Background: A complex interplay of genetic and environmental factors are implicated in the pathogenesis of ulcerative colitis (UC), resulting in an abnormal immune response and subsequent destruction of the colonic epithelium. The Icelandic population has a restricted gene pool with extensive medical records in combination with one of the highest incidence of UC in the world . We aimed to assess the exomic genetic data and colonic transcriptomics of patients with UC and healthy controls to identify novel deleterious mutations and its influence on the colonic mucosa.
Methods: We performed exome sequencing and whole genome wide microarray analysis on macroscopically normal colonic mucosa from patients with a histological diagnosis of UC and healthy patients with no family history of UC undergoing colonoscopy. Gene-ontology analysis was used to identify common processes and pathways differentially expressed in diseased tissue. Exon sequencing screening for rare or novel mutations was performed on both cohorts.
Results: Non-inflamed colonic tissue from UC patients demonstrated significant alteration in the transcriptomic profile when compared with control tissue. Over 2,000 genes were differentially expressed in the rectum. Gene-ontology analysis identified up-regulation in genes associated with cell cycle and protein metabolism in patients with UC. Exome sequencing identified 2 missense mutations in thiopurine S-methytransferase (TPMT) in 7/13 of the UC biopsies compared to 1/14 controls. The mutations identified are known to result in a loss of enzyme function leading to high levels of toxic metabolites from thiopurine analogues, which cause liver toxicity and bone marrow suppression.  This variant seems to be significantly more prevalent in this population. We identified 2 significant possibly damaging mutations which have influence on rectal gene expression.
The mutations correspond with differential expression of SPOP with TPMT variant and DUOXA2 and DUOX2 with SLC26A3 variant.
Conclusions: Rectal mucosal samples from UC patients show an elevation in cell cycle activity and protein metabolism. The perceived increase in the TPMT variant would suggest screening of the UC population to avoid the serious toxicity associated with thiopurine analogue therapy. Significantly enriched deleterious mutations in the UC cohort, also have an influence on rectal gene expression of DUOXA2, DUOX2 and SPOP.
 Bjornsson, S et al. (2015). Incidence of inflammatory bowel disease in Iceland 1995–2009. A nationwide population-based study, Scand. J. Gastroenterolgy, 5521, 1–8
 Roberts, R.L. & Barclay, M.L, (2015). Update on thiopurine pharmacogenetics in inflammatory bowel disease, Pharmacogenomics, 16, 891–903