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Background: The IL23/IL17 pathway is pivotal in the development of chronic mucosal inflammation seen in Crohn's disease (CD). Genetic variants in the IL23R and IL12B have been associated with CD susceptibility. We investigated 10 genes within the IL23/IL17 pathway in a case‐control study of 763 CD cases and 254 healthy controls. Methods: We identified a novel association in haplotypes in IL17A (empirical P = 0.02), IL17RA (P = 0.001), IL17RD (P = 0.001), IL12RB1 (P = 0.003), and IL12RB2 (P = 0.001) as well as confirming the association with IL12B variants (P = 0.003). Results: The cumulative risk for carrying an increased number of CD risk haplotypes from genes in this pathway rises to an odds ratio of 4.3 for carrying 5 risk haplotypes. We have previously demonstrated an association between this cohort and IL23R haplotypes. Pairwise analyses suggest that there is statistical interaction between variants in IL17A and IL23R (P = 0.047) and between variants in IL17RA and IL23R (P = 0.036). Furthermore, a significant association between CD and the widely replicated IL23R variants is only seen in the presence of IL17A or IL17RA variants. Conclusions: These data support the investigation of pathways implicated in CD pathogenesis in order to identify further susceptibility genes and also suggest that important gene–gene interaction is present in CD susceptibility. (Inflamm Bowel Dis 2009)

Background: Despite recent advances the majority of inflammatory bowel disease (IBD) susceptibility ‘genes’ remain undiscovered. Recent data suggest that autoimmune conditions may ‘share’ susceptibility loci. Epidemiological evidence indicates an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGI2, recently implicated in ulcerative colitis (UC) and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGI2 variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens. Methods: We genotyped 113 MAGI2 single nucleotide polymorphisms (SNPs) in 681 cases of Crohn's disease (CD), 259 UC cases, and 195 controls. Results: The most significant IBD association was in intron 6 (rs2160322, P = 0.009) and both UC (P = 0.006) and CD (P = 0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, P = 0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, P = 0.002) and also significant associations in introns 2, 6, and 20. Significant associations were seen with: immunoglobulin G (IgG) anti‐Saccharomyces cerevisiae antibodies (ASCA)‐positive CD in intron 3 (P = 0.003), intron 6 (P = 0.003), and intron 20 (P = 0.001); anti‐CBir1‐positive CD in intron 3 (P = 0.0001) and intron 6 (P = 0.008); and anti‐outer membrane porin C (OmpC)‐positive CD in intron 3 (P = 0.0009), and intron 9 (P = 0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti‐IgA ASCA, P = 0.0003 and anti‐IgG ASCA, P = 0.0002). Conclusions: These findings support the significance of the epithelial barrier in IBD pathogenesis. (Inflamm Bowel Dis 2008)

Nat. Genet. 42, 332–337 (2010); published online 14 March 2010; corrected after print 29 March 2011 In the version of this article initially published, Kathryn Roeder's affiliation was incorrect. Her correct affiliation is the Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

The IL23/IL17 pathway is pivotal in the development of chronic mucosal inflammation seen in Crohn's disease (CD). Genetic variants in the IL23R and IL12B have been associated with CD susceptibility. We investigated 10 genes within the IL23/IL17 pathway in a case-control study of 763 CD cases and 254 healthy controls.MethodsWe identified a novel association in haplotypes in IL17A (empirical P = 0.02), IL17RA (P = 0.001), IL17RD (P = 0.001), IL12RB1 (P = 0.003), and IL12RB2 (P = 0.001) as well as confirming the association with IL12B variants (P = 0.003).ResultsThe cumulative risk for carrying an increased number of CD risk haplotypes from genes in this pathway rises to an odds ratio of 4.3 for carrying 5 risk haplotypes. We have previously demonstrated an association between this cohort and IL23R haplotypes. Pairwise analyses suggest that there is statistical interaction between variants in IL17A and IL23R (P = 0.047) and between variants in IL17RA and IL23R (P = 0.036). Furthermore, a significant association between CD and the widely replicated IL23R variants is only seen in the presence of IL17A or IL17RA variants.ConclusionsThese data support the investigation of pathways implicated in CD pathogenesis in order to identify further susceptibility genes and also suggest that important gene–gene interaction is present in CD susceptibility.

BackgroundDespite recent advances the majority of inflammatory bowel disease (IBD) susceptibility ‘genes’ remain undiscovered. Recent data suggest that autoimmune conditions may ‘share’ susceptibility loci. Epidemiological evidence indicates an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGI2, recently implicated in ulcerative colitis (UC) and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGI2 variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens.MethodsWe genotyped 113 MAGI2 single nucleotide polymorphisms (SNPs) in 681 cases of Crohn's disease (CD), 259 UC cases, and 195 controls.ResultsThe most significant IBD association was in intron 6 (rs2160322, P = 0.009) and both UC (P = 0.006) and CD (P = 0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, P = 0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, P = 0.002) and also significant associations in introns 2, 6, and 20. Significant associations were seen with: immunoglobulin G (IgG) anti-Saccharomyces cerevisiae antibodies (ASCA)-positive CD in intron 3 (P = 0.003), intron 6 (P = 0.003), and intron 20 (P = 0.001); anti-CBir1-positive CD in intron 3 (P = 0.0001) and intron 6 (P = 0.008); and anti-outer membrane porin C (OmpC)-positive CD in intron 3 (P = 0.0009), and intron 9 (P = 0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti-IgA ASCA, P = 0.0003 and anti-IgG ASCA, P = 0.0002).ConclusionsThese findings support the significance of the epithelial barrier in IBD pathogenesis.

OBJECTIVE: Cost-effective strategies for identifying patients with Barrett’s esophagus who are most likely to develop cancer have not been developed. Surveillance endoscopy is currently used, and we hypothesized that more frequent surveillance intervals would identify patients with “transient positive” diagnoses of dysplasia—dysplasia found on one examination but not on subsequent ones. Our aim was to explore the potential economic impact of transient positive diagnoses of dysplasia on alternative surveillance strategies over a 10-yr period. METHODS: Data were derived from a 2-yr randomized, prospective study comparing omeprazole to ranitidine in 95 patients with Barrett’s esophagus. A transient positive diagnosis of dysplasia was defined as a patient who was diagnosed with dysplasia during the study period but whose 24-month biopsies revealed no dysplasia. We calculated the number of transient positive diagnoses of dysplasia and modeled the potential economic impact of a diagnosis of dysplasia over a 10-yr period. RESULTS: Thirty patients (31%) had at least one reading of dysplasia during the study period. Nineteen patients (20%) had a transient positive diagnosis of dysplasia. During the study period, no cancers were found. A surveillance strategy of every other year and every 6 months for dysplasia would result in 1072 endoscopies over a 10-yr period at a discounted cost of $1,587,184. A total of 61% of endoscopies would be because of transient positive diagnoses of dysplasia. A strategy of yearly surveillance and every 6 months for dysplasia would result in 1404 endoscopies at a discounted cost of $2,096,733, of which 28% would result from transient positive diagnoses of dysplasia. The discounted incremental costs of more frequent surveillance in this cohort of patients over 10 yr is $509,549. CONCLUSIONS: Based on current practice strategies, transient positive diagnoses of dysplasia account for 28–61% of endoscopies in Barrett’s surveillance programs. This analysis suggests that the endoscopy workload and costs associated with surveillance could be substantially reduced if patients with transient positive diagnoses of dysplasia reverted to usual surveillance after two negative examinations.

Cost-effective strategies for identifying patients with Barrett's esophagus who are most likely to develop cancer have not been developed. Surveillance endoscopy is currently used, and we hypothesized that more frequent surveillance intervals would identify patients with “transient positive” diagnoses of dysplasia—dysplasia found on one examination but not on subsequent ones. Our aim was to explore the potential economic impact of transient positive diagnoses of dysplasia on alternative surveillance strategies over a 10-yr period. Data were derived from a 2-yr randomized, prospective study comparing omeprazole to ranitidine in 95 patients with Barrett's esophagus. A transient positive diagnosis of dysplasia was defined as a patient who was diagnosed with dysplasia during the study period but whose 24-month biopsies revealed no dysplasia. We calculated the number of transient positive diagnoses of dysplasia and modeled the potential economic impact of a diagnosis of dysplasia over a 10-yr period. Thirty patients (31%) had at least one reading of dysplasia during the study period. Nineteen patients (20%) had a transient positive diagnosis of dysplasia. During the study period, no cancers were found. A surveillance strategy of every other year and every 6 months for dysplasia would result in 1072 endoscopies over a 10-yr period at a discounted cost of $1,587,184. A total of 61% of endoscopies would be because of transient positive diagnoses of dysplasia. A strategy of yearly surveillance and every 6 months for dysplasia would result in 1404 endoscopies at a discounted cost of $2,096,733, of which 28% would result from transient positive diagnoses of dysplasia. The discounted incremental costs of more frequent surveillance in this cohort of patients over 10 yr is $509,549. Based on current practice strategies, transient positive diagnoses of dysplasia account for 28–61% of endoscopies in Barrett's surveillance programs. This analysis suggests that the endoscopy workload and costs associated with surveillance could be substantially reduced if patients with transient positive diagnoses of dysplasia reverted to usual surveillance after two negative examinations.

Background: Despite recent advances the majority of inflammatory bowel disease (IBD) susceptibility genes remain undiscovered. Recent data suggest that autoimmune conditions may share susceptibility loci. Epidemiological evidence indicates an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGb, recently implicated in ulcerative colitis (UC) and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGb variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens. Methods: We genotyped 113 MAGb single nucleotide polymorphisms (SNPs) in 681 cases of Crohn's disease (CD), 259 UC cases, and 195 controls. Results: The most significant IBD association was in intron 6 (rs2160322, P = 0.009) and both UC (P = 0.006) and CD (P = 0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, P = 0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, P = 0.002) and also significant associations in introns 2, 6, and 20. Significant associations were seen with: immunoglobulin G (IgG) anti-Saccharomyces cerevisiae antibodies (ASCA)-positive CD in intron 3 (P = 0.003), intron 6 (P = 0.003), and intron 20 (P = 0.001); anti-CBir1-positive CD in intron 3 (P = 0.0001) and intron 6 (P = 0.008); and anti-outer membrane porin C (OmpC)-positive CD in intron 3 (P = 0.0009), and intron 9 (P = 0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti-IgA ASCA, P = 0.0003 and anti-IgG ASCA, P = 0.0002). Conclusions: These findings support the significance of the epithelial barrier in IBD pathogenesis. (Inflamm Bowel Dis 2008).