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Elevation in Cell Cycle and Protein Metabolism Gene Transcription in Inactive Colonic Tissue From Icelandic Patients With Ulcerative Colitis.

ABSTRACT: Background:A combination of genetic and environmental factors is thought to be involved in the pathogenesis of ulcerative colitis (UC). In Iceland, the incidence of UC is one of the highest in the world. The aim of this study was to characterize patients with UC and identify potential germline mutations and pathways that could be associated with UC in this population. Methods:Exome sequencing and genome-wide microarray analysis on macroscopically noninflamed colonic mucosa from patients and controls were performed. Exome sequence data were examined for very rare or novel mutations that were over-represented in the UC cohort. Combined matching of variant analysis and downstream influence on transcriptomic expression in the rectum were analyzed. Results:One thousand eight hundred thirty-eight genes were differentially expressed in rectal tissue from UC patients and identified an upregulation in genes associated with cell cycle control and protein processing in the endoplasmic reticulum (ER). Two missense mutations in thiopurine S-methyltransferase (TPMT) with a minor allele frequency of 0.22 in the UC patients compared with a reported 0.062 in the Icelandic population were identified. A predicted damaging mutation in the gene SLC26A3 is potentially associated with increased expression of DUOX2 and DUOXA2 in rectal tissue. Conclusions:Colonic mucosa of UC patients demonstrates evidence of an elevation in genes involving cell proliferation and processing of proteins within the ER. Exome sequencing identified a possible increased prevalence of 2 damaging TPMT variants within the UC population, suggesting screening the UC population before initiation of thiopurine analogue therapy to avoid toxicity associated with these mutations.

SUBMITTER: Vinayaga-Pavan M

PROVIDER: S-EPMC6327231 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Elevation in Cell Cycle and Protein Metabolism Gene Transcription in Inactive Colonic Tissue From Icelandic Patients With Ulcerative Colitis.

Vinayaga-Pavan Mathena M Frampton Matthew M Pontikos Nikolas N Levine Adam P AP Smith Phillip J PJ Jonasson Jon G JG Björnsson Einar S ES Segal Anthony W AW Smith Andrew M AM

Inflammatory bowel diseases 20190101 2

<h4>Background</h4>A combination of genetic and environmental factors is thought to be involved in the pathogenesis of ulcerative colitis (UC). In Iceland, the incidence of UC is one of the highest in the world. The aim of this study was to characterize patients with UC and identify potential germline mutations and pathways that could be associated with UC in this population.<h4>Methods</h4>Exome sequencing and genome-wide microarray analysis on macroscopically noninflamed colonic mucosa from pa ...[more]

PMID: 30452647

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Project description:BACKGROUND & AIMS: Ulcerative colitis (UC) is a chronic relapsing inflammatory disorder that affects the colonic epithelium. A combination of genetic and environmental factors is thought to be involved in the pathogenesis, resulting in an abnormal immune response and destruction of the colonic epithelium. In Iceland, the incidence of UC is one of the highest in the world and is three times more common than Crohn’s disease. Previous studies have suggested a genetic component may have an influence on the increased incidence. The aim of this study was to characterise a cohort of patients with UC and identify potential germ line mutations and pathways which could be associated with UC in this population. METHODS: We performed exome sequencing of genomic DNA and genome-wide microarray analysis on macroscopically non-inflamed colonic mucosa from Icelandic patients with UC and age and sexed matched controls. Gene-ontology analysis was used to identify common processes and pathways differentially expressed in tissue from UC cases. Exome sequence data were examined for very rare or novel mutations which might be over represented in the UC cohort. Combined matching of variant analysis and downstream influence on transcriptomic expression in the rectum was also analysed. RESULTS: Non-inflamed colonic tissue from patients with UC demonstrated a significant alteration in the transcriptomic profile compared to controls. Over 2,000 genes were differentially expressed in rectal tissue from UC patients and gene ontology analysis identified an up-regulation in genes associated with cell cycle control and protein processing in the endoplasmic reticulum. Exome sequencing identified two missense mutations in thiopurine S-methyltransferase (TPMT) with a minor allele frequency of 0.22 in the UC patients compared to a reported 0.062 in the Icelandic population and 0.03 in the non-Finnish European populations. A predicted damaging mutation in the inflammatory bowel disease associated gene SLC26A3 was identified which was associated with increased expression of DUOX2 and DUOXA2 in UC rectal tissue. CONCLUSIONS: In patients with UC, the colonic mucosa demonstrates a clear alteration in gene expression compared to control subjects. There is evidence of an elevation in genes involved with cell proliferation and the processing of proteins within the endoplasmic reticulum. Exome sequencing identified an increased prevalence of two damaging TPMT variants within the Icelandic UC population, which would suggest screening the UC population prior to initiation of therapy is warranted in order to avoid the serious toxicity associated with these mutations and azathioprine treatment.

Dataset Information

Elevation in Cell Cycle and Protein Metabolism Gene Transcription in Inactive Colonic Tissue From Icelandic Patients With Ulcerative Colitis.

Publications

Elevation in Cell Cycle and Protein Metabolism Gene Transcription in Inactive Colonic Tissue From Icelandic Patients With Ulcerative Colitis.

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