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Title: The genetics of IBD : from susceptibility to drug response and patient outcome
Author: Sazonovs, Aleksejs
ISNI:       0000 0004 9347 8045
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Inflammatory bowel disease (IBD) is a group of immune-mediated autoinflammatory disorders, primarily manifesting in the gastrointestinal tract. Affecting millions of people around the world, IBD has a severe impact on patients’ quality of life. Several pharmacologic treatments have been available since the 1950s. However, the majority of patients either do not respond to a given therapy or lose response to a previously effective treatment and thus require therapeutic escalation. In the first research chapter of my thesis, I describe the results of the Personalised Anti-TNF Therapy in Crohn’s disease study. Immunogenicity to anti-TNF therapy is a major cause of loss of response, hypersensitivity reactions, and discontinuation of treatment in patients. Currently, immunogenicity cannot be predicted prior to treatment. My analysis has identified a strong dominant association in the HLA region on chromosome 6 (HLA-DQA1*05, P=5.9e-13; HR=1.90; 95% CI, 1.60 to 2.25). Around 40% of individuals of European ancestry carry HLA-DQA1*05, and the data suggest that around 95% of these would develop immunogenicity within the first year of infliximab monotherapy treatment (a common anti-TNF treatment regime). In the second research chapter of my thesis, I describe a genome-wide association study of thiopurine-induced liver damage (TILI). Ultimately, the study was underpowered to detect any associations of moderate effect size and did not detect any associations of high effect size amongst the common genetic variants. Interestingly, I was not able to replicate the association in PTPN22, which was reported to be a risk factor for drug-induced liver damage by Cirulli et al. – suggesting that its effect might be heterogeneous depending on the therapy. Finally, the third research chapter describes the initial analysis of the IBD 15x dataset – a whole-genome sequencing association study of around 7,000 IBD patients paired with 12,000 matching controls. I provide an overview of the sample quality control procedures and describe some of the novel challenges that sequencing studies bring in comparison to standard GWAS (e.g., sample cross-contamination due to index mismatching). Finally, I also provide the results of the initial meta-analysis of the exome-sequencing dataset produced by the Broad Institute. The results demonstrate that rare coding genetic variants play a role in IBD pathogenesis.
Supervisor: Anderson, Carl Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: IBD ; Crohn's disease ; GWAS ; anti-TNF immunogenicity ; thiopurine-induced liver injury ; rare genetic variation ; drug response