Genetic studies in ulcerative colitis

Thesis

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), are lifelong inflammatory disorders of complex and multifactorial aetiology. Genetic studies have played an important role in the identification of immunological pathways involved in the pathogenesis of IBD. Genome wide association studies have revealed more than 160 genetic polymorphisms associated with IBD, although the expected heritability in UC is smaller than for CD, and the relationship between genotype and phenotype in UC is unclear. The source of the missing heritability in UC, may be at least accounted for by rare variants which carry a larger effect size. In this thesis, the influence of polygenic burden on disease phenotype in UC is investigated. In addition, functional characterisation of a rare genetic variant is performed, in order to investigate for a pathogenic association with a very early onset colitis phenotype.

Polygenic risk burden, as measured using genetic risk scores (GRS), is assessed amongst a well-phenotyped cohort of patients with UC. GRS are shown to be greater amongst patients diagnosed with UC before the age of 10 years, as compared to those diagnosed in adulthood. GRS are also shown to be greater amongst patients with a history of acute severe UC (ASUC), as compared to those with a mild UC disease course. Although lacking in power, variance analysis suggests enrichment of genetic polymorphisms within the IL-10 cytokine signalling pathway amongst patients with a history of ASUC.

Exploration of a possible causal relationship between a novel and rare mutation in the NOX1 gene, encoding NADPH oxidase 1, and a clinical phenotype of very early onset colitis in a single patient is undertaken in this thesis. It is shown that NOX1 mRNA is highly expressed in colonic epithelial cells and that the NOX1 p.N122H variant impairs function of the gene product. The findings implicate that the NOX1 p.N122H variant contributes to development of severe and early onset colitis by attenuating colonic epithelial superoxide production.

Authors: Bryant, RV

• Publication date: 2015
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: ulcerative colitis; inflammatory bowel disease; NOX1; genetics
• Subjects: Immunology; Gastroenterology; Genetics (medical sciences)