Introduction Studies show that single nucleotide polymorphisms (SNPs) in non-steroidal antiinflammatory drug (NSAID)-metabolising enzymes (mainly CYP2C9 and CYP2C8) may predispose NSAID-users to peptic ulcer disease (PUD) or upper gastrointestinal bleeding (UGIB), but results have been inconclusive.
Methods We hypothesised that the eight closely-linked clinically important SNPs in the CYP2C family of genes, namely CYP2C8*3 (rs11572080 and rs10509681), CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 predispose to PUD via impaired NSAID metabolism as well as other potentially important mechanisms (eg, metabolism of arachidonic acid (AA) and proton-pump inhibitors-PPIs). Subjects diagnosed with PUD/UGIB at 13 hospitals in the UK between 2005 and 2011 were recruited and interviewed using a structured questionnaire, and categorised as either NSAID-users or non-users. 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 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/CYP2C8-substrate 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 gastric ulcers (p=0.02), while only rs11572080 was associated with 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.
Competing interests None declared.
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