Identification of CYP2D6 impaired functional alleles in Mexican Americans

Huai Rong Luo, Andrea Gaedigk, Vasileios Aloumanis, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Objectives: To extend the genotyping analysis of the CYP2D6 gene and further explain variability of CYP2D6 activity in Mexican Americans by genetic factors. Methods: CYP2D6 gene sequence variations associated with *6, *7, *8, *9, *11, *14, *29, *41, *45, and *46 alleles as well as the 2988G>A SNP were examined in 264 Mexican Americans; 236 had previously been phenotyped with dextromethorphan. All subjects were previously genotyped for CYP2D6*2, *3, *4, *5, *10, *17, and the presence of a gene duplication. Associations between genotype and CYP2D6 activity were determined. Results: Mexican Americans revealed a high frequency of functional alleles (CYP2D6*1 and *2; 73.1%), followed by CYP2D6*4 (non-functional, 10.0%) and the reduced-function allele *41 (9.5%). The frequencies of CYP2D6*5, *6, *9, *10, duplication, and 2988A were 1.7%, 0.4%, 1.1%, 2.8%, 0.8%, and 5.7%, respectively. CYP2D6*3, *17, and *29 were found only in one individual (CYP2D6*2/ *3, *1/*17, and *4/*29), while CYP2D6*7, *8, *11, *14, *45, and *46 were absent in this study population. Decreased CYP2D6 activity was more accurately predicted by the presence*41[-1584C] compared to *41[2988A]. One genotype/phenotype discordant subject was resolved by the presence of a CYP2D6*6 allele (*4/*6), while two other cases remained discordant (*41/*41 and *1/*1). Conclusions: The CYP2D6*4, *5, and *6 null alleles along with the reduced function alleles *9, *10, and *41 are the major cause for diminished dextromethorphan oxidative capacity in Mexican Americans. These findings may have implications for the safety and efficacy of CYP2D6 substrates taken by Mexican Americans.

Original languageEnglish (US)
Pages (from-to)797-802
Number of pages6
JournalEuropean Journal of Clinical Pharmacology
Volume61
Issue number11
DOIs
StatePublished - Dec 2005
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP2D6
Alleles
Dextromethorphan
Genotype
Gene Duplication
Gene Frequency

Keywords

  • CYP2D6
  • Dextromethorphan
  • Genetic polymorphism
  • Mexican Americans

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Identification of CYP2D6 impaired functional alleles in Mexican Americans. / Luo, Huai Rong; Gaedigk, Andrea; Aloumanis, Vasileios; Wan, Yu-Jui Yvonne.

In: European Journal of Clinical Pharmacology, Vol. 61, No. 11, 12.2005, p. 797-802.

Research output: Contribution to journalArticle

Luo, Huai Rong ; Gaedigk, Andrea ; Aloumanis, Vasileios ; Wan, Yu-Jui Yvonne. / Identification of CYP2D6 impaired functional alleles in Mexican Americans. In: European Journal of Clinical Pharmacology. 2005 ; Vol. 61, No. 11. pp. 797-802.
@article{28a506f20dd844b086f5c71c14681687,
title = "Identification of CYP2D6 impaired functional alleles in Mexican Americans",
abstract = "Objectives: To extend the genotyping analysis of the CYP2D6 gene and further explain variability of CYP2D6 activity in Mexican Americans by genetic factors. Methods: CYP2D6 gene sequence variations associated with *6, *7, *8, *9, *11, *14, *29, *41, *45, and *46 alleles as well as the 2988G>A SNP were examined in 264 Mexican Americans; 236 had previously been phenotyped with dextromethorphan. All subjects were previously genotyped for CYP2D6*2, *3, *4, *5, *10, *17, and the presence of a gene duplication. Associations between genotype and CYP2D6 activity were determined. Results: Mexican Americans revealed a high frequency of functional alleles (CYP2D6*1 and *2; 73.1{\%}), followed by CYP2D6*4 (non-functional, 10.0{\%}) and the reduced-function allele *41 (9.5{\%}). The frequencies of CYP2D6*5, *6, *9, *10, duplication, and 2988A were 1.7{\%}, 0.4{\%}, 1.1{\%}, 2.8{\%}, 0.8{\%}, and 5.7{\%}, respectively. CYP2D6*3, *17, and *29 were found only in one individual (CYP2D6*2/ *3, *1/*17, and *4/*29), while CYP2D6*7, *8, *11, *14, *45, and *46 were absent in this study population. Decreased CYP2D6 activity was more accurately predicted by the presence*41[-1584C] compared to *41[2988A]. One genotype/phenotype discordant subject was resolved by the presence of a CYP2D6*6 allele (*4/*6), while two other cases remained discordant (*41/*41 and *1/*1). Conclusions: The CYP2D6*4, *5, and *6 null alleles along with the reduced function alleles *9, *10, and *41 are the major cause for diminished dextromethorphan oxidative capacity in Mexican Americans. These findings may have implications for the safety and efficacy of CYP2D6 substrates taken by Mexican Americans.",
keywords = "CYP2D6, Dextromethorphan, Genetic polymorphism, Mexican Americans",
author = "Luo, {Huai Rong} and Andrea Gaedigk and Vasileios Aloumanis and Wan, {Yu-Jui Yvonne}",
year = "2005",
month = "12",
doi = "10.1007/s00228-005-0044-4",
language = "English (US)",
volume = "61",
pages = "797--802",
journal = "European Journal of Clinical Pharmacology",
issn = "0031-6970",
publisher = "Springer Verlag",
number = "11",

}

TY - JOUR

T1 - Identification of CYP2D6 impaired functional alleles in Mexican Americans

AU - Luo, Huai Rong

AU - Gaedigk, Andrea

AU - Aloumanis, Vasileios

AU - Wan, Yu-Jui Yvonne

PY - 2005/12

Y1 - 2005/12

N2 - Objectives: To extend the genotyping analysis of the CYP2D6 gene and further explain variability of CYP2D6 activity in Mexican Americans by genetic factors. Methods: CYP2D6 gene sequence variations associated with *6, *7, *8, *9, *11, *14, *29, *41, *45, and *46 alleles as well as the 2988G>A SNP were examined in 264 Mexican Americans; 236 had previously been phenotyped with dextromethorphan. All subjects were previously genotyped for CYP2D6*2, *3, *4, *5, *10, *17, and the presence of a gene duplication. Associations between genotype and CYP2D6 activity were determined. Results: Mexican Americans revealed a high frequency of functional alleles (CYP2D6*1 and *2; 73.1%), followed by CYP2D6*4 (non-functional, 10.0%) and the reduced-function allele *41 (9.5%). The frequencies of CYP2D6*5, *6, *9, *10, duplication, and 2988A were 1.7%, 0.4%, 1.1%, 2.8%, 0.8%, and 5.7%, respectively. CYP2D6*3, *17, and *29 were found only in one individual (CYP2D6*2/ *3, *1/*17, and *4/*29), while CYP2D6*7, *8, *11, *14, *45, and *46 were absent in this study population. Decreased CYP2D6 activity was more accurately predicted by the presence*41[-1584C] compared to *41[2988A]. One genotype/phenotype discordant subject was resolved by the presence of a CYP2D6*6 allele (*4/*6), while two other cases remained discordant (*41/*41 and *1/*1). Conclusions: The CYP2D6*4, *5, and *6 null alleles along with the reduced function alleles *9, *10, and *41 are the major cause for diminished dextromethorphan oxidative capacity in Mexican Americans. These findings may have implications for the safety and efficacy of CYP2D6 substrates taken by Mexican Americans.

AB - Objectives: To extend the genotyping analysis of the CYP2D6 gene and further explain variability of CYP2D6 activity in Mexican Americans by genetic factors. Methods: CYP2D6 gene sequence variations associated with *6, *7, *8, *9, *11, *14, *29, *41, *45, and *46 alleles as well as the 2988G>A SNP were examined in 264 Mexican Americans; 236 had previously been phenotyped with dextromethorphan. All subjects were previously genotyped for CYP2D6*2, *3, *4, *5, *10, *17, and the presence of a gene duplication. Associations between genotype and CYP2D6 activity were determined. Results: Mexican Americans revealed a high frequency of functional alleles (CYP2D6*1 and *2; 73.1%), followed by CYP2D6*4 (non-functional, 10.0%) and the reduced-function allele *41 (9.5%). The frequencies of CYP2D6*5, *6, *9, *10, duplication, and 2988A were 1.7%, 0.4%, 1.1%, 2.8%, 0.8%, and 5.7%, respectively. CYP2D6*3, *17, and *29 were found only in one individual (CYP2D6*2/ *3, *1/*17, and *4/*29), while CYP2D6*7, *8, *11, *14, *45, and *46 were absent in this study population. Decreased CYP2D6 activity was more accurately predicted by the presence*41[-1584C] compared to *41[2988A]. One genotype/phenotype discordant subject was resolved by the presence of a CYP2D6*6 allele (*4/*6), while two other cases remained discordant (*41/*41 and *1/*1). Conclusions: The CYP2D6*4, *5, and *6 null alleles along with the reduced function alleles *9, *10, and *41 are the major cause for diminished dextromethorphan oxidative capacity in Mexican Americans. These findings may have implications for the safety and efficacy of CYP2D6 substrates taken by Mexican Americans.

KW - CYP2D6

KW - Dextromethorphan

KW - Genetic polymorphism

KW - Mexican Americans

UR - http://www.scopus.com/inward/record.url?scp=28444496691&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=28444496691&partnerID=8YFLogxK

U2 - 10.1007/s00228-005-0044-4

DO - 10.1007/s00228-005-0044-4

M3 - Article

VL - 61

SP - 797

EP - 802

JO - European Journal of Clinical Pharmacology

JF - European Journal of Clinical Pharmacology

SN - 0031-6970

IS - 11

ER -