Evidence for genetic heterogeneity in inflammatory bowel disease (IBD); HLA genes in the predisposition to suffer from ulcerative colitis (UC) and Crohn's disease (CD)

Bouma, Gerd; Pool, M. Oudkerk; Crusius, J.B.A.; Schreuder, G. M. T.; Hellemans, H.P.R.; Meijer, Berrie; Kostense, P.J.; Giphart, M. J.; Meuwissen, S. G. M.; Peña, A. S.

doi:10.1046/j.1365-2249.1997.4121510.x

Cited by 55 publications

(19 citation statements)

References 30 publications

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“…Several previous studies have also observed associations of CD with DR13 in predominantly non-Jewish populations (1 6,25,28). Our association of CD with DR15 in the Jewish population has never previously been observed in CD patients although it has been observed in some studies of UC patients (15,24,27).…”

Section: Discussionsupporting

confidence: 56%

HLA class II alleles associated with susceptibility and resistance to Crohn's disease in the jewish population

Gulwani‐Akolkar¹,

Akolkar²,

Lin³

et al. 2007

Inflamm Bowel Dis

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Summary:Previous studies have suggested that susceptibility to Crohn's disease (CD) is associated with the histocompatibility complex (HLA) class I1 alleles DR1, DQ5, and DR13 in the Caucasian population, DR7 in the French and German populations, and DR4 and DQ4 in the Japanese population. However, little is known about the relationship between HLA class I1 alleles and CD in the Jewish population since these previous studies included few Jewish individuals. In order to determine whether the HLA associations observed with predominantly non-Jewish populations were also present in the Jewish CD population and whether there were any HLA class I1 alleles uniquely associated with CD in the Jewish population, 132 CD patients, of which 82 were Ashkenazi Jewish, were HLA-typed using serologic and DNA methods. Ethnically matched controls were similarly typed. No association with DR1 or DR13 was observed in the Jewish CD population although an association with DRI 3 (OR [odds ratio] = 5.3, p = 0.02) was observed in the non-Jewish CD population. However, an association with DR15 (OR = 2.7, p = 0.03), which is normally associated with ulcerative colitis, was observed in the Jewish, but not non-Jewish, CD group. In addition, a strong negative association was observed with DR3, which was especially striking in the Jewish population (OR = 0.35, p = 0.025); similar negative associations with DR3 have been observed by others using non-Jewish populations. Furthermore, a significant negative association with DR7 (OR = 0.45, p = 0.04) was observed in the Jewish, but not non-Jewish, population. Consistent with this was the negative association with DQ2 (OR = 0.38, p = 0.005), which is in strong linkage disequilibtium with both DR3 and DR7, in the Jewish, but not non-Jewish, population. These studies support previous suggestions that susceptibility to CD in Jewish and non-Jewish populations is determined by distinct genes and provide further support to the hypothesis that a gene on the DR3 haplotype may protect against CD. Furthermore, protection is conferred by the same or another gene found on Jewish, but not non-Jewish, DR7 haplotypes.

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Section: Discussionsupporting

confidence: 56%

HLA class II alleles associated with susceptibility and resistance to Crohn's disease in the jewish population

Gulwani‐Akolkar¹,

Akolkar²,

Lin³

et al. 2007

Inflamm Bowel Dis

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“…Differences in the frequency of HLA haplotypes between males and females occur in inflammatory bowel disease: DR3-DQ2 frequency was reduced in females with UC 25 and DRB1*15 was increased only in female UC patients. 30 Two other regions that showed strong evidence for malespecific linkage were chromosomes 1q31-32 and 18p11 (Table 2 and Figure 1). Neither of these regions was identified by genome scans.…”

Section: 29mentioning

confidence: 99%

Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6

et al. 2002

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Inflammatory bowel disease (IBD) is a multifactorial disorder, with both genetic and environmental factors contributing to the two clinical phenotypes of Crohn's disease (CD) and ulcerative colitis (UC). The underlying genetic model is thought to involve multiple genes with complex interactions between disease loci, and the NOD2 gene on chromosome 16 has recently been identified as a CD susceptibility locus. Several genome-wide linkage studies have identified candidate regions, but there has been little replication across studies. Here we investigate the role of sex-specific loci in susceptibility to IBD. Linkage data from our previously reported genome search and follow-up study were stratified by the sex of the affected sib pair. Non-parametric linkage analysis was performed using Genehunter Plus. Simulation studies were used to assess the significance of differences in LOD scores between male and female families for each chromosome. Several regions of sex-specific linkage were identified, including existing and novel candidate loci. The major histocompatibility region on chromosome 6p, referred to as IBD3, showed evidence of male-specific linkage with a maximum LOD score of 5.9 in both CD and UC male-affected families. Regions on chromosomes 11, 14 and 18 showed strong evidence of linkage in male-affected families but not in female-affected families. No evidence of sex-specific linkage was found in the IBD1 or IBD2 candidate regions of chromosomes 16 and 12. The existence of sex-specific linkage is further evidence of the complex mechanisms involved in IBD and will facilitate future studies to identify susceptibility genes.

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“…Ulcerative colitis (UC) is a chronic inflammatory mucosal disease associated with a strong familial pattern and a number of genetic loci implicated in disease susceptibility (5,29,36,37,49,53,54). Variation in penetrance, as well as demographic and epidemiologic features, indicates an important role for environmental factors in the inflammatory process of UC (38,48).…”

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confidence: 99%

Colonic Bacteria Express an Ulcerative Colitis pANCA-Related Protein Epitope

Cohavy¹,

Bruckner²,

et al. 2000

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Bacteria are a suspected pathogenic factor in inflammatory bowel disease, but the identity of the relevant microbial species remains unresolved. The pANCA autoantibody is associated with most cases of ulcerative colitis (UC) and hence reflects an immune response associated with the disease process. This study addresses the hypothesis that pANCA identifies an antigen(s) expressed by bacteria resident in the human colonic mucosa. Libraries of colonic bacteria were generated using aerobic and anaerobic microbiologic culture conditions, and bacterial pools and clonal isolates were evaluated for cross-reactive antigens by immunoblot analysis using the pANCA monoclonal antibody Fab 5-3. Two major species of proteins immunoreactive to pANCA monoclonal antibodies were detected in bacteria from the anaerobic libraries. Colony isolates of the expressing bacteria were identified as Bacteroides caccae and Escherichia coli. Isolation and partial sequencing of the B. caccae antigen identified a 100-kDa protein without database homologous sequences. The E. coli protein was biochemically and genetically identified as the outer membrane porin OmpC. Enzyme-linked immunosorbent assay with human sera demonstrated elevated immunoglobulin G anti-OmpC in UC patients compared to healthy controls. These findings demonstrate that a pANCA monoclonal antibody detects a recurrent protein epitope expressed by colonic bacteria and implicates colonic bacterial proteins as a target of the disease-associated immune response.

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Evidence for genetic heterogeneity in inflammatory bowel disease (IBD); HLA genes in the predisposition to suffer from ulcerative colitis (UC) and Crohn's disease (CD)

Cited by 55 publications

References 30 publications

HLA class II alleles associated with susceptibility and resistance to Crohn's disease in the jewish population

HLA class II alleles associated with susceptibility and resistance to Crohn's disease in the jewish population

Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6

Colonic Bacteria Express an Ulcerative Colitis pANCA-Related Protein Epitope

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