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Rare disease susceptibility alleles in children with Crohn disease

ABSTRACT: Rare disease susceptibility alleles in children with Crohn disease

PROVIDER: PRJNA507828 | ENA |

REPOSITORIES: ENA

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Rare disease susceptibility alleles in children with Crohn disease

Project description:Rare disease susceptibility alleles in children with Crohn disease

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Rare disease susceptibility alleles in children with Crohn disease

Project description:<p>The overall goal of this proposed project is to identify rare genetic variants contributing to childhood onset-Crohn disease. Crohn disease is a chronic inflammatory disorder of the gastrointestinal tract of unclear etiology and no known cure. Affected children suffer from diarrhea, abdominal pain, growth disturbances, and an impaired quality of life. The identified Crohn disease susceptibility alleles have improved our understanding of Crohn disease pathogenesis. However, the identified susceptibility alleles do not account for the observed heritability, nor have disease-causing alleles in many genomic regions been identified. For the proposed studies, we will use 1) existing DNA samples collected from high-risk Crohn kindreds identified using the extensive genealogical records available only in Utah, 2) existing DNA samples obtained from very young children with Crohn disease and their parents, and 3) existing DNA samples obtained from healthy controls that are free of a personal or family history of autoimmune disorders.</p>

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Core Ileal Transcriptome in Pediatric Crohn Disease

Project description:We report the global pattern of ileal gene expression in a cohort of 359 treatment-naïve pediatric Crohn Disease, Ulcerative Colitis patients and controls. We focus on genes with consistent altered expression in inflamed and unaffected ileum of CD [ileal-involved CD (iCD) and non-invloved ileal CD (cCD)], but not in the ileum of ulcerative colitis or control.

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Project description:Purpose: To clarify the biological processes underlying variation in disease location and antimicrobial sero-reactivity across age-of onset in pediatric Crohn disease. Methods: We characterize the ileal global pattern of gene expression using single-end, 50bp RNA-sequencing using the Illumina HiSeq2000 in 304 treatment-naïve pediatric Crohn patients and non-IBD controls. Reads were quantified using Kallisto with Gencodev23 annotations. For all analyses, data were stratified by patient age-of-onset. Results: Performing differential analysis of all reasonably-expressed transcripts (TPM>5 in ≥5 samples, with significance defined as FDR-corrected p-value<0.05 and fold change≥1.5), we identify a robust gene signature with higher expresison of an immune gene set in older patients (≥10 years at diagnosis) compared to younger patients (<10 years at diagnosis), and a decrease in expression of antimicrobial Paneth cell-derived α-defensins. Conclusion: We provide evidence for maturation of mucosal Th1 immune response and loss of epithelial antimicrobial α-defensins with increasing age-of-onset.

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