CROHN DISEASE-ASSOCIATED GROWTH FAILURE, SUSCEPTIBILITY TO, INCLUDED
IBD1 REGIONAL ENTERITIS, INCLUDED
ULCERATIVE COLITIS, INCLUDED
CROHN DISEASE, INCLUDED
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 ... 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.
- 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 ... - 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. 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 dbSNP 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 dbSNP 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 dbSNP 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 (dbSNP 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 (dbSNP 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 dbSNP 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 dbSNP rs6672995 (G) was associated with a decrease in LPS-induced IL1-beta production, and the risk allele of dbSNP 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 dbSNP rs2078178 in patients with medically refractory ulcerative colitis (logistic regression, p = 0.007). Notably, a 2-marker haplotype, dbSNP rs2078178 to dbSNP 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, dbSNP 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 dbSNP 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 dbSNP 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. 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 IDDM; 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, dbSNP rs2298428 in UBE2L3 (603721) (p = 5.22 x 10(-5)) and dbSNP 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.