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Title: Pharmacogenomics of non-steroidal antiinflammatory drug-induced gastrointestinal complications
Author: Esume, C. O.
ISNI:       0000 0004 6059 8964
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Over 30 million people worldwide use aspirin and other non-aspirin non-steroidal antiinflammatory drugs (NSAID) on a daily basis. It is estimated that over 25% of patients treated for arthritis with NSAIDs have experienced gastrointestinal (GI) complications that required hospital admission and 60% of deaths from adverse drug reactions (ADRs) are attributable to NSAID use. Significant non-genetic risk factors for the development of NSAID-related gastrointestinal complications include gender, H. pylori infection, and concomitant medications. Three genes (UGT1A6, PAI-1 and EYA1) with biological plausibility for roles in NSAID-related ulcers were analysed. Our analysis of genetic risk factors for NSAID-related GI complications in 1197 case-control subjects showed no association between a UGT1A6 polymorphism and NSAIDinduced GI toxicity (p=0.052). Furthermore, a meta-analysis of UGT1A6 studies confirmed that there was no association between NSAID-related GI complications and UGT1A6. The PAI-1 4G/5G polymorphism was also not associated with NSAID-related ulcers and bleeding (n=756), while the EYA1 rs12678747 single nucleotide polymorphism (SNP) was significantly (p<0.05, OR 1.52; 95% CI 1.21, 1.91) associated with binary ulcer status. In healthy volunteers, EYA1 gene expression in gastric biopsies was not related to the carriage of this SNP; this contrasts with the difference observed in patients with ulceration suggesting that there may be a SNP-disease interaction, which needs further study. EYA1 was found to be expressed in atypical gastrin secreting (AGS) cells, but the relative expression was significantly (p < 0.05) lower than in healthy human gastric epithelial cells and in renal cortical epithelial cells. Functional assays performed to explore the mechanism of NSAID-related gastric cell death and validate a plausible role for EYA1 in this process showed that there are multiple cell death pathways occurring concurrently in this cell model depending on the concentration of aspirin. At lower concentrations (10-20mM), PARP cleavage was observed suggestive of an apoptotic process, while at 50mM, necrotic cell death was the predominant mode of cell death. There was a significant (p < 0.05) concentration-dependent decrease in the caspase 3 and 7 activity in AGS cells despite a significant (p < 0.05) fall in the viability of the cells compared to the controls, suggesting that there is a role for non-caspase dependent mechanisms in the cell death. In summary, the thesis has focused on the clinical, molecular and functional aspects of peptic ulceration caused by NSAIDs (including aspirin). A novel pathway involving EYA1 has been investigated; this needs further work to define the exact mechanisms by which EYA1 leads to cell death and gastrointestinal injury in patients taking NSAIDs (including aspirin).
Supervisor: Pirmohamed, M. ; Carr, D. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral