Inflammatory Bowel Disease 3

For a general description and a discussion of genetic heterogeneity of inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, see IBD1 (266600).

Mapping

Satsangi et al. (1996) found that D6S276, adjacent to the major histocompatibility complex (MHC; see 142800), provided no evidence for linkage with Crohn disease or inflammatory bowel disease overall, but a distortion in allele sharing for sibs with ulcerative colitis was observed. In general, their data suggested that Crohn disease and ulcerative colitis are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.

In a genomewide linkage scan involving 268 IBD families of northern European descent containing 353 affected sib pairs, Hampe et al. (1999) found suggestive linkage to the MHC locus on chromosome 6, with a maximum multipoint lod score of 2.07 obtained in a region defined by markers D6S289 and D6S276.

Hampe et al. (1999) reported on a 2-stage linkage and association analysis of both a basic population of 353 affected sib pairs and an extension of this population to 428 white affected sib pairs of northern European extraction. Genotyping 28 microsatellite markers on chromosome 6, they found a peak multipoint lod score of 4.2 at D6S461 for the IBD phenotype. A transmission/disequilibrium test (TDT) result of P = 0.006 was detected for D6S426 in the basic population and was confirmed in the extended cohort. The subphenotypes of Crohn disease, ulcerative colitis, and mixed IBD contributed equally to this linkage, suggesting a general role for the chromosome 6 locus in IBD. Analysis of 5 single-nucleotide polymorphisms in the TNFA (TNF; 191160) and LTA (153440) genes, both located at 6p21.3, did not reveal evidence for association of these candidate genes with IBD.

Koss et al. (2000) found that women but not men with extensive colitis compared to distal colitis were significantly more likely (31% vs 12%; p = 0.028) to bear the -308G-A promoter polymorphism of the TNF gene (191160.0004). The association was even stronger (56% vs 21%; p = 0.0007) in women who also had an A rather than a C at position 720 in the LTA gene (153440). These polymorphisms were also associated with significantly higher TNF production in patients with Crohn disease, while an A instead of a G at position -238 in the TNF gene was associated with lower production of TNF in patients with ulcerative colitis.

Ruuls and Sedgwick (1999) reviewed the problem of unlinking TNF biology from that of the MHC. Dysregulation and, in particular, overproduction of TNF have been implicated in a variety of human diseases, including Crohn disease, and the TNF gene is considered a candidate predisposing gene. However, unraveling the importance of genetic variation in the TNF gene to disease susceptibility or severity is complicated by its location within the MHC, a highly polymorphic region that encodes numerous genes involved in immunologic responses. Ruuls and Sedgwick (1999) reviewed studies that had analyzed the contribution of TNF and related genes to susceptibility to human disease, and they discussed how the presence of the TNF gene within the MHC may potentially complicate the interpretation of studies in animal models in which the TNF gene is experimentally manipulated.

Dechairo et al. (2001) conducted a replication study on the chromosome 6p region. Ten microsatellite markers across the 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. As the IBD3 region overlaps with the MHC region, Dechairo et al. (2001) suggested that an MHC autoimmune susceptibility gene may be responsible for the positive linkage results.

Sashio et al. (2002) investigated the role of polymorphisms of the TNF gene and the TNFRSF1B gene in susceptibility to inflammatory bowel disease. They investigated 124 patients with Crohn disease, 106 patients with ulcerative colitis, and 111 unrelated healthy controls. They examined 2 SNPs of the TNFA gene, -308G-A and -238G-A, and found a difference in the carrier frequency for haplotype AG (-308A, -238G) between ulcerative colitis patients and the controls (odds ratio, 4.76).

Fisher et al. (2002) investigated the role of sex-specific loci in susceptibility to IBD. In a total of 428 European affected sib pairs genotyped with markers in the major histocompatibility region on chromosome 6p, nuclear families were stratified according to the sex of affected individuals and lod scores were calculated for male and female affected families. The highest lod score for IBD occurred at chromosome region 6p21.3, where linkage was identified in male affected families only (maximum multipoint lod score of 5.91), with evidence for linkage in both Crohn disease and ulcerative colitis phenotypes. Fisher et al. (2002) suggested that the hormonal differences between males and females could lead to differential expression of disease susceptibility genes in males and females.

Van Heel et al. (2002) stated that TNF expression is increased in IBD and showed by transmission disequilibrium and case-control analyses that in 2 independent Caucasian cohorts, a novel association of the TNF-857C promoter polymorphism with IBD was evident (overall P = 0.001 in 587 IBD families). Further genetic associations of TNF-857C with IBD subphenotypes were seen for ulcerative colitis and for Crohn disease, but only in patients not carrying common NOD2 (605956) mutations. These data suggested a recessive model of inheritance. The transcription factor OCT1 (602607) binds TNF-857T but not TNF-857C, and interacts in vitro and in vivo with the proinflammatory NFKB p65 subunit RELA (164014) at an adjacent binding site. The authors hypothesized that interaction of these transcription factors with specific alleles of TNF in gut tissue may be relevant to the pathogenesis of IBD.

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. A region on chromosome 6p containing the HLA region met genomewide significance for inflammatory bowel disease.

In a case-control study of 304 Australian patients with Crohn disease and 231 healthy controls, Fowler et al. (2005) analyzed 2 polymorphisms in the TNF gene and 2 polymorphisms in the IL10 gene (124092) on chromosome 1q31-q32 (see IBD23, 612381). They found a significant association of the higher-producing IL10 -1082G and TNF -857C alleles with stricturing disease; the association was strongest when these alleles were combined and persisted after multivariate analysis. Fowler et al. (2005) concluded that these 2 SNPs may help to predict disease behavior in Crohn disease patients.

Using a staged experimental design involving 1,841 ulcerative colitis cases and 1,470 controls, Fisher et al. (2008) found that multiple MHC markers showed strong association with ulcerative colitis in the first stage, with a peak (p = 4.7 x 10(-8)) around rs6927022 in a 400-kb haplotype block containing the BTNL2 gene (606000) and the HLA loci HLA-DQA1 (146880), HLA-DRA (142860), HLA-DRB5 (604776), and HLA-DRB1 (142857). Clear residual association with a SNP within the BTNL2 gene (rs9268480; p = 0.0036) suggested contribution of that gene or another in linkage disequilibrium with it.

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. Three SNPs near the HLA class II genes on chromosome 6p21, rs9268877, rs9268858, and rs9268480, were significantly associated with ulcerative colitis (combined p = 6.48 x 10(-18), 2.58 x 10(-12), and 3.15 x 10(-9), respectively).

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. McGovern et al. (2010) confirmed association with UC at rs2395185 (combined p = 8.8 x 10(-23)).