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

Area of Science:

• Gastroenterology
• Genetics
• Molecular Biology

Background:

• Ulcerative colitis (UC) pathogenesis involves genetic and environmental factors.
• Iceland has one of the world's highest UC incidence rates.
• Characterizing UC patients in Iceland can reveal population-specific genetic associations.

Purpose of the Study:

• To characterize ulcerative colitis (UC) patients in Iceland.
• To identify potential germline mutations associated with UC.
• To investigate pathways involved in UC pathogenesis.

Main Methods:

• Exome sequencing and genome-wide microarray analysis of colonic mucosa.
• Analysis of rare or novel mutations over-represented in UC patients.
• Correlation of variant analysis with transcriptomic expression in rectal tissue.

Main Results:

• Upregulation of genes for cell cycle control and endoplasmic reticulum (ER) protein processing in UC rectal tissue.
• Identification of two missense mutations in thiopurine S-methyltransferase (TPMT) with increased frequency in UC patients.
• A potentially damaging mutation in SLC26A3 associated with increased DUOX2 and DUOXA2 expression.

Conclusions:

• UC colonic mucosa shows elevated cell proliferation and ER protein processing.
• Increased prevalence of damaging TPMT variants in UC patients suggests pre-therapy screening.
• This screening can help avoid toxicity associated with thiopurine analogue therapy.