohn disease-associated growth failure.

For information on genetic heterogeneity of IBD, see MAPPING and MOLECULAR GENETICS sections.

Inflammatory bowel disease is characterized by a chronic relapsing intestinal inflammation. IBD is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease and ulcerative colitis have a combined prevalence of 200 to 300 per 100,000 in the United States. Crohn disease may involve any part of the gastrointestinal tract, but most frequently the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. In approximately 10% of cases confined to the rectum and colon, definitive classification of Crohn disease or ulcerative colitis cannot be made and are designated 'indeterminate colitis.' Both diseases include extraintestinal inflammation of the skin, eyes, or joints.

Crohn disease and ulcerative colitis are commonly classified as autoimmune diseases. The prevalence of inflammatory bowel disease is increased in individuals with other autoimmune diseases, particularly ankylosing spondylitis, psoriasis, sclerosing cholangitis, and multiple sclerosis. There is strong evidence from twin studies, familial risk data, and segregation analysis that inflammatory bowel disease, especially Crohn disease, is genetic (Yang and Rotter, 1994; Duerr, 1996). Crohn disease and ulcerative colitis are considered complex genetic traits as inheritance does not follow any simple mendelian models. Both genetic and environmental factors seem to be important in its etiology.

Monsen et al. (1989) performed segregation analysis in 124 families with ulcerative colitis in 2 or more members. They concluded that a rare additive major gene causes the disease, with about 20% affected among those heterozygous for the gene. They found no evidence for multifactorial inheritance. They raised the possibility that the major gene may be associated with a separate type of ulcerative colitis with more extensive involvement, younger age of onset, and more immunologic side effects such as extraintestinal manifestation.

Prevalence in first-degree relatives has been estimated to be between 4 and 16% (Lewkonia and McConnell, 1976; Farmer et al., 1980). Orholm et al. (1991) found that first-degree relatives of patients with either ulcerative colitis or Crohn disease had a 10-fold increase in the risk of having the same disease as the patients. The risk of having the other of the 2 diseases was also increased, but less so, and the increase in the risk of having Crohn disease was not significant in the relatives of patients with ulcerative colitis. Yang et al. (1993) found evidence of higher frequency of inflammatory bowel disease among first-degree relatives of Jewish patients than among the relatives of non-Jewish patients. The first-degree relatives of Jewish patients had a lifetime risk for inflammatory bowel disease of 7.8% and 4.5% when probands had Crohn disease and ulcerative colitis, respectively. The values for first-degree relatives of non-Jewish probands were 5.2% and 1.6%.

Satsangi et al. (1996) studied the clinical characteristics (disease type, extent, age of onset, need for surgery, and presence of extraintestinal manifestations) in affected subjects in multiply-affected families with inflammatory bowel disease. They identified 54 families in which 1 parent and at least 1 child were affected (a total of 77 parent-child pairs) and 155 families in which 2 sibs were affected (a total of 190 affected sib pairs). In affected parent-child pairs, parent and child were concordant for 'disease type' (Crohn disease or ulcerative colitis) in 58 of 77 pairs (75.3%), for extent in 63.6%, for extraintestinal manifestations in 70.1%, and for smoking history in 85%. The median age of onset in parents was significantly higher than in offspring (p = less than 0.0001). In 40 pairs (60.6%) the parent was at least 10 years older than the child at age of onset. Sibs were concordant for disease type in 81.6% of the affected sib pairs, extent in 76.0%, extraintestinal manifestations in 83.8%, and smoking history in 81.3%. In contrast with the parent-child pairs, 68.1% of sibs (111 sib pairs) were diagnosed within 10 years of each other. Median age of onset was 24.0 years. Satsangi et al. (1996) felt that the differences in age of onset between parents and children was not readily explained by a simple cohort effect or ascertainment bias, and may it reflect effects of genetic factors, producing anticipation between generations.

Crohn Disease

About 10% of persons with regional enteritis have 1 or more close relatives with granulomatous disease of the bowel. In 5 persons of Ashkenazi Jewish origin (ancestors from area of Russia-Poland around Vilna), Sheehan et al. (1967) found red cell glucose-6-phosphate dehydrogenase deficiency associated with regional enteritis or granulomatous colitis. The affected persons were 2 males and 3 females. Regional enteritis and sarcoidosis have been observed in the same family (see 181000); Gronhagen-Riska et al. (1983) commented on the association. Schwartz et al. (1980) found no HLA association in sporadic cases or in familial cases. However, in 5 affected sib pairs, 4 shared both haplotypes (i.e., were HLA-identical) and the 5th shared one haplotype. Only 1 unaffected sib shared both haplotypes with an affected sib. Kuster et al. (1989) suggested that a recessive gene with incomplete penetrance is responsible for susceptibility to Crohn disease. McConnell (1988) suggested polygenic inheritance; an individual inheriting few susceptibility genes would develop ulcerative colitis, while someone inheriting a larger number of these genes would develop regional enteritis.

Although controversial, epidemiologic evidence (Greenstein et al., 1988) suggests that there may be 2 distinct clinical forms of Crohn disease: perforating and nonperforating. Patients with perforating Crohn disease have abscesses and/or free perforations. Perforating Crohn disease is the more aggressive form with a higher reoperation rate. By contrast, nonperforating Crohn disease has a more indolent clinical course and is associated with obstruction and bleeding as the main features. Gilberts et al. (1994) reasoned that the host immune response may determine which clinical presentation the disease assumes. Leprosy is an incontrovertible example of 2 clinical forms of disease, tuberculous and lepromatous, with the same etiologic factor. Resected intestinal tissue from control patients, as well as perforating and nonperforating Crohn disease patients, was evaluated for mRNA levels of a housekeeping gene (beta-actin; 102630), a human T-cell marker, CD3-delta (186790), and 6 cytokines. Differences were observed with interleukin-1-beta (IL1B; 147720) and with interleukin-1 receptor alpha (IL1RA; 147810). Nonperforating Crohn disease, the more benign form, was associated with increased IL1B and IL1RA mRNA expression.

Cattan et al. (2000) studied the incidence of IBD in non-Ashkenazi Jewish patients with familial Mediterranean fever (FMF; 249100). The association was 8 to 14 times greater than expected. The prevalence of IBD in non-Ashkenazi Jews is 120 per 100,000, whereas Cattan et al. (2000) estimated a prevalence of at least 3 per 300 (or 3 per 173 if the calculation is done through probands) in non-Ashkenazi Jews with FMF. They postulated that the inflammatory processes of FMF and IBD are additive, resulting in increased severity of disease in the new patients.

Lawrance et al. (2001) examined global gene expression profiles of inflamed colonic tissue using DNA microarrays. They identified several genes with altered expression not previously linked to IBD. In addition to the expected upregulation of various cytokine and chemokine genes, novel immune function-related genes such as IGHG3 (147120), IGLL2, and CD74 (142790), inflammation-related lipocalins HNL and NGAL (600181), and proliferation-related GRO genes (see, e.g., 139110) were overexpressed in ulcerative colitis. Certain cancer-related genes such as DD96, DRAL (602633), and MXI1 (600020) were differentially expressed only in ulcerative colitis. Other genes overexpressed in both ulcerative colitis and Crohn disease included the REG gene family (see 167770) and the calcium-binding S100 protein genes S100A9 (123886) and S100P (600614). The natural antimicrobial defensin DEFA5 (600472) and DEFA6 (600471) genes were particularly overexpressed in Crohn disease. Overall, significant differences in the expression profiles of 170 genes identified ulcerative colitis and Crohn disease as distinct molecular entities.

By yeast 2-hybrid analysis and reciprocal immunoprecipitations, Barnich et al. (2005) found that NOD2 interacts directly with GRIM19 (NDUFA13; 609435). The authors also found that expression of GRIM19 was significantly reduced in affected mucosa from Crohn disease and ulcerative colitis patients, whereas uninvolved patient mucosa showed GRIM19 mRNA expression comparable with that in control patients.

By microarray analysis, Moehle et al. (2006) found coordinated downregulation of mucins, including MUC1 (158340), MUC2 (158370), MUC4 (158372), MUC5AC (158373), MUC5B (600770), MUC12 (604609), MUC13 (612181), MUC17 (608424), and MUC20 (610360), in ileum and colon of Crohn disease and ulcerative colitis patients compared with controls. They identified NF-kappa-B (see 164011)-binding sites in all mucin promoters and showed that activation of the NF-kappa-B signaling pathway by inflammatory cytokines TNF-alpha (TNF; 191160) and TGF-beta (TGFB1; 190180) upregulated mRNA expression of all the mucin genes under study.

Baumgart and Carding (2007) reviewed the pathogenesis of Crohn disease and ulcerative colitis, including environmental factors and immunobiologic mechanisms.

Abraham and Cho (2009) reviewed normal function of the intestinal immune system and discussed mechanisms of disease in inflammatory bowel disease, including genetic associations with Crohn disease and ulcerative colitis.

Khor et al. (2011) gave an excellent review of the genetics and pathogenesis of inflammatory bowel disease.

Crohn Disease

Targan and Murphy (1995) reviewed briefly the current literature on both potential animal models for Crohn disease and human research on the mechanisms of its pathogenesis and molecular genetics. They stated that an updated hypothesis of Crohn disease pathogenicity 'holds that the foundation for its heterogeneity is at the primary genetic level, and expression of genetic susceptibility requires environmental triggers.'

Because of the parallel to the tuberculoid and lepromatous forms of leprosy, Mishina et al. (1996) investigated the possibility of a Mycobacterium, namely M. paratuberculosis, as a cause of Crohn disease. They used RT-PCR with M. paratuberculosis subspecies-specific primers on total RNA from 12 ileal mucosal specimens of which 8 were from patients with Crohn disease, 2 represented cases of ulcerative colitis, and 2 represented cases of colonic cancer. As a negative control, they used M. avium DNA, originally cultured from the drinking water of a major city in the United States. Their cDNA sequence analysis showed that all 8 cases of Crohn disease and both samples from the patients with ulcerative colitis contained M. paratuberculosis RNA. Additionally, the M. avium control had the DNA sequence of M. paratuberculosis. They then demonstrated the DNA sequence of M. paratuberculosis from mucosal specimens in humans with Crohn disease. They concluded that the potable water supply may be a reservoir of infection. They suggested that clinical trials with therapy directed against M. paratuberculosis is indicated in patients with Crohn disease.

Pizarro et al. (1999) detected increased IL18 (600953) mRNA and protein expression in intestinal epithelial cells and lamina propria mononuclear cells in Crohn disease tissue compared with ulcerative colitis and normal tissue.

By immunohistochemical analysis, Corbaz et al. (2002) showed that IL18-binding protein (IL18BP; 604113) expression in intestinal tissue is increased in endothelial cells as well as cells of the submucosa and overlying lymphoid aggregates in Crohn disease patients compared with controls. Immunofluorescent microscopy demonstrated colocalization with macrophage and endothelial cell markers, but not with those of lymphocytes or epithelial cells. Real-time PCR and ELISA analysis detected increased levels of both IL18 and IL18BP in the Crohn disease intestinal tissue. Unbound neutralizing isoforms a and c of IL18BP were in excess compared with IL18 in the Crohn disease patients, indicating that IL18BP upregulation correlates with increased IL18 expression in Crohn disease. Corbaz et al. (2002) suggested that despite the presence of IL18BP, which has been shown to ameliorate colitis in a mouse model (ten Hove et al., 2001), some IL18 activity may be available for perpetuating the pathogenesis of Crohn disease.

Lovato et al. (2003) found that intestinal T cells from Crohn disease patients, but not healthy volunteers, showed constitutive activation of STAT3 (102582) and STAT4 (600558). SOCS3 (604176), a STAT3-regulated protein, was also constitutively expressed in Crohn disease T cells. Lovato et al. (2003) concluded that there is abnormal STAT/SOCS signaling in Crohn disease.

Van Heel et al. (2005) analyzed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced strong IL8 (146930) secretion and substantially upregulated the secretion of TNF-alpha (191160) and IL1B (147720) induced by Toll-like receptor (see 601194) ligands. At low nanomolar MDP concentrations, these effects were abolished by the most common Crohn disease NOD2 double-mutant genotypes (702W (605956.0003)/1007fs (605956.0001), 702W/702W, 1007fs/1007fs, and 908R (605956.0002)/1007fs). Van Heel et al. (2005) suggested that NOD2 activation provides a priming signal to condition a broad early immune response to pathogens, and that the absence of this priming signal in NOD2-associated Crohn disease causes failure of early immune pathogen clearance and explains the abnormal adaptive immune responses to microbial antigens in Crohn disease patients.

In 15 patients with CD and 9 controls, Barnich et al. (2007) found that adherent-invasive E. coli (AIEC) adhesion was dependent on type 1 pili expression on the bacterial surface and on CEACAM6 (163980) expression on the apical surface of ileal epithelial cells. CEACAM6 acted as a receptor for AIEC adhesion and was upregulated in the ileal mucosa of CD patients compared to colonic mucosa or to controls. In vitro studies showed increased CEACAM6 expression in cultured intestinal epithelial cells after IFN-gamma (147570) or TNF-alpha (191160) stimulation and after infection with AIEC.

Adolph et al. (2013) showed that impairment of either the unfolded protein response (UPR) or autophagy function in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn disease-like transmural ileitis if both mechanisms are compromised. Xbp1 (194355)-deficient mouse intestinal epithelial cells showed autophagosome formation in hypomorphic Paneth cells, which is linked to endoplasmic reticulum (ER) stress via protein kinase RNA-like ER kinase (PERK; 604032), elongation initiation factor 2-alpha (eIF2-alpha; 609234), and activating transcription factor-4 (ATF4; 604064). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol-requiring enzyme 1-alpha (IRE1-alpha; 604033)-regulated NF-kappa-B (see 164011) activation, and TNF signaling, which are synergistically increased when autophagy is deficient. ATG16L1 (610767) restrains IRE1-alpha activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-kappa-B overactivation and intestinal epithelial cell death. ER stress, autophagy induction, and spontaneous ileitis emerge from Paneth cell-specific deletion of Xbp1. Adolph et al. (2013) concluded that genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn disease as a specific disorder of Paneth cells.

Yoneno et al. (2013) examined TGR5 (GPBAR1; 610147) expression in peripheral blood monocytes and in vitro-differentiated macrophages and dendritic cells. They found that macrophages differentiated with MCSF (CSF1; 120420) and IFNG, which are similar to intestinal lamina propria CD14 (158120)-positive macrophages that contribute to Crohn disease pathogenesis by producing proinflammatory cytokines (e.g., TNF), highly expressed TGR5 compared with other types of differentiated macrophages and dendritic cells. TNF production was inhibited in these cells by 2 types of bile acid, deoxycholic acid and lithocholic acid, as well as by a TGR5 agonist. The inhibitory effect was mediated through the TGR5-cAMP pathway to induce phosphorylation of FOS (164810), which regulates NFKB p65 (RELA; 164014) activation. Analysis of lamina propria mononuclear cells from Crohn disease patients and controls showed increased TGR5 expression in Crohn disease patients compared with controls. A TGR5 agonist inhibited TNF production by isolated intestinal CD14-positive differentiated macrophages from Crohn disease patients. Yoneno et al. (2013) proposed that control of TGR5 signaling may modulate immune responses in inflammatory bowel disease.

Ulcerative Colitis

A role for PLA2G2A (172411) in the pathogenesis of ulcerative colitis was postulated by Haapamaki et al. (1997), who demonstrated expression of the PLA2G2A gene in metaplastic Paneth cells and columnar epithelial cells in inflamed colonic mucosa from patients with ulcerative colitis. No expression was detected in other tissues from the same patients or, by Northern blot analysis, in colonic biopsies from disease-free controls. Haapamaki et al. (1997) hypothesized that intraluminal secretion of PLA2G2A during the active phase of ulcerative colitis is a host defense mechanism.

Hofseth et al. (2003) studied the relationship between the chronic inflammation of ulcerative colitis and the development of colon cancer. They examined tissues from noncancerous colons of ulcerative colitis patients to determine the activity of 2 base excision repair enzymes, 3-methyladenine DNA glycosylase (AAG; 156565) and apurinic/apyrimidinic endonuclease (APE1; 107748), and the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in ulcerative colitis colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. The results were consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with ulcerative colitis.

Fuss et al. (2004) examined lamina propria T cells from patients with ulcerative colitis and found that they produced significantly greater amounts of IL13 (147683) and IL5 (147850) than control or Crohn disease cells and little IFN-gamma (147570). The authors stimulated ulcerative colitis lamina propria T cells bearing the NK marker CD161 with anti-CD2 (186990)/anti-CD28 (186760) or with B cells expressing transfected CD1d (188410) and observed substantial IL13 production. Fuss et al. (2004) noted that these ulcerative colitis NKT cells did not express the invariant cell receptors characteristic of most NKT cells. The authors demonstrated that human NKT cell lines and the ulcerative colitis CD161+ lamina propria cells were cytotoxic for HT-29 epithelial cells and that this cytotoxicity was augmented by IL13. Fuss et al. (2004) concluded that ulcerative colitis is associated with an atypical Th2 response mediated by nonclassic NKT cells that produce IL13 and have cytotoxic potential for epithelial cells.

Pang et al. (2007) investigated the expression of IL12B (161561), IFNG (147570), and the activational state of STAT4 (600558) signaling in mucosal tissues at the site of disease in 30 Chinese patients with active ulcerative colitis compared with 30 healthy controls. They found increased mRNA expression of IL12B, but not IFNG, in the UC patients, and Western blot analysis demonstrated increased levels of STAT4 in the cytoplasm and phosphorylated STAT4 in the nucleus of mucosal cells from UC patients. The authors concluded that a heightened, perhaps persistent, activational state of IL12/STAT4 and/or IL23/STAT4 signaling may be present in active Chinese UC patients and may be involved in the chronic inflammation of UC.

Crohn Disease

Miller et al. (2003) and Ghosh et al. (2003) reported clinical trials of natalizumab, a recombinant anticlonal antibody against alpha-4-integrins (192975), for the treatment of multiple sclerosis (126200) and Crohn disease, respectively. Miller et al. (2003) reported that a group of patients with multiple sclerosis who received monthly injections of natalizumab had significantly fewer new inflammatory central nervous system lesions than the placebo group (a reduction of approximately 90%) and had approximately half as many clinical relapses. Ghosh et al. (2003) reported that patients with Crohn disease also had a favorable response to natalizumab, with remission rates that were approximately twice as high in patients who received 2 injections of the antibody as in patients from the placebo group. The rate of adverse events did not differ significantly between the natalizumab and placebo groups in either trial. Von Andrian and Engelhardt (2003) stated that natalizumab probably has therapeutic effects because it blocks the ability of alpha-4/beta-1 and alpha-4/beta-7 to bind to their respective endothelial counter-receptors, VCAM1 (192225) and MADCAM1 (102670). In both disorders, lesions result from autoimmune responses involving activated lymphocytes and monocytes. Alpha-4-integrin is expressed on the surface of these cells and plays an integral part in their adhesion to the vascular endothelium and migration into the parenchyma.

Using immunohistochemistry, immunofluorescence microscopy, and RT-PCR, Ricciardelli et al. (2008) showed that children with Crohn disease treated with infliximab, an anti-TNF antibody, had increased FOXP3 (300292)-positive T regulatory cells (Tregs) in their mucosa after treatment. Before treatment, FOXP3-positive T cells were reduced compared with controls. Ricciardelli et al. (2008) concluded that infliximab not only neutralizes soluble TNF, but also affects the activation and possibly the expansion of mucosal Tregs. They suggested that anti-TNF immunotherapy may restore mucosal homeostasis in Crohn disease.

Monteleone et al. (2015) conducted a double-blind, placebo-controlled, phase 2 trial to evaluate the efficacy of mongersen, an oral SMAD7 (602932) antisense oligonucleotide, for the treatment of individuals with active Crohn disease. Mongersen targets ileal and colonic SMAD7. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (p less than 0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (p = 0.04, p less than 0.001, and p less than 0.001, respectively). Most adverse events were related to complications and symptoms of Crohn disease.

IBD1 on Chromosome 16q12

Hugot et al. (1996) performed a genomewide linkage study of 2 consecutive and independent panels of Crohn disease families with multiple affected members using a nonparametric 2-point sib pair linkage method. They identified a putative Crohn disease locus on chromosome 16 (P less than 0.01 for each panel) centered near loci D16S409 and D16S419 by using multipoint sib pair analysis. The authors stated that the locus on chromosome 16 probably accounts for only a small fraction of the 10-fold increased risk for first-degree relatives of Crohn disease patients. The most conspicuous examples of Crohn disease candidate genes that map to the pericentromeric region of chromosome 16 are CD19 (107265), which is involved in B-lymphocyte function; sialophorin (182160), which is involved in leukocyte adhesion; the CD11 integrin cluster (153370), which is involved in mycobacterial cell adhesion; and the interleukin-4 receptor (IL4R; 147781) because IL4-mediated regulation of mononuclear phagocyte effector functions is altered in inflammatory bowel diseases. The authors noted that some of the genetic factors involved in Crohn disease may also contribute to ulcerative colitis susceptibility. Indeed, Crohn disease and ulcerative colitis share the same ethnic predisposition, and mixed families in which some members are affected with Crohn disease and others with ulcerative colitis are commonly found. The studies of Hugot et al. (1996) also suggested the possible involvement of a locus on 1p.

In an accompanying editorial comment, Ott (1996) pointed to the study by Hugot et al. (1996) in the analysis of complex traits. The parametric approach determines the recombination fraction between disease and marker loci on the basis of family data and the mode of inheritance and penetrance assumed for the trait. A misspecification of mode of inheritance generally results in an overestimation of the recombination fraction. In sib pair analysis, pairs of affected sibs are studied and all linkage information is gained from the inheritance of marker alleles by the 2 sibs, with no assumptions as to mode of inheritance. One determines the number of alleles inherited by sib 2 that are copies of the same parental alleles as those inherited by sib 1, i.e., the number of alleles shared identical by descent. Hugot et al. (1996) used multipoint sib pair analysis, implemented in the MAPMAKER/SIBS computer program, for their genomic screen for complex-trait loci. Although the number of families was relatively small (78 in the final analysis), this new approach allowed them to localize the gene for Crohn disease with greater confidence than had been possible using conventional methods.

Ohmen et al. (1996) and Parkes et al. (1996) concluded that the localization to chromosome 16 is important for susceptibility to Crohn disease rather than ulcerative colitis. Cavanaugh et al. (1998) investigated the contribution of this localization to the inheritance of inflammatory bowel disease in 54 multiplex Australian families and confirmed its importance in a significant proportion of Crohn disease families. They refined the localization to a region near D16S409, obtaining a maximum lod score of 6.3 between D16S409 and D16S753.

Annese et al. (1999) conducted a linkage study in a series of 58 Italian families with inflammatory bowel disease: 16 with Crohn disease, 23 with ulcerative colitis, and 19 with coexistent Crohn disease and ulcerative colitis. The findings of their study supported the 16p localization; no significant linkage was found for markers on chromosomes 3, 6, 7, and 12.

In an extended sample of 82 Italian families with inflammatory bowel disease, Forabosco et al. (2000) performed combined linkage and segregation analysis in the identified IBD1 region, which allowed them to estimate the mode of inheritance. A 2-loci model gave a significantly better fit than a single-locus model when information on severity was included in the analysis. A model with a major dominant gene in linkage with D16S408 (theta = 0.0) and a modifier recessive gene, with a major effect on severity of the trait, provided the best fit. The possibility that both putative major genes in the IBD1 region represent the same gene could not be ruled out. The authors suggested the presence of a major gene in the IBD1 region involved in both ulcerative colitis and Crohn disease, with a single mutation in the gene leading more frequently to ulcerative colitis and 2 mutant alleles resulting in the more severe Crohn disease.

Zouali et al. (2001) genotyped 26 microsatellite markers from the pericentromeric region of chromosome 16 in 77 multiplex Crohn disease families that included 179 patients, or 100 independent affected pairs. Nonparametric linkage analyses gave a maximum NPL score of 3.49 around the marker D16S3117. A BAC contig map of 2.5 Mb spanning the genetic region from D16S541 to D16S2623 in chromosome 16q12 was built, consisting of 99 BAC clones and 102 STSs. The results provided a crucial step toward linkage disequilibrium mapping for the identification of the IBD1 gene.

The IBD International Genetics Consortium (2001) investigated the proposed linkage to the pericentric region of chromosome 16 (IBD1) and 12p (IBD2; 601458) of Crohn disease susceptibility loci. They found unequivocal evidence of a Crohn disease susceptibility locus on chromosome 16 (maximum lod score 5.79). In this study of 12 microsatellite markers from the 2 chromosomal regions in 613 families they could not replicate the previous evidence for linkage on chromosome 12; however, the results of their study indicated the need to investigate further the potential role of the chromosome 12 locus in susceptibility to ulcerative colitis.

Van Heel et al. (2004) obtained genome scan data (markers, significance scores) from 10 separate IBD studies and performed metaanalysis using the genome scan metaanalysis (GSMA) method. The studies comprised 1,952 inflammatory bowel disease, 1,068 Crohn disease, and 457 ulcerative colitis affected relative pairs. Study results were divided into 34-cM chromosomal bins, ranked, weighted by study size, summed across studies and bin-by-bin significance obtained by simulation. The authors identified the chromosome 16 locus (NOD2/CARD15 region) as one meeting suggestive significance for both inflammatory bowel disease and Crohn disease; they also obtained suggestive evidence for linkage to chromosome 2q for ulcerative colitis, inflammatory bowel disease, and Crohn disease.

Shugart et al. (2008) performed a high-density SNP genomewide linkage study of 993 multiply affected IBD pedigrees, 25% of which were of Jewish ancestry, and observed the strongest linkage evidence at the IBD1 locus on chromosome 16q12.1, for all CD pedigrees (peak lod score, 4.86).

Elding et al. (2011) reanalyzed Crohn disease GWAS data from the Wellcome Trust Case-Control Consortium and National Institute of Diabetes and Digestive and Kidney Diseases and found genetic heterogeneity within the NOD2 locus, as well as independent involvement of a neighboring gene, CYLD (605018). They also found associations on chromosome 16q with the IRF8 (601565) region and the region containing CDH1 (192090) and CDH3 (114021), as well as substantial phenotypic and genetic heterogeneity for CD itself.

IBD2 on Chromosome 12p13.2-q24.1

See IBD2 (601458) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 12p13.2-q24.1.

IBD3 on Chromosome 6p21.3

See IBD3 (604519) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 6p21.3.

IBD4 on Chromosome 14q11-q12

See IBD4 (606675) for a Crohn disease susceptibility locus on chromosome 14q11-q12.

IBD5 on Chromosome 5q31

See IBD5 (606348) for a Crohn disease susceptibility locus on chromosome 5q31.

IBD6 on Chromosome 19p13

See IBD6 (606674) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 19p13.

IBD7 on Chromosome 1p36

See IBD7 (605225) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 1p36.

IBD8 on Chromosome 16p

See IBD8 (606668) for an ulcerative colitis susceptibility locus on chromosome 16p.

IBD9 on Chromosome 3p26

See IBD9 (608448) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 3p26.

IBD10 on Chromosome 2q37.1

See IBD10 (611081) for a Crohn disease susceptibility locus on chromosome 2q37.1. This locus is associated with variation in the ATG16L1 gene (610767).

IBD11 on Chromosome 7q22

See IBD11 (191390) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 7q22. This locus may be associated with variation in the MUC3A gene (158371).

IBD12 on Chromosome 3p21

See IBD12 (612241) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 3p21. This locus may be associated with variation in the MST1 gene (142408) or in the BSN gene (604020).

IBD13 on Chromosome 7q21.1

See IBD13 (612244) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 7q21.1. This locus is associated with variation in the ABCB1 gene (171050).

IBD14 on Chromosome 7q32

See IBD14 (612245) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 7q32. This locus is associated with variation in the IRF5 gene (607218).

IBD15 on Chromosome 10q21

See IBD15 (612255) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 10q21.

IBD16 on Chromosome 9q32

See IBD16 (612259) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 9q32. This locus may be associated with variation in the TNFSF15 gene (604052).

IBD17 on Chromosome 1p31.1

See IBD17 (612261) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 1p31.1. This locus is associated with variation in the IL23R gene (607562).

IBD18 on Chromosome 5p13.1

See IBD18 (612262) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 5p13.1.

IBD19 on Chromosome 5q33.1

See IBD19 (612278) for a Crohn disease susceptibility locus on chromosome 5q33.1.

IBD20 on Chromosome 10q24

See IBD20 (612288) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 10q23-q24.

IBD21 on Chromosome 18p11

See IBD21 (612354) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 18p11.

IBD22 on Chromosome 17q21

See IBD22 (612380) for a Crohn disease susceptibility locus on chromosome 17q21.

IBD23 on Chromosome 1q32

See IBD23 (612381) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 1q32. This locus may be associated with variation in the IL10 gene (124092).

IBD24 on Chromosome 20q13

See IBD24 (612566) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 20q13.

IBD25 on Chromosome 21q22

See IBD25 (612567) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 21q22. This locus is associated with mutation in the IL10RB gene (123889).

IBD26 on Chromosome 12q15

See IBD26 (612639) for an ulcerative colitis susceptibility locus on chromosome 12q15.

IBD27 on Chromosome 13q13.3

See IBD27 (612796) for a Crohn disease susceptibility locus on chromosome 13q13.3.

IBD28 on Chromosome 11q23.3

See IBD28 (613148) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 11q23.3. This locus is associated with mutation in the IL10RA gene (146933).

IBD29 on Chromosome 1q32

See IBD29 (618077) for a Crohn disease/ulcertative colitis susceptibility locus on chromosome 1q32. IBD29 is associated with variation in the INAVA gene (618051).

Genomewide Association Studies

Satsangi et al. (1996) undertook a systematic screening of the entire genome for identification of susceptibility genes for inflammatory bowel disease involving 186 affected sib pairs from 160 nuclear families. They provided strong evidence for the presence of susceptibility loci for both Crohn disease and ulcerative colitis on chromosomes 3, 7, and 12. The highest lod score (5.47) was obtained with marker D12S83 and lod scores of 3.08 and 2.69 were obtained for markers D7S669 and D3S573, respectively. The data suggested that Crohn disease and ulcerative colitis are closely related but distinct polygenic disorders that share some, but not all, susceptibility genes.

Cho et al. (1998) used 377 autosomal markers in a genomewide linkage screen on 297 Crohn disease, ulcerative colitis, or mixed relative pairs from 174 families, of which 37% were Ashkenazi Jewish. They observed evidence for linkage at 3q for all families (multipoint lod score = 2.29), with greatest significance for non-Ashkenazi Caucasians (multipoint lod = 3.39), and at chromosome 1p (multipoint lod = 2.65) for all families. In a limited subset of mixed families, containing 1 member with Crohn disease and another with ulcerative colitis, evidence for linkage was observed on 4q (multipoint lod = 2.76), especially among Ashkenazim. There was confirmatory evidence for a Crohn disease locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (multipoint lod = 1.69), particularly among Ashkenazim; however, positive multipoint lod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (multipoint lod less than 1.0) evidence for linkage. This screen provided strong evidence that there are several major susceptibility loci contributing to the genetic risk for Crohn disease and ulcerative colitis.

In a large European cohort, Hampe et al. (1999) confirmed previously described linkages on chromosomes 16 and 12. Evidence for a previous chromosome 4 linkage was extended. New suggestive evidence for autosomal linkage was observed on chromosomes 1, 6, 10, and 22. A maximum lod score of 1.76 was observed on the X chromosome, for ulcerative colitis, which is consistent with the clinical association of IBD with Turner syndrome. The finding of linkage to 6p was of interest because of the possible contribution of HLA and tumor necrosis factor genes in IBD.

In a genomewide search of 158 Canadian sib-pair families, Rioux et al. (2000) identified 3 regions of suggestive linkage (3p, 5q31-q33, and 6p) and 1 region of significant linkage to 19p13 (lod score 4.6). Higher-density mapping in the 5q31-q33 region revealed a locus of genomewide significance (lod score 3.9) that contributed to Crohn disease susceptibility in families with early-onset disease. Both the chromosome 19 and chromosome 5 regions contain numerous genes that are important to the immune and inflammatory systems and that provided good targets for candidate gene studies. Lo and Zheng (2004) applied a novel approach to the analysis of the genome-scan data of Rioux et al. (2000): the backward haplotype transmission association (BHTA) algorithm. They showed that the method has increased efficiency in the use of available data and can lead to novel and surprising results.

Dechairo et al. (2001) conducted a replication study on the chromosome 6p region (IBD3) and extension studies on 2 other regions on chromosomes 3p and 7q. Microsatellite markers across each region were genotyped in 284 IBD-affected sib pairs from 234 UK Caucasian families. A nonparametric peak multipoint lod score of 3.04 was detected near D6S291, thus replicating the previous linkage to chromosome 6p. There was almost equal contribution from Crohn disease and ulcerative colitis sib pairs to the linkage. Nominal evidence of linkage was observed at both the 3p and 7q regions, and the largest LOD score for each region was 1.25 and 1.26, respectively, for Crohn disease patients.

Van Heel et al. (2003) performed a genomewide scan of 137 Crohn disease affected relative pairs from 112 families. The authors verified linkage of Crohn disease to regions on chromosome 3 (p = 0.0009) and X (p = 0.001) in their cohort. Linkage to chromosome 16 was observed in Crohn disease pairs not possessing common CARD15 mutations (p = 0.0007), approximately 25 cM telomeric of CARD15. Evidence for linkage to chromosome 19 was observed in Crohn disease pairs not possessing CARD15 mutations (p = 0.0001), and in pairs possessing 1 or 2 copies of the IBD5 risk haplotype (p = 0.0005), with significant evidence for genetic heterogeneity and epistasis, respectively. These analyses demonstrated the complex genetic basis to Crohn disease, and that the discovery of disease-causing variants may be used to aid identification of further susceptibility loci in complex diseases.

Gaya et al. (2006) reviewed advances in genetics of IBD since the discovery of the CARD15 gene and discussed plausible candidate genes for analysis.

The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals and a shared set of approximately 3,000 controls for each of 7 major diseases. They replicated associations of Crohn disease with CARD15, IL23R (607562), and ATG16L1 (610767), and the association of the risk haplotype represented by IBD5 (606348). They also identified several new associations.

Rioux et al. (2007) reported a genomewide association study of ileal Crohn disease and 2 independent replication studies that identified several new regions of association to Crohn disease: in addition to the previously established CARD15 (605956) and IL23R (607562) associations, they identified strong and significantly replicated associations with an intergenic region on 10q21.1 and the rs2241880-coding variant in ATG16L1 (610767). Rioux et al. (2007) also reported strong associations with independent replication to variation in the genomic regions encoding PHOX2B (603851), NCF4 (601488), and a predicted gene on 16q24.1.

Cho and Weaver (2007) reviewed the genetics of inflammatory bowel disease, including murine genetic models relevant to IBD.

Mathew (2008) reviewed new links to the pathogenesis of CD provided by genomewide association scans; they noted that because most of the SNPs that were genotyped in these scans were selected to tag the genome efficiently rather than for their possible effect on gene function, most CD-associated SNPs are unlikely to be the causal variants that actually confer disease susceptibility.

In a metaanalysis of data from 3 studies of Crohn disease involving a total of 3,230 cases and 4,829 controls (Rioux et al., 2007, the Wellcome Trust Case Control Consortium, 2007, and Libioulle et al., 2007) with replication in 3,664 independent cases, Barrett et al. (2008) strongly confirmed 11 previously reported loci, including the NOD2 locus (combined p = 5.10 x 10(-24); case-control odds ratio, 3.99), and identified 21 additional CD susceptibility loci on chromosomes 1, 5, 6, 7, 8, 9, 10, 11, 12, 13, 17, and 21.

Glas et al. (2009) attempted to replicate the findings of Rioux et al. (2007) in a European cohort involving 854 German patients with CD, 476 with UC, and 1,503 healthy controls. Of the 7 strongest associations in the earlier study, Glas et al. (2009) confirmed the 3 strongest, e.g., NOD2/CARD15, IL23R, and ATG16L1; however, they found no association between CD and PHOX2B (rs16853571), NCF4 (rs4821544), FAM92B (rs8050910), or rs224136, a SNP in the intergenic region on chromosome 10q21.1, even after subanalysis of 529 German patients with an ileal CD phenotype. Noting that other European studies had shown similar results (e.g., Wellcome Trust Case Control Consortium, 2007, Libioulle et al., 2007, and Barrett et al., 2008), Glas et al. (2009) concluded that these findings were likely due to ethnic differences between the North American and European IBD populations.

Franke et al. (2008) conducted a genomewide association study involving 440,794 SNPs genotyped in 1,167 ulcerative colitis patients and 777 healthy controls, followed by testing for replication of the 20 most significantly associated SNPs in 3 independent European case-control panels comprising a total of 1,855 ulcerative colitis patients and 3,091 controls, and confirmed association at chromosomes 6p21, 1p31, and 1q32. They also found a new association at rs12612347 near the ARPC2 locus (604224) on chromosome 2q35 (p = 8.42 x 10(-6) in the initial panel, odds ratio = 1.60; combined p = 2.00 x 10(-4), combined odds ratio 1.18), and noted that Van Heel et al. (2004) had previously obtained suggestive linkage to chromosome 2q for ulcerative colitis, CD, and IBD.

Wang et al. (2009) applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium and uncovered significant association between Crohn disease and the IL12/IL23 pathway (see 161561), harboring 20 genes (p = 8 x 10(-5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2, 147796) or homologs of genes (STAT3, 102582 and CCR6, 601835) that had been identified as genuine susceptibility genes only through metaanalysis of several genomewide association studies. In addition, the pathway contains other susceptibility genes for Crohn disease, including IL18R1 (604494), JUN (165160), IL12RB1 (601604), and TYK2 (176941), which do not reach genomewide significance by single marker association tests. The observed pathway-specific association signal was subsequently replicated in 3 additional genomewide association studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Wang et al. (2009) concluded that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to realizing the true power of genomewide association studies. It was notable, however, that examination of the IL12/IL23 pathway failed to detect the well-known association between Crohn disease and NOD2 (605956).

In a study involving 2,731 Dutch and Belgian IBD patients, including 1,656 CD patients and 1,075 UC patients, Weersma et al. (2009) found association at rs916977 in the HERC2 gene (605837) on chromosome 15q13.1 for CD (corrected p = 4.48 x 10(-3); odds ratio, 1.39); there was no significant association with UC.

In a genomewide association study involving 1,897,764 SNPs in 1,043 German UC cases and 1,703 controls, Franke et al. (2010) found significant association at a nonsynonymous SNP (L333P; rs5771069) in the IL17REL gene (613414) on chromosome 22q13 (p = 4.37 x 10(-5)). Combined analysis, including 6 replication panels involving a total of 2,539