title: Identification of CYP2D6 impaired functional alleles in Mexican Americans.
abstract: 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.
authors.affiliation: 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.
authors.forename: Huai-Rong
authors.initials: HR
authors.lastname: Luo
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.forename: Vasileios
authors.initials: V
authors.lastname: Aloumanis
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
mesh_terms: 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*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6