Identification of CYP2D6 impaired functional alleles in Mexican Americans.
OBJECTIVE
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 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.
Luo
Huai-Rong
HR
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Mail Stop 1018, Breidenthal Building, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
Gaedigk
Andrea
A
Aloumanis
Vasileios
V
Wan
Yu-Jui Yvonne
YJ
D000328:Adult; D000483:Alleles; D019389:Cytochrome P-450 CYP2D6 / Q000145:classification / Q000235:genetics*; D003915:Dextromethorphan / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D005260:Female; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008297:Male; D017058:Mexican Americans / Q000235:genetics*
D018691:Excitatory Amino Acid Antagonists; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6