An update on the pharmacogenomics of NSAID metabolism and the risk of gastrointestinal bleeding

ABSTRACT

Introduction: Several reports suggest a possible association between polymorphisms in the cytochrome P450 2C9 (CYP2C9) gene and the risk for non-steroidal anti-inflammatory drug (NSAID)-related adverse gastrointestinal events, including gastrointestinal bleeding. Because findings were controversial, a systematic review and a meta-analysis of eligible studies on this putative association was conducted.

Areas covered: The authors have revised the relationship between CYP2C9 polymorphisms and the risk of developing NSAID-related gastrointestinal bleeding, as well as other adverse gastrointestinal events, and performed meta-analyzes. The bias effect and potential sources of heterogeneity between studies was analyzed.

Expert opinion: Individuals classified as poor metabolizers after CYP2C9 genotyping (activity scores equal to 0 or 0.5) have an increased risk of developing NSAID-related gastrointestinal adverse events with an odds ratio (OR) = 1.86, (p = 0.004) and the OR for subjects with gastrointestinal bleeding is = 1.90, (p = 0.003). Gene-dose effect for variant CYP2C9 alleles (p = 0.005 for all gastrointestinal adverse events, and p = 0.0001 for bleeding patients) was observed. Also, there is an allele-specific effect in the association: CYP2C9*2 is a poor risk predictor, whereas CYP2C9*3 is a highly significant predictor of gastrointestinal adverse events (p = 0.006) and gastrointestinal bleeding (p = 0.0007).

KEYWORDS:

• Adverse drug events
• cyp2c9 polymorphisms
• gastrointestinal bleeding
• genetics
• meta-analysis
• non-steroidal anti-inflammatory drugs

Article highlights

• Common CYP2DC9 genotypes are significantly associated with the risk of developing NSAID-related gastrointestinal adverse events; the association is stronger in patients with gastrointestinal bleeding.

• The association has marginal significance in individuals who are heterozygous for one detrimental allele, although this significance is lost after bias assessment.

• The association is highly significant in individuals who are homozygous or double heterozygous for detrimental CYP2C9 alleles, and the significance remains high after bias assessment.

• The association is higher if patients are classified according to their activity score, rather than as carriers of detrimental CYP2C9 alleles.

• There is a significant allele-specific effect: CYP2C9*2 is a poor risk predictor whereas CYP2C9*3 is a highly significant predictor for both overall gastrointestinal events and, especially, gastrointestinal bleeding.

Acknowledgments

Professor James McCue revised in detail the quality of the English language.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported in part by Grants P/15100303, P/18100540, and RETICS ARADyAL RD16/0006/0004 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Madrid, Spain, and IB16170 and GR18145 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union.