Dataset Information

Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population.

ABSTRACT: Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn's disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Altogether, out of 88 selected SNPs, 31 SNPs were replicated for association with IBD. A novel BRD2 (rs1049526) association reached significance of P?=?5.2?×?10-11 and odds ratio (OR)?=?2.43. Twenty SNPs were shared between pediatric and adult patients; 1 and 7 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare and potentially deleterious variants in IBD-associated or innate immunity-associated genes. Deleterious alleles in both groups were over-represented among rare variants in affected children. Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare and deleterious variants in affected children suggests a contribution by yet unexplained genetic components.

SUBMITTER: Ostrowski J

PROVIDER: S-EPMC5180213 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population.

Ostrowski Jerzy J Paziewska Agnieszka A Lazowska Izabella I Ambrozkiewicz Filip F Goryca Krzysztof K Kulecka Maria M Rawa Tomasz T Karczmarski Jakub J Dabrowska Michalina M Zeber-Lubecka Natalia N Tomecki Roman R Kluska Anna A Balabas Aneta A Piatkowska Magdalena M Paczkowska Katarzyna K Kierkus Jaroslaw J Socha Piotr P Lodyga Michal M Rydzewska Grazyna G Klopocka Maria M Mierzwa Grazyna G Iwanczak Barbara B Krzesiek Elzbieta E Bak-Drabik Katarzyna K Walkowiak Jaroslaw J Klincewicz Beata B Radwan Piotr P Grzybowska-Chlebowczyk Urszula U Landowski Piotr P Jankowska Agnieszka A Korczowski Bartosz B Starzynska Teresa T Albrecht Piotr P Mikula Michal M

Scientific reports 20161223

Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn's disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by indivi ...[more]

PMID: 28008999

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Project description:Background: Vedolizumab (vedo) is effective for induction and maintenance of remission in adults with inflammatory bowel disease (IBD). Pediatric data are still limited, especially for the youngest children with very early onset disease (VEO-IBD). The aim of this study was to assess the safety and efficacy of vedo in VEO-IBD. Methods: We performed a retrospective review of pediatric IBD patients with VEO-IBD (defined as aged <6 years) receiving vedo. Data on demographics, disease behavior, activity, and previous treatments/surgeries were collected. Disease activity was assessed using the pediatric Crohn's disease (CD) activity index (PCDAI) for CD or pediatric ulcerative colitis (UC) activity index (PUCAI) for UC. Primary outcome was clinical response after induction therapy with vedolizumab (4th dose week). It was defined as a decrease in PCDAI of at least 12.5 points between baseline and 4th dose week for CD, and a decrease in PUCAI of at least 20 points between baseline and this time for UC. Descriptive statistics were performed to analyze the data. Results: The study included 16 patients with VEO-IBD who have received vedo: 4/16 (25%) with CD, and 12/16 (75%) with UC at the median age of diagnosis 33.7 months (6.6 months-4.5 years). Median age at vedo initiation was 6.5 years (2.2-16.5 years). Among the analyzed individuals, 56.25% had failed more than one anti-tumor necrosis factor (TNF) alfa agent. Clinical response at 4th dose week was observed in 9/16 (56.3%) patients: mean baseline PCDAI score was 34.4 ± 1.9 and 10.6 ± 1.8 after induction therapy with vedo, while PUCAI score was 26 ± 6 vs. 18 ± 8, respectively. There was improvement in patients' nutritional state: at baseline 2/16 (12.5%) children had body mass index (BMI) below 1 percentile and no child had such BMI after induction therapy with vedo. No infusion reactions or serious adverse events/infections were reported. Conclusion: Vedolizumab is safe and effective in the medical management of pediatric patients with VEO-IBD.

Project description:Background & aimsThe incidence of inflammatory bowel diseases (IBDs) in older adults is increasing. We performed a systematic review and meta-analysis to evaluate progression of elderly onset (EO) IBD in population-based cohorts and compared it with adult onset (AO) IBD.MethodsIn a systematic review through June 1, 2019, we identified population-based cohort studies of EO IBD reporting the cumulative risk of hospitalization, surgery, mortality, treatment patterns, escalation, and/or malignancy. Data were synthesized using random-effects meta-analysis as cumulative risk of events at 1 year, 5 years, and 10 years, and compared with data from patients with AO IBD in the same cohorts.ResultsWe identified 9 studies, comprising 14,765 patients with EO IBD. In patients with EO Crohn's disease (CD), the cumulative 5-year risk of surgery was 22.6% (95% CI, 18.7-27.2) and was similar to that of patients with AO CD (relative risk [RR], 1.04; 95% CI, 0.80-1.34). Overall exposure to corticosteroids was comparable between patients with EO CD vs AO CD (5-year risk: 55.4%; 95% CI, 53.4-57.4; RR, 0.88; 95% CI, 0.78-1.00), but exposure to immunomodulators (31.5%; 95% CI, 29.7-33.4; RR, 0.62; 95% CI, 0.51-0.77) or biologic agents (6.5%; 95% CI, 5.6-7.6; RR, 0.36; 95% CI, 0.25-0.52) was significantly lower for patients with EO CD than for patients with AO CD. Similarly, in patients with EO ulcerative colitis (UC), the cumulative 5-year risk of surgery was 7.8% (95% CI, 5.0-12.0), similar to the risk for patients with AO UC (RR, 1.29; 95% CI, 0.79-2.11). Overall exposure to corticosteroids was comparable between patients with EO UC vs AO UC (5-year risk: 57.2%; 95% CI, 55.6-58.7; RR, 0.98; 95% CI, 0.91-1.06), but exposure to immunomodulators (16.1%; 95% CI, 15.0-17.2; RR, 0.58; 95% CI, 0.54-0.62) or biologic agents (2.0%; 95% CI, 1.6-2.5; RR, 0.36; 95% CI, 0.24-0.52) was significantly lower for patients with EO UC than for patients with AO UC. Patients with EO IBD appeared to have increased mortality, but not malignancy, compared with the general population. There were few data on comorbidities or adverse effects of medications.ConclusionsIn a systematic review and meta-analysis, we found that patients with EO IBD have a similar risk of surgery as patients with AO IBD. However, patients with EO IBD are less likely to receive treatment with immunomodulators or biologic agents.

Dataset Information

Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population.

Publications

Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population.

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