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Identification of CYP2C19*4B: pharmacogenetic implications for drug metabolism including clopidogrel responsiveness

S A Scott1, S Martis, I Peter

  • 1Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA. stuart.scott@mssm.edu

The Pharmacogenomics Journal
|March 2, 2011
PubMed

Insights

CYP2C19 genetic variations impact clopidogrel effectiveness. New findings reveal specific alleles (CYP2C19*4B and *17) are crucial for accurate risk assessment in Jewish populations, affecting cardiovascular event risk.

Area of Science:

  • Pharmacogenomics
  • Genetics
  • Cardiovascular Medicine

Background:

  • CYP2C19 is key for clopidogrel activation; loss-of-function alleles correlate with cardiovascular risks.
  • The CYP2C19*17 increased activity allele's impact and other variants in Jewish populations require investigation.

Purpose of the Study:

  • Assess CYP2C19*17 allele impact in Ashkenazi Jewish (AJ) and Sephardi Jewish (SJ) populations.
  • Determine frequencies of additional CYP2C19 variant alleles and P-glycoprotein (ABCB1) c.3435C>T.
  • Identify novel haplotypes and their clinical significance for clopidogrel response.

Main Methods:

  • Genotyped 250 AJ and 135 SJ individuals for CYP2C19 alleles (*2-*10, *12-*17, *22) and ABCB1 c.3435C>T.
  • Analyzed linkage disequilibrium between alleles, particularly *17 and *4.
  • Reclassified metabolizer status based on *17 allele presence.

Main Results:

  • Identified CYP2C19*4 in linkage disequilibrium with *17, forming a novel haplotype CYP2C19*4B.
  • Genotyping *17 reclassified ~30% of individuals from extensive to ultrarapid metabolizers (reducing efficacy from ~70% to ~40%).
  • Combined CYP2C19 and ABCB1 data indicated ~1 in 3 AJ and ~1 in 2 SJ individuals face increased adverse clopidogrel response risk.

Conclusions:

  • The novel CYP2C19*4B haplotype significantly alters clopidogrel pharmacogenetic interpretation.
  • Clinical CYP2C19 genotyping must include *4B and *17 for accurate risk stratification.
  • Targeted genotyping is essential for optimizing clopidogrel therapy and mitigating cardiovascular risks in AJ and SJ populations.

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