Su1781 Reactive Gastropathy and Correlation With Medications, Helicobacter pylori and Gastric Inflammation

Abstract

INTRODUCTION: Studies show that single nucleotide polymorphisms (SNPs) in nonsteroidal anti-inflammatory drug (NSAID)-metabolising enzymes (mainly CYP2C9 & CYP2C8) may predispose NSAID-users to peptic ulcer disease (PUD) or upper gastrointestinal bleeding (UGIB). However, results to date have been inconclusive due to small sample sizes and different study designs. METHODS: We hypothesised that the eight closely-linked clinically important SNPs in the CYP2C family of genes, namely CYP2C8*3 (rs11572080 & rs10509681), CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 may predispose to PUD via impaired NSAID metabolism as well as other potentially important mechanisms such as metabolism of arachidonic acid (AA) and protonpump inhibitors (PPIs). Subjects endoscoped for suspected PUD/UGIB at 13 hospitals in the UK between 2005 and 2011 were recruited and interviewed using a structured questionnaire. Recruits were categorised as either NSAID-users (use within 2 weeks) or non-users (no use within 3 months). UGIB was defined as haematemesis, melaena or anaemia, and endoscopic stigmata of recent bleeding. H. pylori status was ascertained in most subjects. Following extraction of genomic DNA, genotyping was performed by KBioscience Ltd (UK). Logistic regression analysis was used to test for association between each SNP and risk of PUD/ UGIB. Interaction terms were introduced to determine whether any observed genetic effects were influenced by factors including type of NSAID, PPI use and gender. RESULTS: Overall,1246 white patients were recruited and categorised as follows: 485 (39%) PUD+/NSAID+; 357 (29%) PUD+/NSAID-; 125 (10%) PUD-/NSAID+; 280 (22%) PUD-/NSAID-. Seven SNPs were included in the final analysis (CYP2C19*3 was monomorphic and excluded). All SNPs were in Hardy-Weinberg equilibrium. Logistic regression analysis of cases (PUD+; n=842) and controls (PUD-; n=405), assuming an additive mode of inheritance at each SNP, showed that only CYP2C19*17 was significantly associated with PUD (p=0.006), with suggestion of an allele-dose effect, even on classifying cases as those using only CYP2C9/CYP2C8substrate NSAIDs (p=0.005). Post-hoc analysis showed no interaction between CYP2C19*17 and NSAID type, PPI use or gender. Subgroup analysis per ulcer type showed CYP2C19*17 was significantly associated with risk of gastric ulcers (p=0.02), whilst only rs11572080 was associated with risk of duodenal ulcers (p=0.04). No SNPs were associated with UGIB. CONCLUSION: Possession of CYP2C19*17 allele is associated with PUD, especially gastric ulcers, regardless of aetiology. We postulate that this could be through its effect on the metabolism of AA or other endogenous substances, leading to impairment of gastrointestinal mucosal defences. Further studies are needed to correlate the functional consequences of CYP2C19*17 in the pathogenesis of PUD.