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DLG5 Variants in Inflammatory Bowel Disease
Abstract
Genetic variants within DLG5 were recently reported to be associated with inflammatory bowel disease (IBD). The aim of our study was to test for allelic and haplotype associations of six DLG5 variants in 668 IBD patients from two European populations. Furthermore, we evaluated whether DLG5 variants alter gastrointestinal permeability in Crohn's disease (CD).
Six DLG5 variants (p.R30Q, p.P1371Q, p.G1066G, rs2289308, DLG_e26, p.D1507D) were genotyped in two study populations: (1) German IBD patients (CD n = 250; ulcerative colitis (UC) n = 150) and German healthy controls (n = 422); (2) Hungarian IBD patients (CD n = 144; UC n = 124) and Hungarian healthy controls (n = 205). Subtyping analysis was performed in respect of CARD15 mutations and clinical characteristics. We also tested for differences within DLG5 genotypes in German CD patients with respect to gastroduodenal and intestinal permeability measured by triple-sugar-test.
Allele as well as genotype frequencies of DLG5 variants did not differ between IBD patients and controls in either study population. Indeed, the p.R30Q polymorphism was found more frequently in controls than in patients. The distribution of DLG5 genotypes in German and Hungarian CD patients with CARD15 mutations was not different from patients without mutated CARD15. We did also not observe any association between DLG5 variants and clinical parameters. Importantly, DLG5 variants were not associated with gastroduodenal or intestinal permeability.
We could not replicate that DLG5 is a relevant disease susceptibility gene for IBD in German or Hungarian subjects. In addition, we have no evidence that DLG5 variants are involved in altered gastrointestinal permeability in CD.
... 20 However, since this promising beginning there has been a sequence of studies that failed to replicate the original associations of the DLG5 30Q allele with increased risk, and haplotype A with reduced risk. [21][22][23][24][25][26][27][28][29][30] The association with the P1371Q variant has been replicated in 1 study, 29 but has not been replicated in 4 other studies. 20,24,26,27 The question of DLG5's involvement in the pathogenesis of CD and UC does not yet have a clear answer. ...
... [21][22][23][24][25][26][27][28][29][30] The association with the P1371Q variant has been replicated in 1 study, 29 but has not been replicated in 4 other studies. 20,24,26,27 The question of DLG5's involvement in the pathogenesis of CD and UC does not yet have a clear answer. We tested R30Q, P1371Q, and the rs2289311 SNP (tagging haplotype A) for association with CD, UC, and IBD in a New Zealand Caucasian population and performed extensive exploratory analysis using patient subgroups defined by age of first diagnosis, disease location, disease behavior, presence of family history of IBD, need for surgery, smoking status at diagnosis, use of immunomodulators, and presence of extraintestinal manifestations. ...
... Two studies have reported evidence of epistatic interaction of CARD15 CD susceptibility variants and DLG5 variants, 16,25 but most studies have not found evidence of interaction of CARD15 and DLG5 variants. [22][23][24]26,27,30 Allelic heterogeneity (multiple susceptibility variants within DLG5) and indirect association may also explain some of the difficulties replicating the association. 48 There may be 1 or more risk-conferring SNPs in linkage disequilibrium with the R30Q and rs2289311 SNPs. ...
Variants in the DLG5 gene have been associated with inflammatory bowel disease (IBD) in samples from some, but not all populations. In particular, 2 nonsynonymous single-nucleotide polymorphisms (SNPs), R30Q (rs1248696) and P1371Q (rs2289310), have been associated with an increased risk of IBD, and a common haplotype (called haplotype "A") has been associated with reduced risk.
We genotyped R30Q, P1371Q, and a haplotype A tagging SNP (rs2289311) in a New Zealand Caucasian cohort of 389 Crohn's disease (CD) patients, 406 ulcerative colitis (UC) patients, and 416 population controls. Each SNP was tested for association with disease susceptibility and clinical phenotypes. We also performed a meta-analysis of R30Q data from published association studies.
The haplotype A tagging SNP was associated with reduced risk of IBD at the 0.05 significance level (P=0.036) with an allelic odds ratio of 0.83 (95% confidence interval [CI]: 0.69-0.99). Association with haplotype A was strongest (odds ratio approximately 0.57) in UC patients with familial IBD or extraintestinal manifestations. The R30Q and P1371Q polymorphisms were not significantly associated with UC, CD, or IBD. Analysis of male and female data did not find any gender-specific associations. Meta-analysis gave no evidence of association of R30Q with IBD.
Meta-analysis demonstrates that the minor allele of R30Q is not a risk factor for IBD across populations. This study provides some evidence that DLG5 haplotype A is associated with reduced risk of IBD in the New Zealand Caucasian population, but this association will need to be replicated in an independent sample.
... 论 [110][111][112][113][114][115][116][117][118] . P1371Q与C D的关系只在1项研究中 ...
... 得到了验证 [117] , 另外4项均未能 [109,94,[114][115] . 新西 兰人群 [119] [120] 、Tenesa et al [121] 、Biank et al [122] 及Browning et al [ ...
The mechanism of inflammatory bowel disease (IBD) is partially understood, but it is certain that a genetic predisposition, through the inheritance of a number of contributory genetic polymorphisms, contributes to the pathogenesis of IBD. These variant forms of genes may be associated with an abnormal response to normal luminal bacteria. Those genes that have been consistently associated with IBD thus far primarily fall into one of three classes: those affecting bacterial recognition, those affecting immune response, and a third group affecting mucosal transport polarity or mucosal transporter function. This article reviews the IBD related genes mentioned above.
... Further, Scribble was found to accumulate in colorectal neoplasia in association with an altered distribution of b-catenin (Kamei et al. 2007). In addition to Scribble, the human ortholog of the Drosophila melanogaster tumor suppressor gene Lgl, was found to be reduced in colorectal tumor samples in a stage-dependent manner (Schimanski et al. 2005), and the human ortholog of D. melanogaster Discs Large (Dlg) has been associated with inflammatory bowel diseases (Stoll et al. 2004;Weersma et al. 2009), albeit debated (Büning et al. 2006), and colon cancer (Subbaiah et al. 2012). Altogether, these findings suggest a role for the cell polarity -regulating Scribble/Lgl/Dlg complex in the pathogenesis of inflammatory bowel disease (Ivanov et al. 2010) and in colon carcinogenesis (Kamei et al. 2007). ...
Intestinal epithelial cell polarity is instrumental to maintain epithelial homeostasis and balance communications between the gut lumen and bodily tissue, thereby controlling the defense against gastrointestinal pathogens and maintenance of immune tolerance to commensal bacteria. In this review, we highlight recent advances with regard to the molecular mechanisms of cell polarity–controlled epithelial homeostasis and immunity in the human intestine. © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.
... While not fully understood, human IBD is also thought to stem from a breach in the intestinal epithelium, which exposes immune cells in the underlying lamina propria to bacteria or bacterial products from the gut (reviewed in [63]). Genetic variants in DLG5 (a human homolog of C. elegans dlg-1 and Drosophila dlg) are associated with IBD [64,65], and intestinal permeability has been correlated with peripheral immune activation and clinical relapse in patients with Crohn's disease [66,67]. In IL-10 knockout mouse models of IBD, an unchecked T H 1 inflammatory response is associated with increased intestinal permeability [68]; other mouse models indicate that disruption of intestinal epithelial junction integrity alone, through expression of dominant negative E-cadherin, is sufficient to initiate the disease [69]. ...
Gut bacteria-host interactions have been implicated in the pathogenesis of numerous human diseases, but few mechanisms have been described. The genetically tractable nematode worm Caenorhabditis elegans can be infected with pathogenic bacteria, such as the human gut commensal Enterococcus faecalis, via feeding, making it a good model for studying these interactions.
An RNAi screen of 17 worm candidate genes revealed that knockdown of the transcription factor nhr-49, a master regulator of fat metabolism, shortens worm lifespan upon infection with E. faecalis (and other potentially pathogenic bacteria) compared to Escherichia coli. The functional similarity of nhr-49 to the mammalian peroxisome proliferator-activated receptors (PPARs) suggests that this is mediated through a link between fatty acid metabolism and innate immunity. In addition, knockdown of either dlg-1 or ajm-1, which encode physically interacting proteins in the C. elegans epithelial junction, also reduces worm lifespan upon E. faecalis challenge, demonstrating the importance of the intestinal epithelium as an immune barrier.
The protective roles identified for nhr-49, dlg-1, and ajm-1 suggest mechanistic interactions between the gut microbiota, host fatty acid metabolism, innate immunity, and epithelial junction integrity that are remarkably similar to those implicated in human metabolic and inflammatory diseases.
... In weiteren unabhängigen, großen Populationen wurden diese Ergebnisse überprüft, konnten aber nicht repliziert werden[68,69]. Ein Erklärungsversuch stellte die Arbeit von Friedrichs et al. aus derselben Arbeitsgruppe, die die intiale Assoziation beschrieben hat-tische Enzyme und Phosphatasen zur Degradation des Proteininhalts enthalten. ...
... Por otro lado, en un estudio realizado en Alemania, Italia y Canadá, se determinó que variantes del gen DLG5 R30Q constituyen un factor de susceptibilidad a la EC en hombres pero no así en mujeres (20). Por el contrario, Buning et al. (9) hallaron que variantes del mismo gen DLG5 R30Q no estarían implicadas en estas alteraciones gastrointestinales. ...
... However, DLG5 polymorphisms have been not replicated in different populations with IBD. 4,5 In order to elucidate the contribution of the DLG5 gene in the etiology of IBD, we performed the first study, to our best knowledge, that investigates DLG5 gene expression in colonic mucosa from patients with ulcerative colitis (UC). We studied DLG5 gene expression from colonic biopsies of UC patients from August 2009 to July 2010. ...
... However, DLG5 polymorphisms have been not replicated in different populations with IBD. 4,5 In order to elucidate the contribution of the DLG5 gene in the etiology of IBD, we performed the first study, to our best knowledge, that investigates DLG5 gene expression in colonic mucosa from patients with ulcerative colitis (UC). We studied DLG5 gene expression from colonic biopsies of UC patients from August 2009 to July 2010. ...
... Due to strong linkage disequilibrium in the region [93] a combination of functional and genetic evidence was used to implicate SNPs around the SLC22A4/5 genes (solute carrier family 22 (organic cation transporter), member 4/5; encoding for OCTN1/2) genes as potentially causative variants [94]. Both findings were replicated in independent CD cohorts [95][96][97], however several negative replication findings [98][99][100] have also emphasized the potential heterogeneity of the disease in different populations and the need for large, population-representative replication samples [101,102]. In addition, to these positional findings, several candidate studies included antibacterial peptides (with an interesting association of a copy number variant in the -defensin locus on 8p23.1 [103]) and other secreted mucus proteins, such as deleted in malignant brain tumour (DMBT)1 [104] and anterior gradient (AGR)2 [105]. ...
Recent advances have enabled a comprehensive understanding of the genetic architecture of inflammatory bowel disease (IBD) with over 30 identified and replicated disease loci. The pathophysiological consequences of disease gene variants in Crohn disease and ulcerative colitis, the two main subentities of IBD, so far are only understood on the single disease gene level, yet complex network analyses linking the individual risk factors into a molecular risk map are still missing. In this review, we will focus on recent pathways and cellular functions that emerged from the genetic studies (e.g. innate immunity, autophagy) and delineate the existence of shared (e.g. IL23R, IL12B) and unique (e.g. NOD2 for CD) risk factors for the disease subtypes. Ultimately, the defined molecular profiles may identify individuals at risk early in life and may serve as a guidance to administer personalized interventions for causative therapies and/or early targeted prevention strategies. Due to this comparatively advanced level of molecular understanding in the field, IBD may represent precedent also for future developments of individualized genetic medicine in other polygenic disorders in general.
... 101 Since the publication of the paper by Stoll et al, these variant alleles of the DLG5 gene have been the subject of a large number of association studies, generally with conflicting results with at best a very modest effect on CD susceptibility and phenotype. [105][106][107][108][109][110][111][112][113][114][115][116][117][118][119] In our Scottish childhood-onset population, we have demonstrated association of the 113A allele with increased risk of IBD, and on further analysis our data suggest that penetration of this variant is influenced by affluence. 106 ...
The discovery of nucleotide-binding oligomerization domain 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15) as the first susceptibility gene in Crohn's disease (CD) has shifted the focus of research into the pathogenesis of inflammatory bowel disease (IBD) firmly to the innate immune response and the integrity of the epithelial barrier. The subsequent implication in IBD of variant alleles of OCTN, DLG5, MDR1, and TLRs has provided further support for a new, more complex model of innate immunity function in the gastrointestinal tract. In this review, we examine the recent advances in our understanding of the influence of genetics of the innate immune response on IBD. We will focus on germline variation of genes encoding pathogen-recognition receptors, proteins involved in epithelial homeostasis and secreted antimicrobial proteins.
... Mammalian Dlg5/P-Dlg is a PDZ-containing (PSD-95, Dlg, ZO-1) MAGUK (membraneassociated guanylate kinase) protein with homology to Drosophila neoplastic tumor-suppressor discs large dlg. Sequence variation in human DLG5 was initially reported to associate with inflammatory bowel disease; however, this association was not observed in some subsequent studies (Buning et al., 2006;Stoll et al., 2004). Based on sequence similarity, it has been proposed that Dlg5 is another vertebrate homolog of Drosophila dlg, hence the gene was named Dlg5 (Nakamura et al., 1998). ...
Epithelial tubes represent fundamental building blocks of metazoan organisms; however, the mechanisms responsible for their formation and maintenance are not well understood. Here, we show that the evolutionarily conserved coiled-coil MAGUK protein Dlg5 is required for epithelial tube maintenance in mammalian brain and kidneys. We demonstrate that Dlg5(-/-) mice develop fully penetrant hydrocephalus and kidney cysts caused by a deficiency in membrane delivery of cadherin-catenin adhesion complexes and loss of cell polarity. Dlg5 travels with cadherin-containing vesicles and binds to syntaxin 4, a t-SNARE protein that regulates fusion of transport vesicles with the lateral membrane domain. We propose that Dlg5 functions in plasma membrane delivery of cadherins by linking cadherin-containing transport vesicles with the t-SNARE targeting complex. These findings show that Dlg5 is causally involved in hydrocephalus and renal cysts and reveal that targeted membrane delivery of cadherin-catenin adhesion complexes is critical for cell polarity and epithelial tube maintenance.
... 12 Numerous genetic variants initially believed to be associated with either CD or UC have failed replication in other cohorts. 13,14 Thus, it is of fundamental importance to elucidate these variants in other IBD cohorts. In addition, our progress in understanding the genetic background in IBD should go along with the attempt to correlate genotyping results with disease behaviour. ...
A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease.
To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour.
We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics.
The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes.
The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.
... MAGUK proteins are known to form scaffolds for other proteins involved in intracellular signal transduction and could therefore interfere with the integrity of the epithelial barrier. Since the publication of the index paper, germline variation of DLG5 has been studied in a large number of populations but replication has only been demonstrated in a few (77) (Table 3) (51,57,60,76,(79)(80)(81)(82)(83)(84)(85)(86)(87)(88). Whether true genetic heterogeneity, phenotypic differences between patient populations, and/or stratification of control groups are responsible for these discrepancies remains a subject of intense debate, but a meta-analysis of most published studies suggests it does not have a major role to play in IBD susceptibility (78). ...
Great progress in the understanding of the molecular genetics of inflammatory bowel disease (IBD) has been made over the last 10 years. Strong epidemiological evidence, based initially on concordance data in twin/family studies, led to the application of genome-wide linkage analysis involving multiply affected families and the identification of a number of susceptibility loci. Further characterization of the IBD1 locus on chromosome 16 led to the discovery of the NOD2/CARD15 gene as the first susceptibility gene in Crohn's disease for 2001. This landmark finding has led to a redirection of basic research in IBD with interest focused principally on regulation of the innate immune response and mucosal barrier function. Within the last year, the use of genome-wide association studies has provided new insights into primary pathogenetic mechanisms; several new genes such as the Interleukin-23 receptor (IL23R) and ATG16L1 (autophagy-related 16-like 1) genes are strongly implicated. Overall, these studies promise to change our fundamental understanding of IBD pathophysiology and to have implications for clinical practice.
... 71 Initial enthusiasm has been discouraged by several studies from Europe and Japan, failing to show any association for DLG5 with IBD. [72][73][74][75] In the same way as for OCTN, large population-based case-control studies are needed to elucidate the role of DLG5 in IBD susceptibility. ...
Inflammatory bowel disease (IBD) comprising ulcerative colitis (UC) and Crohn's disease (CD) is multigenic disorder. Tremendous progress has been achieved in unravelling the genetic background of IBD. It has led to the discovery of mutations in NOD2 associated with ileal CD and numerous other genes have been found to be associated with IBD susceptibility.
A review of the literature on the genetic background of IBD was performed.
It is only partially understood how mutations in NOD2 lead to CD. Mouse models, in vitro data and studies in humans offer conflicting data as regards whether there is a loss or gain of function of NOD2 in CD. Several additional genes have been identified of which only a few are currently being recognized as potential disease causing or disease modifying genes. Promising candidate genes include TLR4, MDR1, NOD1 (CARD4), DLG5 as well as the IBD5 locus including SLC22A4/5.
Although genetic research has not yet led to a better prediction of the disease course or patient selection for medical therapy, remarkable progress has been made in the understanding of the pathogenesis of IBD. For future genetic research, accurate phenotyping of patients is very important and large population-based cohorts are needed. Eventually, genetic research may be able to classify different disease phenotypes on a more detailed molecular basis and may provide important contributions in the development of new therapeutic approaches.
p>Inflammatory bowel disease (IBD) is the collective term for a group of chronic idiopathic conditions that affect the gastrointestinal tract. These cause significant long-term morbidity in both adults and children. The pathogenesis involves the gut mucosal immune system and genetic factors affect disease expression.
Previous studies have shown that Smad7, a negative regulatory of transforming growth factor (TGF)-β, is expressed at high levels in IBD in gut mucosal biopsies and lamina propria mononuclear cells, preventing the anti-inflammatory effects of TGF-β. We confirm high Smad7 levels in IBD. This persists in lamina propria mononuclear cells ex-vivo . Tumour necrosis factor-α, but not interferon-γ or TGF-β, increases Smad7 in lamina propria mononuclear cells from normal gut mucosa. However, Smad7 mRNA levels are not significantly different in normal and IBD tissue.
Clinical studies of IBD patients examine the use of non-invasive methods to assess chronic gut symptoms and disease activity. Faecal calprotectin, a neutrophil protein, is a marker of gut inflammation. Using a highly sensitive assay, faecal calprotection >50μg/g has 85% sensitivity for pathology in children with chronic gut symptoms, but is not specific for IBD. Calprotectin levels correlate with disease activity in ulcerative colitis, but not in Crohn’s disease. Ultrasound imaging of the colon and terminal ileum shows that increased bowel wall thickens is also a marker of disease activity in IBD, but superior mesenteric artery blood flow, measured by Doppler analysis, does not correlate with disease activity. These data define new roles for both calprotectin and ultrasonography in the assessment of children with chronic gut symptoms and IBD.</p
Growing evidence from recent studies has demonstrated an association between inflammatory bowel disease (IBD) susceptibility and two polymorphisms of DLG5 R30Q (rs1248696) and P1371Q (rs2289310), but the results remain controversial. We conducted a meta-analysis including a total of 22 studies with 10,878 IBD patients and 7917 healthy controls for R30Q and 5277 IBD cases and 4367 controls for P1371Q in order to systematically assess their association with the disease. The results indicated that R30Q was significantly associated with reduced susceptibility to IBD in Europeans by allelic and dominant comparisons, but not in overall population. No significant association was found between R30Q and Crohn’s disease (CD) or ulcerative colitis (UC). P1371Q was associated with increased risk of IBD in Europeans and Americans. On the contrary, a decreased risk of IBD was observed in Asian population for P1371Q. In disease subgroup analysis, we found that P1371Q was also significantly associated with CD, but this relationship was not present for UC. In conclusion, our results strongly suggest that the both polymorphisms of DLG5 are correlated with IBD susceptibility in an ethnic-specific manner. Additional well-designed studies with large and diverse cohorts are needed to further strengthen our findings.
The inflammatory bowel diseases (IBD), Crohn disease and ulcerative colitis, are immune-mediated disorders resulting in chronic, relapsing inflammation of the gastrointestinal tract. The complex nature of IBD supports the notion that its origin is likely multifactorial, constituting both genes and environmental factors. It has been hypothesized that environmental factors and maladaptive immune responses to gastrointestinal flora generate a dysregulated inflammatory cascade creating mucosal injury in genetically susceptible individuals. Over the last decade, considerable interest and research has focused on the genetic aspect of IBD. The identification of linkage between Crohn disease and the pericentromeric region of chromosome 16 (IBD1) by Hugot in 1996 spawned a series of genome scans and linkage analyses in search of susceptibility and phenotypic modifier genes (Nature 379:821–3, 1996). In 2001, the discovery that specific polymorphisms in the CARD15/NOD2 gene at the IBD1 locus were associated with Crohn disease engendered a new era of genotype–phenotype investigations (Nature 411:599–603, 2001; Nature 411:603–6, 2001). The advent of genome-wide association studies has resulted in the successful identification of new, well-replicated disease associations. The heterogeneity of IBD phenotypes suggests that it is a polygenic disorder in which susceptibility loci act in epistasis with other disease-modifying genes and the environment to produce disease. Understanding genetic associations of IBD can provide patients and their families with useful information that may help them cope with the disease. Furthermore, as our knowledge of genotype–phenotype associations grows, it is anticipated that genotyping at the onset of disease may enable physicians to predict disease course and tailor medical therapies specific for each patient.
The genetic susceptibility is clearly important in the complex inheritance of inflammatory bowel disease (IBD). Furthermore,
the etiologic basis of the relationship between Crohn’s disease (CD) and ulcerative colitis (UC) is as yet unexplained. The
strongest evidence supporting the contribution of inherited factors in the pathogenesis of CD and UC comes from concordance
rates in twin pairs. The development of a linkage map of the human genome with informative microsatellite markers has enabled
hypothesis-free scanning of the human genome for loci associated with the susceptibility to simple monogenic and polygenic
diseases. Many susceptibility loci have been implicated in IBD with varying degrees of replication and statistical support.
Genetic research in IBD has advanced in understanding the clinical heterogeneity of the disease and has started to tackle
the complex interactions between genetic and environmental risk factors in IBD. It is probably to be possible in the future
that these genetic markers will find their place in an integrated molecular diagnostic and prognostic approach to patients
with IBD.
KeywordsGenetic-IBD-Susceptibility-Polymorphisms-Molecular markers
The SNP R30Q (rs1248696) within the discs large homolog 5 (DLG5) gene has been associated with inflammatory bowel disease (IBD). In this study, we examined the genetic association of another DLG5 SNP P1371Q (rs2289310) with IBD and its interaction with R30Q in disease susceptibility.
A total of 213 IBD patients [106 familial; 59 Crohn's disease (CD) and 47 ulcerative colitis (UC)] and 107 sporadic [57 CD and 50 UC] were included in this study. Controls included 139 non-diseased family members of IBD patients and 170 unrelated healthy subjects. Genotypes for P1371Q and G1066G polymorphisms were determined by PCR-based RFLP. Epistasis between P1371Q and R30Q in disease susceptibility was analysed using a novel statistical model.
P1371Q was associated with IBD (OR = 2.335, 95% CI = 1.097-4.972, p = 0.0246), however, the synonymous variant G1066G (rs1648234) was not. Gender distribution analysis revealed the A allele of P1371Q was significantly associated with IBD in women (OR = 3.765, 95% CI = 1.307-10.85, p = 0.0095). Modeling interaction between P1371Q and R30Q showed a significant increase in disease association (OR = 2.265, 95% CI = 1.405-3.652, p = 0.0007) incidence for sporadic and familial IBD patients. Further epistatic analysis identified an increased significance in the association of gender with IBD (OR = 4.311, 95% CI = 2.101-8.846, p = 0.0001).
DLG5 P1371Q was associated with IBD and this association was female-specific. A significant epistatic interaction between P1371Q and R30Q was observed, suggesting that P1371Q is complementary to R30Q, with R30Q exhibiting a dominant effect in IBD susceptibility.
Crohn's disease frequency has increased in recent years in Iran. Genetic and environmental factors predispose people to this disease. Mutation in Caspase Recruitment Domain 15 (CARD15) gene is the most well known genetic predisposing factor to this disease. Frequency of three common CARD15 mutations has been studied in different ethnic groups. We aimed to study the frequency of these mutations in Iranian patients affected with Crohn's Disease.
One hundred fifteen proved cases of Crohn Disease and 115 age and sex matched normal controls were recruited in this study. Lf1007fs, R702W and G908R mutations were studied by Polymerase Chain Reaction-Restriction Fragment Length Polymorphims (PCR-RFLP) followed by sequencing the positive cases.
Lf1007fs and G908R mutations were not found in either patients or age-sex matched controls. Just in two patients, R702W mutation was proved by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and sequencing. None of these patients had illeal or fibrostenotic type of disease while 14.7% of total patients had stricturing type of disease. No complication was seen in these two patients while 50.4% of patients had acquired complications during the course of disease.
The three mutations described are not responsible for the pathogenesis of Crohn's Disease in Iranians. The results are in accordance with other Asian nations' studies on IBD Patients.
The association of DLG5 R30Q with IBD has been replicated in several populations, but is not statistically significant in others. We studied the incidence of DLG5 alleles in a population of IBD patients from Pennsylvania.
DLG5 R30Q (rs1248696) and G1066G (rs1248634) were analyzed with PCR-based RFLP methods in a total of 521 subjects, that included 105 individuals with IBD and 139 without IBD from a familial IBD registry, 107 with sporadic IBD, and 170 unrelated healthy controls. R30Q was further analyzed with SNPlex Genotyping System in 473 samples.
RFLP genotyping data showed that, DLG5 R30Q was significantly associated with IBD overall (p=0.006), and separately with CD (p=0.009) and UC (p=0.024). The association of R30Q with IBD was entirely due to a male-associated effect (male vs female p=0.015 vs 0.241 (IBD), p=0.024 vs 0.190 (CD), and p=0.019 vs 0.575 (UC)). The frequency of the A allele carriage was elevated in both affected and unaffected members in the familial IBD cohort compared to healthy controls (p=0.037). In the family pedigrees, we observed differences in the expression of IBD in individuals carrying the A allele between families.
In the studied population, DLG5 R30Q was associated with all forms of IBD. An elevated presence of the R30Q variant was observed in all members of a familial IBD registry. This association of the R30Q variant with IBD was male-specific.
Coeliac disease (CD) is an auto-immune disease triggered by ingestion of gluten, a protein found in wheat, rye and barley. In susceptible individuals the ingestion of gluten triggers an auto-immune reaction, giving chronic inflammation of the small intestinal mucosa, and generally resulting in villous atrophy. This thesis starts with an overview of CD including the history, pathogenesis, clinical characteristics, diagnosis and genetic factors. We subsequently investigated the reliability of new serological tests as well as the yield of gluten challenge in young children. Serum antibodies against tissue transglutaminase (IgA-tTG) were compared with serum antigliadin antibodies (IgA-AGA and IgG-AGA) and anti-endomysium antibodies (IgA-EMA) in the diagnosis of CD in a group of patients and controls who were all biopsied. Human IgA-tTG had a sensitivity of 96% and a specificity of 100% and is the serological screening method of choice. Thereafter we analyzed a new non-invasive marker for intestinal mucosal damage, the intestinal fatty acid binding protein (I-FABP). The serum levels of I-FABP were significantly elevated in children with biopsy proven CD and correlated significantly with the severity of villous atrophy. Furthermore, I-FABP was of additional value in the follow-up of CD. Thus, I-FABP improves the reliability of the current serologic parameters (IgA-tTG and IgA-EMA) both in the diagnosis of CD and in the follow-up. Then the diagnostic yield of routine gluten challenges was investigated in children diagnosed with CD under the age of two years. Based on our results we could conclude that routine gluten challenge in this group of patients is not necessary when villous atrophy at intestinal biopsy is present in combination with a raised serum IgA-EMA. In the second part an overview of the recent genetic developments is given. We subsequently showed that the newly found MYO9B gene is a risk factor for the development of refractory coeliac disease (RCD) type II and enteropathy-associated T-cell lymphoma (EATL). Both MYO9B and HLA-DQ2 homozygosity seem to be involved in the prognosis of CD and the development of RCD II and EATL. Thereafter three CD associated genes (MYO9B, MAGI2 and PARD3) were studied. These genes might encode tight junction proteins and thus might have a role in regulating intestinal permeability, but evidence for this function is far from complete. It was hypothesized that these three CD-associated genes are associated with an increased intestinal permeability as revealed by elevated antibodies against gliadin (AGA). However in a cohort of patients with Down syndrome we consistently found that AGA concentration was lower instead of increased in patients with a CD associated risk genotype. This might be due to different immunological mechanisms in this group of patients with Down syndrome, possibly involving altered induction and/or maintenance of tolerance. The field of genetics in CD and other autoimmune diseases is moving rapidly. Multiple genes seem to contribute to CD and to each of the major autoimmune disorders, with significant genetic overlap between them. Future studies will extend our knowledge both of the role of intestinal permeability and of associated genetic risk factors in CD and in other autoimmune diseases.
The IBD5 locus (MIM#606348) on chromosome 5q31 has been demonstrated to confer increased risk for inflammatory bowel disease. Controversial reports have been published about the significance of individual loci located in this region. Here we investigated the possible genetic association of inflammatory bowel diseases with C1672T of SLC22A4 and G-207C SLC22A5 alleles, and with IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility variants of the IBD5 region located on chromosome 5q31.
Total of 440 patients, 206 with Crohn's disease, 234 with ulcerative colitis, and 279 controls were studied by PCR-RFLP methods.
Neither the C1672T, and G-207C alleles, nor the TC haplotype were found to confer risk for Crohn's disease or ulcerative colitis. By contrast, both of the minor allele frequencies of IGR2096a_1 T (48.1%) and IGR2198a_1 C (46.1%) were increased in Crohn's disease subjects as compared with the controls (38.5% and 38.4%, respectively; p<0.05). Using regression analysis adjusted to age and gender these alleles were found to confer risk for Crohn's disease (OR=1.694, 95% CI: 1.137-2.522; p=0.010 for T allele, OR=1.644, 95% CI=1.103-2.449; p=0.015 for C allele of IGRs). In UC no such associations were found.
Our results revealed the susceptibility nature of the examined IGR minor alleles in Hungarians, which nation differs historically from the surrounding Caucasian populations in origin of the founders of the state.
Crohn's disease and ulcerative colitis are chronic inflammatory disorders caused by a disruptive interaction between the immune system and gut luminal factors. Although the exact aetiology of IBD remains unclear, accumulating data, including genome-wide association studies (GWAS), have advanced our understanding of the immunopathogenesis. This review highlights the role in gut homeostasis and IBD pathogenesis. It focuses on past and recent advances in our understanding of IBD, including genetics and immunobiology. Recently published GWAS have confirmed earlier findings related to the NOD2 gene and the IBD5 locus. In addition, over 30 novel loci have been identified. Several promising associations between Crohn's disease and gene variants have been identified and replicated, the two most widely replicated being variants in the IL23R and ATG16L1 genes. These findings highlight and further support the importance of the immune system and its interactions with the intestinal flora in the pathogenesis of inflammatory bowel disease.
We investigated the possible association of IBD with C1672T of SLC22A4 and G-207C of SLC22A5 alleles, and with the novel IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility loci, all located on IBD5 locus of chromosome 5q31.
DNA of 217 Crohn's disease, 252 ulcerative colitis, and 290 control patients were analyzed by polymerase chain reaction/restriction fragment length polymorphism methods.
Neither the C1672T and G-207C alleles, nor the TC haplotype were found to be risk factors. By contrast, the minor allele frequencies of IGR2096a_1 T (47.2%) and IGR2198a_1 C (45.9%) were increased in Crohn's disease compared with the controls (38.2% and 37.7%, respectively; p < 0.05); multivariate regression analysis revealed a risk nature for Crohn's disease (OR = 1.748, 95% CI 1.186-2.574; p = 0.007 for T allele, OR = 1.646, 95% CI 1.119-2.423, p = 0.011 for C allele of IGRs).
The data suggest a special haplotype arrangement of susceptibility genes at the IBD5 locus in Hungarians, which nation differs historically from the surrounding Caucasian ethnicities in its origin.
A significant association between the DLG5 variant (R30Q) and inflammatory bowel disease (IBD) has been confirmed in several independent adult IBD cohorts. There is growing evidence that gender significantly influences R30Q susceptibility in Crohn's disease (CD). Pediatric onset CD features a significantly lower incidence for female children compared with male children. We, therefore, studied the influence of gender on R30Q susceptibility in an exclusively pediatric onset IBD cohort.
A total of 281 CD (181 trios) and 479 population-based controls were genotyped for DLG5 R30Q using Taqman assay. Association was tested by case-control and transmission disequilibrium testing analysis. Multivariate logistic regression was performed to investigate gene-gene and gene-gender interactions, as well as genotype-phenotype correlations.
Overall allele frequency for R30Q was 8.5% in CD and 10.3% in controls. Logistic regression showed R30Q had no association with CD (OR 0.81, 95% CI 0.55-1.20, P= 0.3) when the cohort was analyzed as a whole. Stratified by gender, a significant negative association was detected for R30Q in female children (OR 0.39, 95% CI 0.2-0.77, P= 0.006), but not in male children. Gender was found to be an effect modifier of the association between R30Q and CD as the odds ratios in female children and male children differed significantly. The gender-specific association of R30Q and CD was independent of additional CD risk factors such as CARD15 and IBD5.
DLG5 has a gender-specific role in the susceptibility of pediatric CD. Specifically, the significant negative association found between DLG5 R30Q and CD in female children suggests DLG5 may have a protective effect in CD susceptibility for female children.
To assess the contribution of the 113 G-->A missense mutation within the discs, large homolog 5 (DLG5) gene in childhood-onset inflammatory bowel disease (IBD) in Scotland.
Two-hundred and ninety-six children with IBD were studied. Parental DNA was also collected for transmission disequilibrium testing (TDT) analysis. Genotyping was performed by TaqMan. Genotype-phenotype analysis was also undertaken. Socioeconomic status was assigned using a deprivation category (DepCat) score 1 through 7 (1 = most affluent).
TDT analysis demonstrated a significant association with IBD (P = .045). On unifactorial analysis, 113A carriage was associated with: (1) higher social class (DepCat 1 compared with 2-7, and 1-2 compared with 3-7) (66.7% vs 22.6%, P = .0005, OR 6.84 [1.99-23.55] and 37.2% vs 22.2%, P = .03, OR 2.08 [1.04-4.17], respectively); (2) higher height centile (>75th centile vs <75th centile) (42.9% vs 23.1%, P = .01, OR 2.50 [1.18-5.28]); and (3) male sex in Crohn's disease (CD) (29.3% vs 16.9%, P = .04, OR 2.04 [1.01-4.11]). Multifactorial analysis demonstrated that higher social class (DepCat 1) was independently associated with carriage of variants of 113A (P = .001, OR = 6.92 [2.24-21.33]).
DLG5 113A is associated with increased susceptibility to IBD in Scottish children. The effect may be most marked for those children living in relative affluence.
Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.
Genetic susceptibility may play a more important role in the etiology of early-onset inflammatory bowel disease (IBD) than in late-onset IBD, and therefore pediatric-onset IBD patients can be expected to have a higher frequency of gene mutations. We aimed to determine genotypes and phenotypes of patients with pediatric-onset IBD, to compare them with those of patients with adult-onset IBD and with controls, and to identify genotype-phenotype associations.
Polymorphisms R702W, G908R, and 3020insC of CARD15 (caspase activating recruitment domain 15); Asp299Gly and Thr399Ile of TLR4; -207G-->C, 1672C-->T (L503F), rs3792876, rs274551, rs272893, and rs273900 of SLC22A4/5; and 113G-->A as well as rs2289311, rs1270912, and rs2165047 of DLG5 (Drosophila discs large homologue 5) were assessed in 103 pediatric-onset and 696 adult-onset IBD patients. Phenotypic classification was based on disease localization and behavior.
Homozygosity for 3020insC in CARD15 was significantly higher in patients with pediatric-onset Crohn's disease (CD) than in patients with adult-onset CD (4.2% versus 0.6%, 95% confidence interval [CI] 1.2-42.0). Homozygosity for single-nucleotide polymorphism (SNP) rs3792876 in SLC22A4/5 was significantly higher in patients with pediatric-onset CD than in patients with adult-onset CD (6.1% versus 1.1%, P=0.02). Polymorphism 3020insC in CARD15 was associated with ileal involvement (1.9% versus 13.3%, CI 1.0-53.8) and a positive family history (6.1% versus 20%, CI 1.2-9.0). DLG5 SNP rs2165047 was significantly associated with perianal disease (50% versus 21.2%, CI 1.4-4).
Polymorphisms 3020insC in CARD15 and SNP rs3792876 in SLC22A4/5 occurred statistically significantly more often in patients with pediatric-onset CD than in patients with adult-onset CD. Polymorphisms 3020insC in CARD15 and SNP rs2165047 in DLG5 were associated with specific phenotypes in this pediatric-onset CD cohort.
Paratuberculosis or Johne's disease is a chronic enteritis of the cattle and other small ruminant animals caused by Mycobacterium avium subsp. paratuberculosis. In Argentina, the strains were characterized in beef and dairy cattle and deer in different genetic patterns by molecular tools. M. avium subsp. paratuberculosis has been linked in men to a chronic inflammation of the intestine, named Crohn's disease. There is clinical and experimental evidence to link M. avium subsp. paratuberculosis with Crohn's disease by PCR, positive bacteriological culture from mother milk, blood and affected tissues by in situ hybridization. The milk and sub-products might be one of the possible infection sources and it has been suggested that M. avium subsp. paratuberculosis could resist pasteurization. Several works showed that this mycobacteria could be present in retail milk of countries such as United Kingdom, USA, Czech Republic, and recently in Argentina. M. avium subsp. paratuberculosis was associated with different dairy products and water for human consumption. Therefore, it is possible that these food sources may have a role for transmission. New investigations should emphasize the role of contaminated food and water in human infection around the world and determine the possible zoonotic role of M. avium subsp. paratuberculosis.
Inflammatory bowel disease (IBD) arises in part from a genetic predisposition, through the inheritance of a number of contributory genetic polymorphisms. These variant forms of genes may be associated with an abnormal response to normal luminal bacteria. A consistent observation across most populations is that any of three polymorphisms of the Caspase-activated recruitment domain (CARD15) gene are more prevalent in IBD patients as compared with unaffected controls. Similar aberrant responses to bacteria are associated with variants in Autophagy-related 16-like 1 (ATG16L1) and human defensin (HBD-2, -3 and -4) genes. The defective bacterial signal in turn leads to an excessive immune response, presenting as chronic gut inflammation in susceptible individuals. Inconsistent population reports implicate the major histocompatability complex (MHC), that encodes a number of human leukocyte antigens (HLA), MHC class I chain-related gene A (MICA) or cytokines, such as tumour necrosis factor-alpha (TNF-α). Toll-like receptors encoded by the TLR4 or TLR9 genes may also play a role. Recent whole genome scans suggest that a rare variant in the interleukin-23 receptor (IL23R) gene may actually protect against IBD. Other implicated genes may affect mucosal cell polarity (Drosophila discs large homologue 5, DLG5) or mucosal transporter function (sodium dependent organic cation transporters, SLC22A4 and SLC22A5). A variant in ABCB1 (ATP-binding cassette subfamily B member 1) may be especially associated with increased risk of UC.
DLG5 p.R30Q has been reported to be associated with Crohn disease (CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case-control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male-female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD.
DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male-female frequency differences in controls and for case-control frequency differences in men and in women.
The data showed no male-female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p = 0.049, OR = 0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p = 0.058, OR = 0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p = 0.010, OR = 0.86, 95% CI 0.76 to 0.97), but not in men.
DLG5 30Q is associated with a small reduction in risk of CD in women.
Celiac disease (CD) is associated with HLA-DQ2 and HLA-DQ8 and has been linked to genetic variants in the MYO9B gene on chromosome 19. HLA-DQ2 homozygosity is associated with complications of CD such as refractory celiac disease type II (RCD II) and enteropathy-associated T-cell lymphoma (EATL). We investigated whether MYO9B also predisposes to RCD II and EATL.
Genotyping of MYO9B and molecular HLA-DQ2 typing were performed on 62 RCD II and EATL patients, 421 uncomplicated CD patients, and 1624 controls.
One single nucleotide polymorphism in MYO9B showed a significantly different allele distribution in RCD II and EATL patients compared with controls (P = .00002). The rs7259292 T allele was significantly more frequent in RCD II and EATL patients compared with CD patients (P = .0003; odds ratio [OR], 3.61; 95% confidence interval [CI], 1.78-7.31). The frequency of the haplotype carrying the T allele of this single nucleotide polymorphism was significantly increased in RCD II and EATL patients (11%), compared with controls (2%) and CD patients (3%) (OR, 6.76; 95% CI, 3.40-13.46; P = 2.27E-09 and OR, 4.22; 95% CI, 1.95-9.11; P = .0001, respectively). Both MYO9B rs7259292 and HLA-DQ2 homozygosity increase the risk for RCD II and EATL to a similar extent when compared with uncomplicated CD patients (OR, 4.3; 95% CI, 1.9-9.8 and OR, 5.4; 95% CI, 3.0-9.6, respectively), but there was no evidence for any interaction between these 2 risk factors.
We show that both MYO9B and HLA-DQ2 homozygosity might be involved in the prognosis of CD and the chance of developing RCD II and EATL.
Inflammatory bowel disease (IBD)--Crohn's disease (CD) and ulcerative colitis (UC)--and celiac disease are intestinal inflammatory disorders with a complex genetic background. Recently, two novel genes were found to be associated with IBD susceptibility. One, an uncommon coding variant (rs11209026) in the gene encoding for the interleukin-23 receptor (IL23R), conferred strong protection against CD. The other, rs2241880 in the autophagy-related 16-like 1 gene (ATG16L1), was associated with CD. We performed a case-control study for the association of IBD with IL23R and ATG16L1 in a Dutch cohort. We also looked at the association of IL23R and ATG16L1 with celiac disease.
Five hundred eighteen Dutch white IBD patients (311 CD and 207 UC, including 176 trios of patients with both parents), 508 celiac disease patients, and 893 healthy controls were studied for association with the rs11209026 (IL23R) and rs2241880 (ATG16L1) single nucleotide polymorphisms (SNP).
The rs11209026 SNP in IL23R had a protective effect for IBD in the case-control analysis (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.10-0.37, P= 6.6E-09). Both CD (OR 0.14, CI 0.06-0.37, P= 3.9E-07) and UC (OR 0.33, CI 0.15-0.73, P= 1.4E-03) were associated with IL23R. For ATG16L1, the rs2241880 SNP was associated with CD susceptibility (OR 1.36, CI 1.12-1.66, P= 0.0017). The population-attributable risk of carrying allele G is 0.24 and is 0.19 for homozygosity for allele G in CD. No association was found between IL23R or ATG16L1 and celiac disease.
We confirmed the association of IL23R and ATG16L1 with CD susceptibility and also the association of IL23R with UC. We found IL23R and ATG16L1 were not associated with celiac disease susceptibility.
Inflammatory bowel disease (IBD) results from an aberrant immune response to the indigenous intestinal flora in genetically susceptible hosts. Therefore, the study of candidate genes involved in host pathogen interactions is of key interest.
In this two-center, retrospective German and Hungarian cohort study, patients with Crohn's disease (CD) (n = 379; German n = 235, Hungarian n = 144) and ulcerative colitis (UC) (n = 263; German n = 145, Hungarian n = 118) and healthy controls (n = 605; German n = 403, Hungarian n = 202) were genotyped for the presence of the CD14 c.1-260C>T promoter variant and the TLR4 c.896A>G (p.D299G) variant by melting curve analysis using fluorescence resonance energy transfer probes. Data were stratified according to the presence of NOD2 (CARD15) mutations and a detailed genotype-phenotype analysis was performed.
In the German cohort the CD14 single-nucleotide polymorphism was associated with UC, but not CD (UC p = 0.016 vs. CD p = 0.190), while the opposite was found in the Hungarian cohort (UC p = 0.083 vs. CD p = 0.019). No association of IBD with the TLR4 single-nucleotide polymorphism was found in either cohort (UC p = 0.430, CD p = 0.783 vs. UC p = 0.745, CD p = 0.383).
IBD appears to be associated with the CD14 c.1-260C>T promoter variant in Germans and Hungarians, but not with the TLR4 c.896A>G (p.D299G) variant.
Celiac disease (CD) is a complex genetic disorder with multiple contributing genes. Linkage studies have identified several genomic regions that probably contain CD susceptibility genes. The most important genetic factors identified are HLA-DQ2 and HLA-DQ8, which are necessary but not sufficient to predispose to CD. The associations found in non-HLA genomewide linkage and association studies are much weaker. This might be because a large number of non-HLA genes contributes to the pathogenesis of CD. Hence, the contribution of a single predisposing non-HLA gene might be quite modest. Practically all CD patients carry HLA-DQ2 or HLA-DQ8, while the absence of these molecules has a negative predictive value for CD close to 100%. Genetic risk profiles for CD would be helpful in clinical practice for predicting disease susceptibility and progression.
Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn's disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors. (c) 2008 WJG. All rights reserved.
The noninvasive assessment of intestinal permeability in humans has a 20-year history. Because the tests are increasingly used in clinical practice and research and because there is much controversy, we reviewed the literature and outlined the potential and possible shortcomings of these procedures. Data was obtained from personal files and from a systemic search through MEDLINE and EMBASE. The principle of the differential urinary excretion of orally administered test markers is explained with reference to the desired physicochemical properties of the markers and how the principle can be exploited to allow assessment of various other gastrointestinal functions. The use of intestinal permeability tests for diagnostic screen for small bowel disease and assessment of responses to treatment, the pathogenesis of disease, normal intestinal physiology, and the effect of drugs and toxins on the intestine is described and reviewed. The controversy surrounding the anatomic location of the permeation pathways that the markers use is highlighted. Noninvasive tests of intestinal permeability have fulfilled early promises of usefulness in clinical practice and research. There is now a need for integrated research into the basic mechanisms of regulatory control of the intestinal barrier function.
Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.
Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
Mutations in the NOD2 gene are strongly associated with susceptibility to Crohn's disease (CD). We analyzed a large cohort of European patients with inflammatory bowel disease to determine which mutations confer susceptibility, the degree of risk conferred, their prevalence in familial and sporadic forms of the disease, and whether they are associated with site of disease.
Individuals were genotyped for 4 NOD2 mutations: P268S, R702W, G908R, and 3020insC. Allelic transmission distortion to 531 CD- and 337 ulcerative colitis-affected offspring was assessed by the transmission disequilibrium test. Association was also tested in an independent cohort of 995 patients with inflammatory bowel disease and 290 controls. Cases were stratified by disease site and compared across NOD2 genotypes.
R702W, G908R, and 3020insC were strongly associated with CD but not with ulcerative colitis. Linkage disequilibrium was observed between P268S and the other mutations, forming 3 independent disease haplotypes. Genotype relative risks were 3.0 for mutation heterozygotes and 23.4 for homozygotes or compound heterozygotes. The frequency of NOD2 mutations was higher in cases from families affected only with CD and was significantly increased in ileal-specific disease cases compared with colon-specific disease (26.9% vs. 12.7%, P = 0.0004).
The R702W, G908R, and 3020insC mutations are strong independent risk factors for CD and are associated particularly with ileal disease.
Crohn disease and ulcerative colitis are two subphenotypes of inflammatory bowel disease (IBD), a complex disorder resulting from gene-environment interaction. We refined our previously defined linkage region for IBD on chromosome 10q23 and used positional cloning to identify genetic variants in DLG5 associated with IBD. DLG5 encodes a scaffolding protein involved in the maintenance of epithelial integrity. We identified two distinct haplotypes with a replicable distortion in transmission (P = 0.000023 and P = 0.004 for association with IBD, P = 0.00012 and P = 0.04 for association with Crohn disease). One of the risk-associated DLG5 haplotypes is distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism 113G-->A, resulting in the amino acid substitution R30Q in the DUF622 domain of DLG5. This mutation probably impedes scaffolding of DLG5. We stratified the study sample according to the presence of risk-associated CARD15 variants to study potential gene-gene interaction. We found a significant difference in association of the 113A DLG5 variant with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This is suggestive of a complex pattern of gene-gene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. Further functional studies will evaluate the biological significance of DLG5 variants.
To analyse the impact of NOD2/CARD15 mutations on the clinical course of Crohn's disease patients from an eastern European country (Hungary).
We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg, 1007finsC) in 148 patients with Crohn's disease, 128 patients with ulcerative colitis and 208 controls recruited from the University of Szeged, Hungary. In patients with Crohn's disease, the prevalence of NOD2/CARD15 mutations was correlated to the demographical and clinical parameters.
In total, 32.4% of Crohn's disease patients carried at least one mutant allele within NOD2/CARD15 compared to 13.2% of patients with ulcerative colitis (P = 0.0002) and to 11.5% of controls (P<0.0001). In Crohn's disease patients, the allele frequencies for Arg702Trp, Gly908Arg and 1007finsC were 7.1%, 3.0% and 10.8% respectively. Interestingly, only the 1007finsC mutation was associated with a distinct clinical phenotype. The patients positive for the 1007finsC mutation suffered more frequently from stenotic disease behaviour (P = 0.008). Furthermore, 51.9% of patients positive for the 1007finsC mutation underwent a surgical resection within the ileum compared to only 17.4% of patients without the 1007finsC mutation (P = 0.001). With respect to the other two mutations (Arg702Trp and Gly908Arg), no associations were found with all investigated clinical parameters.
NOD2/CARD15 mutations are frequently found in Crohn's disease patients from Hungary. The 1007finsC mutation is associated with stenotic disease behaviour and frequent ileal resections.
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal system known as the inflammatory bowel diseases (IBD). Recently, Stoll and colleagues reported a novel finding of genetic variation in the DLG5 gene that is associated with IBD (CD and UC combined). We present here a study of the genetic variation described in that report in two well-powered, independent case-control cohorts and one family-based collection, and confirm the proposed association between IBD and the R30Q variant of DLG5 in two of the three studies. We are, however, unable to replicate the other proposed association to the common haplotype described in Stoll et al and suggest that this other finding could conceivably have been partially a statistical fluctuation and partially a result of LD with the replicated R30Q association. This study provides support for the hypothesis that DLG5 constitutes a true IBD risk factor of modest effect.
A multicenter double-blind study of the effectiveness of sulfasalazine and 6-methylprednisolone, alone and in combination, was conducted on 452 patients with Crohn's disease. One hundred sixty patients were previously untreated; 292 patients were previously treated. The Crohn's disease activity index (CDAI) was used to determine whether a patient had active (CDAI greater than or equal to 150, n = 215) or quiescent disease (CDAI less than 150, n = 237). Treatment of active disease consisted of high-dose 6-methylprednisolone, 6-methylprednisolone combined with 3 g of sulfasalazine, 3 g of sulfasalazine alone, or placebo, and lasted 6 wk. Patients in remission received maintenance doses of one of these drug regimens for periods of up to 2 yr. One hundred ninety-two patients completed the 2-yr study period. Results were evaluated using life-table analysis and outcome ranking. These methods showed 6-methylprednisolone to be the most effective drug in overall comparison of all patients (p less than 0.001); in previously treated patients (p less than 0.001); and in subgroups: active disease (p less than 0.001), only small bowel disease (p less than 0.05), and both small bowel and colon disease (p less than 0.05). Combination of 6-methylprednisolone and sulfasalazine was the most effective regimen in previously untreated patients (p less than 0.05) and when disease was localized in the colon (p less than 0.001). Sulfasalazine alone was least effective in overall comparison of all patients (p less than 0.05) and in all strata. Drug treatment was of no significant benefit to patients with quiescent disease. Continuous administration of low doses of 6-methylprednisolone, or the combination regimen, was beneficial in patients who responded initially to treatment of active disease. The addition of sulfasalazine, however, offered no advantage.
To see whether intestinal permeability (IP) predicted relapse in Crohn's disease, we measured IP in 72 patients with quiescent Crohn's disease using the lactulose-mannitol test. The permeability index (lactulose/mannitol) was significantly higher in patients than in controls (0.046 [SEM 0.005] vs 0.018 [SEM 0.002], respectively). Patients were followed for 1 year after the test. 26 of the 37 patients with raised permeability, but only 6 of the 35 with normal permeability relapsed within 1 year after the test (p < 0.001). The sensitivity of the permeability test as a predictor for relapse was 81%. A significant correlation was found between the value of the permeability index and the probability of relapse (p < 0.01). These results show that increases in intestinal permeability precede clinical relapses in Crohn's disease and so are an indicator of subclinical disease. The measurement of intestinal permeability may lead to a better understanding of the pathogenesis of Crohn's disease.
Nonsteroidal anti-inflammatory agents (NSAIDs) commonly cause asymptomatic gastroduodenal damage that may be clinically severe. At present the only method to determine the presence or absence of such damage is by invasive techniques such as endoscopy. Because distal small intestinal damage can be noninvasively detected with oral permeability tests, the hypothesis that gastroduodenal damage could be detected using similar methods was examined in the present study.
Animal data are presented suggesting that sucrose represents an ideal probe molecule to detect increased gastroduodenal permeability in a site-specific manner. With gastroduodenal damage, caused by either ethanol or NSAIDs, sucrose permeability is increased. Furthermore, because sucrose is rapidly degraded within the small intestine, this probe does not detect small intestinal damage, making it specific for the upper gastrointestinal tract. Finally, a pilot study in humans is presented to show the use of this technique in evaluating human gastric permeability.
Sucrose represents a novel permeability probe with specificity for damage of the upper gastrointestinal tract. In animals and humans it appears useful to noninvasively detect gastroduodenal injury caused by several agents.
Small intestinal permeability is increased in a proportion of patients with Crohn's disease (CD) and a subset of their healthy relatives. A primary permeability defect was postulated in the pathogenesis of the disease. The aim of this study was to identify a possible genetic pattern in the distribution of CD and/or abnormal permeability.
Differential urinary excretion of lactulose and mannitol (L/ M) in complete CD families was determined. Controls included healthy families and families with ulcerative colitis. Pedigrees were used to compare the distribution of CD and/or increased permeability.
The L/M was significantly increased in patients with CD. Seventeen of 67 first-degree relatives (25%) had a ratio greater than the upper limit (P95 = 0.0170). Permeability results of CD families showed a highly significant familial aggregation. The lack of a genetic pattern in relation with CD and occurrence of disturbed permeability especially within generation, points toward a shared environmental factor. Five of 14 healthy spouses (36%) of patients with CD had also an increased permeability, and prevalence of increased permeability was not higher in families with known familial occurrence (P = 0.85).
This large family study confirms an increased permeability in a subset of healthy relatives of patients with CD. However, the absence of a typical family pattern and the high prevalence in spouses is in favor of a common nongenetic factor or a subclinical disease manifestation.
We have identified a novel human homolog of the Drosophila dlg tumor suppressor gene, termed P-dlg, which has been mapped at chromosome 10q23. Unlike other human dlg homologs, P-dlg is expressed in placenta and various gland tissues but not in brain. The P-dlg protein is localized at the plasma membrane and cytoplasm, and it is expressed in the gland epithelial cells in normal prostate tissue but not in prostate cancer cell lines. Furthermore, we identified interaction between P-dlg and p55 palmitoylated membrane protein by yeast two-hybrid screening. These findings suggest that P-dlg forms a complex with p55 at the plasma membrane and plays roles in maintaining the structure of epithelial cells and transmitting extracellular signals to the membrane and cytoskeleton, which may negatively regulate cell proliferation.
Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation, typically starting in early adulthood. IBD is subdivided into two subtypes, on the basis of clinical and histologic features: Crohn disease and ulcerative colitis (UC). Previous genomewide searches identified regions harboring susceptibility loci on chromosomes 1, 3, 4, 7, 12, and 16. To expand our understanding of the genetic risk profile, we performed a 9-cM genomewide search for susceptibility loci in 268 families containing 353 affected sibling pairs. Previous linkages on chromosomes 12 and 16 were replicated, and the chromosome 4 linkage was extended in this sample. New suggestive evidence for autosomal linkages was observed on chromosomes 1, 6, 10, and 22, with LOD scores of 2.08, 2.07, 2.30, and 1.52, respectively. A maximum LOD score of 1.76 was observed on the X chromosome, for UC, which is consistent with the clinical association of IBD with Ullrich-Turner syndrome. The linkage finding on chromosome 6p is of interest, given the possible contribution of human leukocyte antigen and tumor necrosis-factor genes in IBD. This genomewide linkage scan, done with a large family cohort, has confirmed three previous IBD linkages and has provided evidence for five additional regions that may harbor IBD predisposition genes.
CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.
Crohn's disease is a common inflammatory disorder of the gut characterized by variation in both location and behavior. Chromosome 16 and the HLA region on chromosome 6 have been implicated in susceptibility to disease. Mutations in the NOD2/CARD15 gene, recently identified on chromosome 16, have been associated with disease overall but are found in only 25% of patients. No data regarding their contribution to specific disease subtypes exist. Here we report a detailed genotype-phenotype analysis of 244 accurately characterized patients.
A total of 244 white patients with Crohn's disease recruited from a single center in the United Kingdom were studied. All patients were rigorously phenotyped and followed-up for a median time of 16 years. By using linkage disequilibrium mapping we studied 340 polymorphisms in 24 HLA genes and 3 NOD2/CARD15 polymorphisms.
We show that NOD2/CARD15 mutations determine ileal disease only. We confirm that alleles on specific long-range HLA haplotypes determine overall susceptibility and describe novel genetic associations with susceptibility, location, and behavior of Crohn's disease.
The clinical pattern of Crohn's disease may be defined by specific genotypes. This study may provide the basis for a future molecular classification of disease.
The caspase recruitment domain gene (CARD15) was recently identified as the underlying gene associated with the IBD1 locus that confers susceptibility to Crohn disease (CD). CARD15 is related to the NOD1/Apaf-1 family of apoptosis regulators, and three sequence variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) in the gene were demonstrated to be associated with CD. We collected a cohort of 231 patients with CD and 71 healthy control individuals from the Canadian province of Quebec, to determine the prevalence of these sequence variants in an independent population. Clinical records of all patients were systematically reviewed, and detailed phenotypic information was obtained. All patient DNA samples were genotyped for the three variants, thus enabling an analysis of genotype-phenotype correlations. In this cohort, 45.0% of patients with CD carried at least one variant in the CARD15 gene, compared with 9.0% of control individuals (P<10-7). Allele frequencies of Arg702Trp, Gly908Arg, and Leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with CD, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Importantly, CARD15 mutants were seen with equal frequency in patients with familial and sporadic CD. Analysis of the relationship between genotype and phenotype convincingly demonstrates that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P<.001). Moreover, we were able to determine the haplotype structure surrounding this disease gene by genotyping 45 single-nucleotide polymorphisms (SNPs) in a 177-kb region that contained the CARD15 gene. This structure helps clarify the history of these causal mutations. Finally, this analysis shows that CARD15 involvement with CD is detectable by use of publicly available SNPs alone.
Crohn's disease is a heterogeneous disorder for which NOD2 (CARD 15) has been identified as a susceptibility gene. We investigate the relation between NOD2 genotype and phenotypic characteristics of patients with Crohn's disease.
Hypotheses about the relation between NOD2 genotype and Crohn's disease phenotype were generated retrospectively from a group of 446 German patients with this disorder. Positive findings (p<0.10) were verified in prospectively established cohorts of 106 German and 55 Norwegian patients with Crohn's disease. All patients were genotyped for the main coding mutations in NOD2, denoted SNP8, SNP12, and SNP13, with Taqman technology.
In the retrospective cohort, six clinical characteristics showed noteworthy haplotype association: fistulising, ileal, left colonic and right colonic disease, stenosis, and resection. In the German prospective cohort, these haplotype associations could be replicated for ileal (p=0.006) and right colonic disease (p < or =0.001). A similar trend was noted in the Norwegian patients.
We recorded a distinct relation between NOD2 genotype and phenotype of Crohn's disease. Test strategies with NOD2 variations to predict the clinical course of Crohn's disease could lead to the development of new therapeutic paradigms.
The clinical manifestations of Crohn's disease (CD) are diverse, ranging from fibrostenosing small-bowel disease to colon-predominant inflammation. These distinctions may represent genetic, immunologic, and microbial heterogeneity. NOD2 gene mutations in CD have been described recently and may alter innate immune responses. We hypothesized that NOD2 mutations may be associated with distinct phenotypic expressions of CD.
Two cohorts of consecutively identified patients referred to an inflammatory bowel disease center (n = 142 collected between 1993 and 1996; n = 59 collected between 1999 and 2001) were genotyped for 3 single nucleotide variants of NOD2-R675W, G881R, and 3020insC-and phenotyped for disease behavior, disease location, and serum immune markers.
Univariate analysis showed that CD-associated NOD2 variants were significantly associated with fibrostenosing disease in each cohort (P = 0.049 and P = 0.002, respectively). When both cohorts were analyzed together, the association between NOD2 variants and fibrostenosing disease was more significant (P = 0.001). These relationships were observed in both Jews and non-Jews. Forty-six percent of patients with fibrostenosing disease carried at least 1 of these alleles, compared with only 23.5% of patients without fibrostenosing disease (odds ratio, 2.8; 95% confidence interval, 1.6-5.2). Multivariate and conditioning analyses showed a primary association between NOD2 allelic variants and fibrostenosing disease, but not with small-bowel disease.
In this description of a genotype/phenotype correlation in CD patients and NOD2 variants, data suggest that variation in this gene contributes to the occurrence of fibrostenotic CD of the small bowel.
Mutations within the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease.
To investigate the clinical impact of the three common NOD2/CARD15 mutations in patients with Crohn's disease.
We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg, 3020insC) in 180 patients with Crohn's disease, 70 patients with ulcerative colitis and 97 controls. In patients with Crohn's disease, prevalence of NOD2/CARD15 mutations were correlated to clinical and demographical parameters.
In Crohn's disease patients, 35.6% carried at least one mutant allele of NOD2/CARD15 mutations compared with 14.3% of patients with ulcerative colitis (P = 0.006) and to 15.5% of controls (P = 0.0001). Genotype phenotype analyses revealed that NOD2/CARD15 mutations determined younger age at disease diagnosis (P = 0.03), ileal disease location (P = 0.01) and ileocecal resections (P = 0.0002). Interestingly, reoperation with resection of the anastomosis was significantly more frequent in patients with NOD2/CARD15 mutations (P = 0.01).
Our investigations support the current hypothesis that NOD2/CARD15 mutations are associated with a phenotype of Crohn's disease with younger age at diagnosis, ileal involvement, ileocecal resections and a high risk of postoperative relapse and reoperation. NOD2/CARD15 mutations might therefore be used to identify high risk patients for relapse prevention strategies.
The inflammatory bowel diseases (IBD) comprise complex genetic disorders, with multiple contributing genes. Linkage studies have implicated several genomic regions as likely containing IBD susceptibility genes, with some observed uniquely in Crohn's disease (CD) or ulcerative colitis (UC), and others common to both disorders. The best replicated linkage region, IBD1, on chromosome 16q contains the CD susceptibility gene, NOD2/CARD15. NOD2/CARD15 is expressed in peripheral blood monocytes and is structurally related to the plant R proteins, which mediate host resistance to microbial pathogens. Three major coding region polymorphisms within NOD2/CARD15 have been highly associated with CD among patients of European descent. Having one copy of the risk alleles confers a 2-4-fold risk for developing CD, whereas double-dose carriage increases the risk 20-40-fold. All 3 major CD variants exhibit a deficit in NF-kappaB activation in response to bacterial components. Carriage of NOD2/CARD15 risk alleles is associated with ileal location, earlier disease onset, and stricturing phenotype. Other IBD genomic regions include IBD2 on chromosome 12q (observed more in UC), and IBD3, containing the major histocompatibility complex region. A short genomic region has been associated with CD on chromosome 5q, but the precise contributing gene is as yet unidentified. The characterization of additional IBD susceptibility genes could potentially lead to the identification of novel therapeutic agents for IBD, make possible a molecular reclassification of disease, and increase understanding of the contribution of environmental factors (notably, tobacco and the intestinal microbial milieu) to intestinal inflammation.
Recent data have suggested that specific haplotypic variants of the DLG5 gene on chromosome 10q23 may be associated with susceptibility to inflammatory bowel disease (IBD) in Germany. Haplotype D, notably characterised by the presence of a G-->A substitution at nucleotide 113, was associated with susceptibility to Crohn's disease (CD) whereas an extended haplotype A conferred protection.
Association of DLG5 haplotypic variants with disease susceptibility, genotype-phenotype relationships, and epistasis with CARD15 was investigated in the Scottish population.
A total of 374 CD, 305 ulcerative colitis (UC), and 294 healthy controls (HC) were studied. Genotyping for the variants rs1248696 (113A, representing haplotype D) and the single nucleotide polymorphism tag rs2289311 (representing haplotype A) were typed using the Taqman system.
On analysis of the DLG5 variant 113A, there were no associations with IBD when allelic frequency (11.4% IBD v 13.2% HC; p = 0.30) and carrier frequency (19.2% IBD v 24.6% HC; p = 0.069) were analysed. No associations were observed between 113A variant allelic frequency (p = 0.37), carrier frequency (p = 0.057), and CD. In fact, 113A heterozygosity rates were lower in CD (16%) and IBD (16.9%) than in HC (23%) (p = 0.029 and p = 0.033, respectively). No associations between DLG5 and UC were observed. Haplotype A was not protective and there was no evidence of epistasis between DLG5 and CARD15.
The present data contrast strongly with previous data from Germany. DLG5 113A is not associated with disease susceptibility and haplotype A does not confer resistance. Further work is required to evaluate the significance of DLG5 in other populations from geographically diverse regions.
Results of drug treatment
- H Malchow
- K Ewe
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Malchow H, Ewe K, Brandes JW, et al. Results of drug treatment. Gastroenterology 1984;86:249–66.