Gene variant boosts ulcer susceptibility in NSAID users

A single nucleotide polymorphism (SNP) in the cytochrome P450 2C (CYP2C) gene cluster influences the risk for peptic ulcer disease in people taking non-steroidal anti-inflammatory drugs (NSAIDs), a study reveals.

If the finding is confirmed, it could open the possibility of risk-stratifying people for ulcer risk and may represent a new therapeutic target for NSAID-resistant disease.

The risks for peptic ulcers and upper gastrointestinal bleeding are thought to be modulated by variations in genes encoding NSAID-metabolizing enzymes but the details to date have been inconclusive.

In this study, Munir Pirmohamed (University of Liverpool, UK) and co-authors focused on eight clinically relevant SNPs in the CYP2C gene cluster - CYP2C8*3 (rs11572080 and rs10509681), CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17.

The CYP2C family of enzymes metabolizes 25-30% of clinically used drugs as well as endogenous substances such as arachidonic acid and estrogens, the researchers explain.

A total of 1239 White UK adults were genotyped, of whom 67.4% had endoscopically confirmed peptic ulcer disease. People with ulcer disease were twice as likely to be NSAID users as those without ulcer disease; a similar preponderance of NSAID use was seen for upper gastrointestinal bleeding.

Logistic regression analysis significantly associated just one of the SNPs - CYP2C19*17 - with the presence of peptic ulcer disease, with an odds ratio of 1.47.

The frequency of peptic ulcer disease varied with CYP2C19*17 genotype, at 64.3% in people with *1/*1 alleles, 71.7% in those with *1/*17 alleles, and 73.8% in people with *17/*17 alleles.

The association was independent of NSAID use or Helicobacter pylori infection, note the authors. None of the SNPs examined were associated with upper gastrointestinal bleeding.

Writing in Clinical Pharmacology & Therapeutics, Pirmohamed and co-authors state that there are plausible biologic mechanisms related to CYP-mediated metabolism of endobiotics that could explain their results.

"CYP2C19*17 is a common gain-of-function polymorphism, with carriers having increased rates of metabolism of substrate drugs," they explain. For instance, CYP2C enzymes influence the metabolism of arachidonic acid, which is well known to be involved in the pathogenesis of peptic ulcer disease.

Alternatively, CYP2C19*17 carriers may have enhanced clearance of gastroprotective proton-pump inhibitors and therefore reduced mucosal gastroprotection against aggressors, such as NSAIDs.

Pirmohamed and colleagues conclude: "Further well-powered studies in a different population are now needed to validate these findings and to evaluate the functional consequences of CYP2C19*17 on peptic ulcer disease pathogenesis."

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