Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response

Rolf Kreutz, Janelle Owens, Yan Jin, Perry Nystrom, Zeruesenay Desta, Yvonne Kreutz, Jeffrey Breall, Lang Li, Chien Wei Chiang, Richard Kovacs, David A. Flockhart

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.

Original languageEnglish
Pages (from-to)185-192
Number of pages8
JournalClinical Pharmacology: Advances and Applications
Volume5
DOIs
StatePublished - Dec 9 2013

Fingerprint

clopidogrel
Cytochrome P-450 CYP3A
Peroxisome Proliferator-Activated Receptors
Cytoplasmic and Nuclear Receptors
Platelet Aggregation
Genes
Genotype
Light
Adenosine Diphosphate
Coronary Artery Disease
Healthy Volunteers

Keywords

  • Clopidogrel
  • CYP450
  • Pharmacogenetics
  • Platelet aggregation

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response. / Kreutz, Rolf; Owens, Janelle; Jin, Yan; Nystrom, Perry; Desta, Zeruesenay; Kreutz, Yvonne; Breall, Jeffrey; Li, Lang; Chiang, Chien Wei; Kovacs, Richard; Flockhart, David A.

In: Clinical Pharmacology: Advances and Applications, Vol. 5, 09.12.2013, p. 185-192.

Research output: Contribution to journalArticle

Kreutz, Rolf ; Owens, Janelle ; Jin, Yan ; Nystrom, Perry ; Desta, Zeruesenay ; Kreutz, Yvonne ; Breall, Jeffrey ; Li, Lang ; Chiang, Chien Wei ; Kovacs, Richard ; Flockhart, David A. / Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response. In: Clinical Pharmacology: Advances and Applications. 2013 ; Vol. 5. pp. 185-192.
@article{5cc5c84f28d140e4aae3d6e3f2fb6dce,
title = "Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response",
abstract = "Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman{\circledR} assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.",
keywords = "Clopidogrel, CYP450, Pharmacogenetics, Platelet aggregation",
author = "Rolf Kreutz and Janelle Owens and Yan Jin and Perry Nystrom and Zeruesenay Desta and Yvonne Kreutz and Jeffrey Breall and Lang Li and Chiang, {Chien Wei} and Richard Kovacs and Flockhart, {David A.}",
year = "2013",
month = "12",
day = "9",
doi = "10.2147/CPAA.S53151",
language = "English",
volume = "5",
pages = "185--192",
journal = "Clinical Pharmacology: Advances and Applications",
issn = "1179-1438",
publisher = "Dove Medical Press Ltd.",

}

TY - JOUR

T1 - Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response

AU - Kreutz, Rolf

AU - Owens, Janelle

AU - Jin, Yan

AU - Nystrom, Perry

AU - Desta, Zeruesenay

AU - Kreutz, Yvonne

AU - Breall, Jeffrey

AU - Li, Lang

AU - Chiang, Chien Wei

AU - Kovacs, Richard

AU - Flockhart, David A.

PY - 2013/12/9

Y1 - 2013/12/9

N2 - Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.

AB - Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.

KW - Clopidogrel

KW - CYP450

KW - Pharmacogenetics

KW - Platelet aggregation

UR - http://www.scopus.com/inward/record.url?scp=84890362511&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890362511&partnerID=8YFLogxK

U2 - 10.2147/CPAA.S53151

DO - 10.2147/CPAA.S53151

M3 - Article

VL - 5

SP - 185

EP - 192

JO - Clinical Pharmacology: Advances and Applications

JF - Clinical Pharmacology: Advances and Applications

SN - 1179-1438

ER -