Other entities represented in this entry:
SNOMEDCT: 34000006; ICD10CM: K50, K50.9, K50.90; DO: 0110892;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p15.3 | {Crohn disease-associated growth failure} | 266600 | Multifactorial | 3 | IL6 | 147620 |
| 16q12.1 | {Inflammatory bowel disease 1, Crohn disease} | 266600 | Multifactorial | 3 | NOD2 | 605956 |
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.
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.
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%.
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.
Parikh et al. (2019) profiled single colonic epithelial cells from patients with IBD and unaffected controls and identified previously unknown cellular subtypes, including gradients of progenitor cells, colonocytes, and goblet cells, within intestinal crypts. At the top of the crypts, Parikh et al. (2019) found a previously unknown absorptive cell expressing the proton channel OTOP2 (607827) and the satiety peptide uroguanylin (GUCA2B; 601271), that sensed pH and was dysregulated in inflammation and cancer. In IBD, Parikh et al. (2019) observed a positional remodeling of goblet cells that coincided with downregulation of WFDC2 (617548), an antiprotease molecule that they found to be expressed by goblet cells and that inhibited bacterial growth. In vivo, WFDC2 preserved the integrity of tight junctions between epithelial cells and prevented invasion by commensal bacteria and mucosal inflammation.
Using whole-exome sequencing data from 76 clonal human colon organoids, Nanki et al. (2020) identified a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. They found that the affected epithelia accumulated somatic mutations in multiple genes that are related to IL17 signaling, including NFKBIZ (608004), ZC3H12A (610562), and PIGR (173880), which are genes that are rarely affected in colon cancer. Targeted sequencing validated the pervasive spread of mutations that are related to IL17 signaling. Unbiased CRISPR-based knockout screening in colon organoids revealed that the mutations conferred resistance to the proapoptotic response that is induced by IL17A. Some of these genetic mutations were known to exacerbate experimental colitis in mice, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Nanki et al. (2020) concluded that their findings highlighted a genetic landscape that adapts to a hostile microenvironment, and demonstrated its potential contribution to the pathogenesis of ulcerative colitis.
Kakiuchi et al. (2020) showed that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodeling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2 (607043), ZC3H12A, PIGR, and HNRNPF (601037) genes and are implicated in the downregulation of IL17 and other proinflammatory signals. Mutational profiles varied substantially between colitis-associated cancer and nondysplastic tissues in ulcerative colitis, which indicated that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ were highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in either sporadic or colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, Kakiuchi et al. (2020) found that tumor formation was significantly attenuated in Nfkbiz-mutant mice, and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Kakiuchi et al. (2020) concluded that their results highlighted common and discrete mechanisms of clonal selection in inflammatory tissues, which revealed unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.
Wang et al. (2020) reported that deficiency of SETDB1 (604396), a histone methyltransferase that mediates the trimethylation of histone H3 (see 602810) at lysine-9, participates in the pathogenesis of IBD. Wang et al. (2020) found that levels of SETDB1 are decreased in patients with IBD, and that mice with reduced SETDB1 in intestinal stem cells developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability, and the loss of SETDB1 in intestinal stem cells released repression of endogenous retroviruses. Excessive viral mimicry generated by motivated endogenous retroviruses triggered Z-DNA-binding protein-1 (ZBP1; 606750)-dependent necroptosis, which irreversibly disrupted homeostasis of the epithelial barrier and promoted bowel inflammation. Genome instability, reactive endogenous retroviruses, upregulation of ZBP1, and necroptosis were all seen in patients with IBD. Pharmaceutical inhibition of RIP3 (605817) showed a curative effect in SETDB1-deficient mice, suggesting that targeting necroptosis of intestinal stem cells may represent an approach for the treatment of severe IBD.
Teratani et al. (2020) reported a liver-brain-gut neural arc that ensures the proper differentiation and maintenance of peripheral regulatory T cells (pTreg cells) in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. In mice, surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pTreg cells; this was attributed to decreased expression of aldehyde dehydrogenase (Aldh1a1, 100640 and Aldh1a2, 603687) and retinoic acid synthesis by intestinal antigen-presenting cells (APCs). Activation of muscarinic acetylcholine receptors (e.g., Chrm1, 118510) directly induced aldehyde dehydrogenase gene expression in both human and mouse colonic APCs, whereas genetic ablation of these receptors abolished the stimulation of APCs in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pTreg cell pool, resulting in increased susceptibility to colitis. Teratani et al. (2020) concluded that their results demonstrated that the novel vago-vagal liver-brain-gut reflex arc controls the number of pTreg cells and maintains gut homeostasis. The authors argued that intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunologic disorders of the gut.
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/ulcerative colitis susceptibility locus on chromosome 1q32. IBD29 is associated with variation in the INAVA gene (618051).
IBD30 on Chromosome 19q13
See IBD30 (619079) for a Crohn disease susceptibility locus on chromosome 19q13. IBD30 is associated with mutation in the CARD8 gene (609051).
IBD31 on Chromosome 2q14
See IBD31 (619398) for an infantile ulcerative colitis susceptibility locus on chromosome 2q14. IBD31 is associated with mutation in the IL37 gene (605510).
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 UC cases and 5,428 controls, yielded a Cochran-Mantel-Haenzsel p = 8.81 x 10(-8) (odds ratio, 1.17; 95% CI 1.11-1.25). Gene ontology analyses for the rs5771069 G allele revealed downregulated transcripts including IL17RE (614995), CSF3 (138970), and CD276 (605715).
McGovern et al. (2010) combined new data from 2 genomewide association studies of ulcerative colitis involving 266,047 SNPs and performed a metaanalysis with previously published data (Silverberg et al., 2009), thus bringing together a discovery set of 2,693 European UC patients and 6,791 controls; the top results from the metaanalysis were then independently replicated with 2,009 additional European UC cases and 1,580 controls. McGovern et al. (2010) identified 13 loci that were significantly associated with UC (p less than 5 x 10(-8)), including SNPs on chromosome 2p16 and 5p15.3, and confirmed association with 14 previously identified UC susceptibility loci. An analysis of known Crohn disease loci showed that roughly half were shared with UC. Overall, these data implicated approximately 30 loci in ulcerative colitis.
Momozawa et al. (2011) used high-throughput sequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn disease in 63 GWAS-identified positional candidate genes, but detected significantly associated low-frequency coding variants only in the IL23R gene (see 607562 and IBD17, 612261). Momozawa et al. (2011) concluded that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn disease.
Jostins et al. (2012) expanded on the knowledge of relevant pathways of inflammatory bowel disease by undertaking a metaanalysis of Crohn disease and ulcerative colitis genomewide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. They identified 71 new associations, for a total of 163 IBD loci, that meet genomewide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favoring one allele over the course of human history) and balancing (favoring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. Jostins et al. (2012) also observed considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene coexpression network analysis emphasized this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
McGovern et al. (2010) performed a GWAS in 896 CD cases and 3,204 healthy Caucasian controls. An association was identified with FUT2 (182100) on chromosome 19q13 (rs602662, p = 3.4 x 10(-5)). Replication was demonstrated in an independent cohort of 1,174 CD cases and 357 controls between the 4 primary FUT2 SNPs and CD (rs602662, combined p = 4.90 x 10(-8)) and also association with FUT2 W143X (182100.0001) (p = 2.6 x 10(-5)).
Association on 10p11
Franke et al. (2008) investigated 50 previously reported susceptibility loci in a German sample of 1,850 CD patients, 1,103 UC patients, and 1,817 controls, and replicated the association between rs3936503 in the CCNY gene (612786) on chromosome 10p11.2 for both CD and UC (corrected p = 5.76 x 10(-5) and 8.90 x 10(-5), respectively). 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) identified a new locus at rs17582416 on chromosome 10p11 (combined p = 1.79 x 10(-9)) in a region containing 3 genes. 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) replicated association at rs3936503 for CD (corrected p = 8.36 x 10(-3); odds ratio, 1.31) but did not find significant association with UC. Combined analysis with data from the Wellcome Trust Case Control Consortium (2007) yielded a p of 1.46 x 10(-8). Anderson et al. (2009) analyzed 45 SNPs tagging 29 CD-associated loci in 2,527 UC cases and 4,070 controls and found association at chromosome 10p11 with rs17582416 (p = 4.27 x 10(-4)).
Association with NOD2/CARD15 on Chromosome 16q12
Using a positional cloning strategy based on linkage analysis followed by linkage disequilibrium mapping, Hugot et al. (2001) identified 3 independent mutations in the NOD2 gene that were associated with Crohn disease. They determined that the relative risk of Crohn disease for individuals who were heterozygous, homozygous, or compound heterozygous for the identified NOD2 mutations was 3-fold, 38-fold, and 44-fold higher than for normal controls, respectively.
Raelson et al. (2007) performed a genomewide association study in 477 parent-proband trios with Crohn disease from the Quebec Founder Population and tested for replication in 2 independent German samples. They confirmed 3 of the most replicated loci, NOD2, IBD5, and IL23R, and replicated a previously reported region on chromosome 3p21.3.
Rivas et al. (2011) used pooled next-generation sequencing to study 56 genes from regions associated with Crohn disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in 9 independent case-control series (16,054 Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy controls), they identified 4 additional independent risk factors in NOD2.
Crohn Disease-Associated Growth Failure
Crohn disease inhibits growth in up to one-third of affected children. Sawczenko et al. (2005) hypothesized that IL6 (147620) on chromosome 7p21, induced by intestinal inflammation, retards growth and suppresses IGF1 (147440). They treated rats with trinitrobenzenesulfonic acid-induced colitis with anti-IL6 and found that nutrient intake and inflammation did not decrease, but linear growth was restored and plasma and hepatic Igf1 levels increased. Sawczenko et al. (2005) suggested that, in humans, Crohn disease-associated growth failure would vary with the genotype at the IL6 -174 G/C promoter polymorphism (147620.0001). They found that English and Swedish children with Crohn disease and the -174 GG genotype were more growth retarded at diagnosis and had higher levels of the IL6-induced inflammatory marker C-reactive protein (CRP; 123260) than children with GC or CC genotypes. After corticosteroid or enteral feeding treatment, CRP levels decreased significantly and became comparable to those in children with GC or CC genotypes. Sawczenko et al. (2005) concluded that IL6 -174 genotype mediates growth failure in Crohn disease.
Associations Pending Confirmation
Polymorphism in the AGT gene (106150.0002) on chromosome 1q42-q43 has been associated with Crohn disease.
In 1,174 Crohn disease cases and 357 controls, McGovern et al. (2010) found association of the FUT2 W143X polymorphism (182100.0001) and CD (p = 2.6 x 10(-5)). McGovern et al. (2010) noted that Barrett et al. (2008) had identified genomewide significant association with CD for SNPs on chromosome 19p13 (combined p = 2.12 x 10(-9)). The FUT2 gene product, alpha-(1,2)fucosyltransferase, regulates the expression of the H antigen, a precursor of the blood group A and B antigens, on the gastrointestinal mucosa. About 20% of Caucasians are nonsecretors who do not express ABO antigens in saliva as a result of homozygosity for the FUT2 W143X allele. McGovern et al. (2010) concluded that FUT2 may play a role in CD susceptibility and highlighted the role of the mucus layer in the development of CD.
Mwantembe et al. (2001) noted that IBD is more prevalent in South African whites than in blacks, a pattern observed elsewhere as well. By restriction enzyme and linkage disequilibrium analysis of IL1B (147720) on chromosome 2q14, IL1RA (147810), and IL1RN (147679) polymorphisms, Mwantembe et al. (2001) determined that a mutant IL1B allele (Taq-) was significantly more common in white patients than in white controls, whose frequency was similar to black patients and controls. On the other hand, a mutant IL1RA allele (Pst-) was significantly more frequent in blacks than in whites, regardless of disease status. Although other population differences were observed, no other alleles were significantly associated with disease in either group. Plasma IL1RN levels were significantly higher in black patients than in black controls or white patients and controls. Plasma concentrations of the alpha-1 protease inhibitor (PI; 107400), an indicator of inflammation, were significantly higher in both black and white patients than in black and white controls. Mwantembe et al. (2001) concluded that the inflammatory processes leading to IBD may be distinct in the different population groups.
Karban et al. (2004) identified 6 nucleotide variants in the NFKB1 gene on chromosome 4q, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using the family-based association test and the pedigree disequilibrium test, they observed modest evidence for linkage disequilibrium between the -94delATTG allele and ulcerative colitis in 131 IBD pedigrees with ulcerative colitis offspring (p = 0.047 and p = 0.052, respectively). The -94delATTG association with ulcerative colitis was replicated in a second set of 258 unrelated, non-Jewish ulcerative colitis patients and 653 non-Jewish controls (p = 0.021). Nuclear proteins from normal human colon tissue and colonic cell lines showed significant binding to -94insATTG-containing but not to -94delATTG-containing oligonucleotides. Cells transfected with reporter plasmid constructs containing the -94delATTG allele showed less promoter activity than comparable constructs containing the -94insATTG allele. Borm et al. (2005) confirmed the association in Dutch patients with ulcerative colitis; however, Oliver et al. (2005) and Mirza et al. (2005) found no association between the -94delATTG allele and ulcerative colitis in Spanish and British ulcerative colitis patients, respectively.
The NOD1 gene (605980), on chromosome 7p15-p14, encodes an intracellular bacterial pathogen-associated molecular pattern receptor that is closely related to NOD2 (605956). McGovern et al. (2005) identified strong association between haplotypes in the terminal exons of NOD1 and IBD (multiallelic p = 0.0000003) in a panel of 556 IBD trios. The deletion allele of a complex functional NOD1 indel polymorphism (ND1+32656*1; partially identified as rs6958571) was significantly associated with early-onset IBD (p = 0.0003) in unrelated cases and controls of 2 independent populations.
Defensins are endogenous antimicrobial peptides that protect the intestinal mucosa against bacterial invasion. DNA copy number of the beta-defensin gene cluster on 8p23.1 is highly polymorphic, and evidence has been presented suggesting that low copy number of the beta-defensin-2 gene (602215) predisposes to Crohn disease of the colon (Fellermann et al., 2006).
In a panel of 1,182 individuals with Crohn disease and 2,024 controls, Parkes et al. (2007) analyzed 37 SNPs from 31 distinct loci that were associated at p values of less than 10(-5) in the Wellcome Trust Case Control Consortium (2007) dataset and obtained replication for multiple loci, including the NKX2C (606727), PTPN2 (176887), and IL12B (161561) genes and the 'gene desert' on chromosome 1q.
In a 3-stage study involving a total of 1,851 patients with IBD and 1,936 controls, Zhernakova et al. (2008) analyzed 85 genes located in 74 genomic regions and found strong association for both Crohn disease and ulcerative colitis with rs917997 (uncorrected combined p = 1.9 x 10(-8)), a SNP located in an extended haplotype block on chromosome 2q11-2q12 that includes 4 genes: IL1RL1 (601203), IL18R1 (604494), IL18RAP (604509), and SLC9A4 (600531). In addition, the authors found an association for Crohn disease and ulcerative colitis with rs10870077 (uncorrected combined p = 3.25 x 10(-5)), located in an extended haplotype block on chromosome 9q34.3 that encompasses multiple genes, including the functional candidates CARD9 (607212), GPSM1 (609491), and SDCCAG3.
Martinez et al. (2008) genotyped 700 Spanish patients with inflammatory bowel disease and 723 ethnically matched controls for a SNP in the STAT4 gene (rs7574865) and found an association with IBD (p = 0.006; odds ratio, 1.29).
In a 2-stage genomewide association and replication study involving a total of 1,384 Japanese patients with ulcerative colitis (UC) and 3,057 controls, Asano et al. (2009) found significant association (heterogeneity-corrected p = 1.56 x 10(-12)) between UC and a nonsynonymous SNP (rs1801274) in the FCGR2A gene (H121R; 146790.0001). The authors noted that the H131 variant was the susceptibility allele for UC, a reversal of previous associations observed between R131 and other autoimmune diseases.
Villani et al. (2009) used a candidate gene approach to identify a set of SNPs located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (606416) that are associated with Crohn disease. The associations were consistently replicated in 4 sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases, and 107 controls), these SNPs were strongly associated with risk of Crohn disease (P combined = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113). In addition, Villani et al. (2009) observed significant associations between SNPs in the associated regions and NLRP3 expression and IL1-beta (IL1B; 147720) production. Since mutations in NLRP3 are responsible for 3 rare autoinflammatory disorders, these results suggested that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn disease. In 2 independent samples of healthy donors, Villani et al. (2009) also found that the risk allele of rs6672995 (G) was associated with a decrease in LPS-induced IL1-beta production, and the risk allele of rs4353135 (T) was associated with a decrease in baseline NLRP3 expression. All 3 SNPs in the associated 5.3-kb region influence NLRP3 at both the gene expression and functional levels.
Iliev et al. (2012) compared a group with medically refractory ulcerative colitis who required colectomy with a group of ulcerative colitis patients who did not, and found an association of CLEC7A rs2078178 in patients with medically refractory ulcerative colitis (logistic regression, p = 0.007). Notably, a 2-marker haplotype, rs2078178 to rs16910631, was more strongly associated with medically refractory ulcerative colitis (AG haplotype: logistic regression, p = 0.00013, and Fisher's test, p = 0.0005), a shorter time to surgery, and thus with a more severe ulcerative colitis. Compared with healthy controls, the haplotype was strongly associated with medically refractory ulcerative colitis and not with nonmedically refractory ulcerative colitis, further consistent with the idea that the haplotype is associated with severe disease.
Rivas et al. (2011) used pooled next-generation sequencing to study 56 genes from regions associated with Crohn disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in 9 independent case-control series (16,054 Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy controls), they identified a significant association with a protective splice variant in CARD9. CARD9 is associated with both Crohn disease and ulcerative colitis risk, with a common coding variant, rs4077515, creating protein substitution S12N with both alleles of roughly equal frequency, that represents a typical GWAS hit (odds ratio approximately 1.2 in both disorders) (Franke et al., 2010; McGovern et al., 2010). In the pooled sequencing, Rivas et al. (2011) identified a splice site variant in CARD9 that altered the first base after exon 11 in 6 controls and zero cases, suggesting a potentially strong protective effect. Follow-up analyses confirmed a significant association (p less than 10(-16)), with the allele appearing in approximately 0.20% of cases and 0.64% of controls (odds ratio approximately 0.3). Although skipping exon 11 places translation out of frame, Rivas et al. (2011) predicted that the resulting transcript would escape nonsense-mediated decay as premature termination occurs close to the final splice junction in exon 12. Indeed, this hypothetical transcript has been observed in cDNA libraries from spleen, lymph node, and peripheral blood mononuclear cells. Notably, Rivas et al. (2011) pointed out that this rare protective variant occurs on a haplotype carrying the risk allele at rs4077515, indicating not only that the 2 associations are independent but also that the splice variant completely eliminates the risk normally associated with the common haplotype. Because the Crohn disease risk allele at rs4077515 has been associated with higher expression of CARD9, a consistent allelic series may exist if the splice variant is substantially lower or nonfunctional and therefore highly protective.
Cao et al. (2015) analyzed immunochip datasets from 33,311 IBD-affected individuals and 33,938 healthy controls from the International Inflammatory Bowel Disease Genetics Consortium and found that 166 cases and 441 controls carried at least 1 copy of the CARD9 IVS11+1G-C splice variant. Conditioning the proportion of cases on the combination of the splice and the S12N variants, Cao et al. (2015) found that individuals with the splice variant were less likely to develop IBD regardless of the presence of the S12N alteration.
Rivas et al. (2011) found association of Crohn disease and inflammatory bowel disease with coding variants in IL18RAP (604509), CUL2 (603135), C1ORF106, PTPN22 (600716), and MUC19 (612170).
Inflammatory bowel disease, including Crohn disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D; see 222100) are autoimmune diseases that may share common susceptibility pathways. Wang et al. (2010) examined known susceptibility loci for these diseases in a cohort of 1,689 CD cases, 777 UC cases, 989 T1D cases, and 6,197 shared control subjects of European ancestry. Multiple previously unreported or unconfirmed disease-loci associations were identified, including CD loci (ICOSLG, 605717; TNFSF15, 604052) and T1D loci (TNFAIP3; 191163) that conferred UC risk; UC loci (HERC2, 605837; IL26, 605679) that conferred T1D risk; and UC loci (IL10, 124092; CCNY, 612786) that conferred CD risk. T1D risk alleles residing at the PTPN22, IL27 (608273), IL18RAP, and IL10 loci protected against CD. The strongest risk alleles for T1D within the major histocompatibility complex (MHC) conferred strong protection against CD and UC. The authors suggested that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effects, and variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations.
Fransen et al. (2010) selected SNPs from CD GWAS that showed a correlation to gene expression (cis-expression quantitative trait loci, or eQTLs). Ten such cis-eQTL SNPs were tested for association with CD in 2 independent cohorts of Dutch CD patients (1,539) and healthy controls (2,648). Two cis-eQTL SNPs were associated with CD, rs2298428 in UBE2L3 (603721) (p = 5.22 x 10(-5)) and rs2927488 in BCL3 (109560) (p = 2.94 x 10(-4)). The authors concluded that UBE2L3 and BCL3 are likely novel risk genes for CD, and that eQTL-based selection is a useful approach for identifying risk loci from a moderately sized GWAS.
Fine Mapping of Associations
Huang et al. (2017) reported fine mapping of inflammatory bowel disease-associated loci using high density genotyping in 67,852 individuals. They pinpointed 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. Among the 45 variants, there were 13 protein-coding changes, 3 causing direct disruption of transcription factor binding sites, and 10 resulting in tissue-specific epigenetic marks, with the last category showing enrichment in specific immune cells among associations stronger in Crohn disease, and in gut mucosa among associations stronger in ulcerative colitis. Huang et al. (2017) concluded that high resolution fine mapping in large samples can convert many discoveries from genomewide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
Mouse models of colitis offer an avenue for identifying IBD genes or pathways that may lead to identification of the human orthologs. Targeted mutations in a variety of mouse genes produce colitis. Mice homozygous for a disrupted interleukin-10 gene (Kuhn et al., 1993) supported the hypothesis that a dysregulated immune response to enteric flora can trigger IBD. The severity of the colitis depends on the inbred strain background in which the disrupted gene is placed. The C3H strain is highly susceptible to several experimentally induced forms of IBD, whereas the B6 background is resistant.
Hermiston and Gordon (1995) transfected embryonic stem cells with a dominant-negative N-cadherin (CDH2; 114020) mutant under the control of promoters active in small intestinal epithelial cells and introduced them into C57BL/6 blastocysts. Analysis of adult chimeric mice revealed that expression of the mutant along the entire crypt-villus axis, but not in the villus epithelium alone, produced an inflammatory bowel disease resembling Crohn disease. The mutation perturbed proliferation, migration, and death patterns in crypts, leading to adenomas. The model provided insights into cadherin function in an adult organ and the factors underlying inflammatory bowel disease and intestinal neoplasia.
Neurath et al. (1996) reported that chronic intestinal inflammation induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) is characterized by a transmural granulomatous colitis that mimics some characteristics of human Crohn disease. They demonstrated that the p65 subunit of transcription factor NF-kappa-B (164014) was strongly activated in TNBS-induced colitis and in colitis of interleukin-10 (IL10; 124092)-deficient mice. They administered a p65 antisense phosphorothioate oligonucleotide to mice intravenously and intrarectally. The p65 antisense treatment abrogated clinical and histologic signs of colitis. The investigators noted that the p65 antisense treatment was more effective in treating TNBS-induced colitis than single or daily administration of glucocorticoids. Neurath et al. (1996) stated that their data provided direct evidence for the involvement of p65 in chronic intestinal inflammation and suggested a potential therapeutic role for p65 antisense oligonucleotides for the treatment of patients with Crohn disease.
Farmer et al. (2001) used quantitative trait locus (QTL) analysis to identify modifiers of cytokine deficiency-induced colitis susceptibility. They found a colitogenic susceptibility QTL on mouse chromosome 3 that exacerbated colitis in combination with modifiers contributed from both parental genomes. The complex nature of interactions among loci in this mouse model, coupled with separate deleterious contributions from both parental strains, illustrated why detection of human inflammatory bowel disease linkages has proven to be so difficult. A human ortholog of the mouse chromosome 3 QTL, if one exists, would map to chromosome 4q or 1p in the human.
Using semiquantitative RT-PCR analysis, Singh et al. (2003) detected increased expression of Ip10 (CXCL10; 147310) and its receptor, Cxcr3 (300574), in mesenteric lymph nodes and inflamed colons of Il10 -/- mice. The Crohn disease-like colitis in Il10 -/- mice was associated with increased serum amyloid A (SAA; 104750), Il6, and Th1 cytokine levels and weight loss, all of which could be abrogated by anti-Ip10 treatment. Singh et al. (2003) concluded that anti-IP10 treatment can successfully impede development of inflammatory bowel disease, and that SAA levels can reveal the intensity of colitis.
Maeda et al. (2005) generated mice with a Nod2 locus harboring the homolog of the most common Crohn disease susceptibility allele, 3020insC (605956.0001), which encodes a truncated protein lacking the last 33 amino acids. Homozygous Nod2 mutant mice were obtained at the expected mendelian ratio, were healthy, and showed no abnormalities of the gastrointestinal tract or other organs. The mutation had no effect on Nod2 mRNA or protein amounts in bone marrow-derived macrophages. Mutant mice exhibited elevated NFKB (164011) activation in response to bacteria-derived muramyl dipeptide and more efficient processing and secretion of the cytokine IL1B. These effects were linked to increased susceptibility to bacteria-induced intestinal inflammation and identified NOD2 as a positive regulator of NFKB activation and IL1B secretion.
Mice deficient in Il10 develop spontaneous IBD. Yen et al. (2006) found that mice deficient in both Il10 and Il12 p35 (IL12A; 161560), but not mice deficient in both Il10 and Il23 p19 (IL23A; 605580), developed spontaneous IBD, indicating that IL23, but not IL12, is necessary for chronic intestinal inflammation. Adding recombinant IL23 to T cells from Il10 -/- mice adoptively transferred to T cell-deficient mice accelerated IBD development, which was accompanied by enhanced production of Il6 and Il17 (603149). Blockade of Il6 and Il17 ameliorated IBD. Yen et al. (2006) concluded that IL23 promotes development and expansion of a pathogenic IL6- and IL17-producing memory-activated T-cell population that triggers the inflammatory cascade leading to intestinal inflammation.
In a murine model of Crohn disease, Gonzalez-Rey et al. (2006) demonstrated that cortistatin (602784) treatment significantly ameliorated the clinical and histopathologic severity of inflammatory colitis, abrogating weight loss, diarrhea, and inflammation and increasing the survival rate of colitic mice. The therapeutic effect was associated with downregulation of inflammatory and Th1-driven autoimmune responses, including regulation of a wide spectrum of inflammatory mediators. Cortistatin was effective in the treatment of established colitis and in avoiding the recurrence of disease. Gonzalez-Rey et al. (2006) concluded that cortistatin is an antiinflammatory factor capable of deactivating intestinal inflammatory response and restoring mucosal immune tolerance at multiple levels.
Using 2 mouse models of Helicobacter hepaticus-induced T-cell-dependent colitis, Kullberg et al. (2006) showed that Il23, but not Il12, was essential for development of maximal intestinal disease. They proposed that IL23 drives both gamma-interferon (IFNG; 147570) and IL17 responses that synergize to trigger severe intestinal inflammation.
Nenci et al. (2007) demonstrated that the transcription factor NFKB, a master regulator of proinflammatory responses, functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial-specific inhibition of NFKB through conditional ablation of NEMO (300248) or both IKK1 (600664) and IKK2 (603258), IKK subunits essential for NFKB activation, spontaneously caused severe chronic intestinal inflammation in mice. NFKB deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides, and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 (602170) prevented the development of intestinal inflammation, demonstrating that Toll-like receptor activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to TNF-induced apoptosis, whereas TNF receptor-1 (TNFR1; 191190) inactivation inhibited intestinal inflammation, demonstrating that TNFR1 signaling is crucial for disease induction. Nenci et al. (2007) concluded that a primary NFKB signaling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory bowel disease-like phenotype. Their results further identified NFKB signaling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease.
To investigate the mechanism by which a polymorphism in the SLC39A8 gene (608732), A391T, might increase the risk of Crohn disease, Nakata et al. (2020) generated a knockin mouse model introducing an Slc39a8 A393T variant, corresponding to the human SLC39A8 polymorphic variant. Using inductively coupled plasma mass spectrometry to quantify trace elements in whole blood and tissues, the authors observed markedly reduced manganese (Mn) levels in whole blood of mutant mice. They noted that levels of zinc and iron were not altered, suggesting a specific requirement of Slc39a8 in maintaining Mn levels. Analysis of tissue Mn revealed reduced levels in the liver and colon of mutant mice compared to controls. Transmission electron microscopy of the distal colon showed that the glycocalyx in the mutant mice was sparse and significantly shorter than in wildtype mice. By FISH targeting of the bacterial EUB338 gene, the authors detected bacterial invasion in the inner mucus layer of the colon, and intestinal permeability assays showed markedly increased permeability in the mutant mice compared to wildtype mice. Immunostaining of whole colons showed that mutant mice had more numerous and larger isolated lymphoid follicles than wildtype mice, suggesting that bacterial invasion in the inner mucus layer induces maturation of isolated lymphoid follicles, consistent with indolent inflammation driven by microbiota. The mutant mice also were more susceptible to DSS-induced colitis than wildtype mice. Wildtype mice on a Mn-depleted diet exhibited increased gut permeability, reduced thickness of the inner mucus layer, penetration by commensal bacteria, and morphologic defects in the glycocalyx. The authors concluded that there is a critical role for manganese and the Mn transporter SLC39A8 in regulating intestinal barrier function.
In 25 families with multiple cases of Crohn disease, Hugot et al. (1994) excluded the Crohn disease predisposing locus from the entire chromosome 6 with lod scores less than -2. The locus was excluded from the major histocompatibility complex and from 91% of the chromosome 6 genetic map with lod scores of less than -4.
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.
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