Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan 10;25(2):317-327.
doi: 10.1093/ibd/izy350.

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

Mathena Vinayaga-Pavan  1 , Matthew Frampton  2 , Nikolas Pontikos  3 , Adam P Levine  2 , Phillip J Smith  2 , Jon G Jonasson  4   5 , Einar S Björnsson  5   6 , Anthony W Segal  2 , Andrew M Smith  1   2
Affiliations

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

Mathena Vinayaga-Pavan et al. Inflamm Bowel Dis. .

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.

PubMed Disclaimer

Figures

FIGURE 1.
FIGURE 1.
Box plots of pairwise ASD across the exome in sample groups. A, 1000 Genomes Project GBR population, all samples in this study (ICE), 1000 Genomes Project TSI population. B, HC, UC patients, and UC-HC, UC.
FIGURE 2.
FIGURE 2.
Assessment of inflammatory status of UC patients and controls. A, Systemic inflammatory markers from peripheral blood samples taken from subjects on the day of endoscopy (CRP, Hb). B, Rectal biopsy transcriptomic profiles of known inflammatory genes for all UC and HC subjects (SAA1, serum amyloid 1; S100A8, S100 calcium binding protein A8; S100A9, S100 calcium binding protein A9; DEFA5, defensin A5; DEFA6, defensin A6; CXCL8, interleukin-8). One UC patient was identified to have an elevated inflammatory transcriptomic signature.
FIGURE 3.
FIGURE 3.
PCA of microarray transcriptome data from bowel biopsies: The biopsies are distinguished by location (ascending colon [circle] or rectum [triangle]), disease status (UC [black] or HC [gray]), and Montreal classification of the UC (E1, proctitis; E2, left-sided colitis; E3, pancolitis).
FIGURE 4.
FIGURE 4.
Differential gene analysis of noninflamed rectal biopsies from UC patients and HCs. A, Volcano plot of all HC vs UC rectal genes. Genes colored red are significantly different, with an adjusted P < 0.01. B, Heatmap of the 50 most differentially expressed genes between UCs and HCs (according to adj P value), where the color scale for relative expression level is from low (red) to high (white).
FIGURE 5.
FIGURE 5.
Variant impact on downstream transcriptomics. A, Rectal expression of TPMT is not affected by the 2 observed TPMT variants (A154T/Y240C), (B) whereas the variants demonstrate a significant downstream impact on SPOP expression within the rectum. C, Expression of SLC26A3 within the colon is not affected by variant status (C307W), but (D) and (E) carriers of this mutation demonstrate an increase in DUOXA2 and DUOX2 expression within the rectum. *Adj P < 0.05.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. de Lange KM, Moutsianas L, Lee JC, et al. . Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. bioRxiv. 2016;49:058255. - PMC - PubMed
    1. Mirkov MU, Verstockt B, Cleynen I.. Genetics of inflammatory bowel disease: beyond NOD2. Lancet Gastroenterol Hepatol. 2017;2:224–234. - PubMed
    1. Jostins L, Ripke S, Weersma RK, et al. . International IBD Genetics Consortium (IIBDGC) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124. - PMC - PubMed
    1. Clark PM, Dawany N, Dampier W, et al. . Bioinformatics analysis reveals transcriptome and microrna signatures and drug repositioning targets for IBD and other autoimmune diseases. Inflamm Bowel Dis. 2012;18:2315–2333. - PubMed
    1. Smith PJ, Levine AP, Dunne J, et al. . Mucosal transcriptomics implicates under expression of BRINP3 in the pathogenesis of ulcerative colitis. Inflamm Bowel Dis. 2014;1802–1812. - PMC - PubMed

Publication types

MeSH terms