Pharmacogenomics of non-steroidal antiinflammatory drug-induced gastrointestinal complications

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)

Hepatoprotective Potentials Of Hibiscus rosasinensis Petal anthocyanin Extracts Against Carbon tetrachloride-Induced Acute Liver Damage in Wistar Rats.

Carbon tetrachloride (CCl4) is haloalkane that possesses a hepatotoxic effect. Material and Methods: The impact of anthocyanin fractions obtained from Hibiscus rosasinensis petal on carbon tetrachloride (CCl4) induced acute liver damage in wistar rats was studied using a combination of alanine transferase (ALT) activity value and liver: body weight gain ratio as indices. Results: CCl4 treatment significantly increased both ALT value and the liver: body weight gain ratio at the 1% probability level when compared with the control values. Conclusion: Pre-treatment with the anthocyanin fractions reduced the levels of these markers and hence, the degree of liver damage, though with varying potentials. The lead precipitated, non slimy red fraction possessed the greatest protective property on the rat liver when compared with the other anthocyanin fractions so tested. Keywords: Anthocyanin, carbon tetrachloride, alanine transferase, Hibiscus rosasinensis, liver damage.Sudan Journal of Medical Sciences Vol. 3 (1) 2008: pp. 33-3

Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration

BACKGROUND: Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD. METHODS: Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) were defined as patients with endoscopically confirmed PUD within 2 weeks of using aspirin and non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). They were compared to two control groups: patients with endoscopically confirmed PUD without any history of NSAID use within 3 months of diagnosis (n=495), and patients with no PUD on endoscopy (n=478). A genome-wide association study (GWAS) of aspirin-induced cases (n=247) was compared to 476 controls. The results were validated by replication in another 84 cases and 162 controls. FINDINGS: The GWAS identified one variant, rs12678747 (p=1·65×10(−7)) located in the last intron of EYA1 on chromosome 8. The association was replicated in another sample of 84 PUD patients receiving aspirin (p=0·002). Meta-analysis of discovery and replication cohort data for rs12678747, yielded a genome-wide significant association (p=3·12×10(−11); OR=2·03; 95% CI 1·65-2·50). Expression of EYA1 was lower at the gastric ulcer edge when compared with the antrum. INTERPRETATION: Genetic variation in an intron of the EYA1 gene increases the risk of endoscopically confirmed aspirin-induced PUD. Reduced EYA1 expression in the upper gastrointestinal epithelium may modulate risk, but the functional basis of this association will need mechanistic evaluation. FUNDING: Department of Health Chair in Pharmacogenetics, MRC Centre for Drug Safety Science and the Barts Cardiovascular NIHR Biomedical Research Centre, British Heart Foundation (BHF