Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans.
BACKGROUND
Although CYP2D6 has been studied extensively in different population groups, relatively little is known for black Americans.


METHODS
CYP2D6 activity was assessed with dextromethorphan in 283 black American subjects and correlated with their genotype (2D6*2 to *12, 2D6*14, 2D6*15, 2D6*17, 2D6*18, and 2D6*29 and gene duplications). Volunteers provided information about ethnicity and concurrent medication, and they participated in either phenotyping (n = 225), genotyping (n = 251), or both (n = 193).


RESULTS
The median urinary dextromethorphan/dextrorphan metabolic ratio (MR) indicated significantly lower CYP2D6 activity in the black American group (0.016) than in a white control population (0.0044; P =.0001) studied previously. The reduced function allele 2D6*17 was more common (frequency [f] = 0.395) among intermediate metabolizers (0.03 < or = MR < or= 0.3) than extensive metabolizers (MR < or = 0.03; f = 0.148; P =.0001). Consistent with reduced function toward dextromethorphan of COS cell-expressed 2D6.29 protein, 2D6*29 also was more frequent in intermediate metabolizers (f = 0.114) than in extensive metabolizers (f = 0.057; P = NS). Frequencies for 2D6*17 and 2D6*29 were f = 0.213 and 0.072, respectively. Of the 193 genotyped and phenotyped subjects, 14 were determined to be poor metabolizers, with dextromethorphan/dextrorphan ratios >0.3 (7.25%), but only 2 subjects (1.04%) carried 2 nonfunctional alleles (2D6*3/*4x2 and 2D6*4/*4). A new allelic variant, 2D6*40, was subsequently found in 2 discordant subjects (2D6*4/*40 and 2D6*6/*40), implying that the 18-base pair (bp) insertion found in 2D6*40 renders it nonfunctional. The frequency of 2D6*40 was 0.006. For genotypes that contain 2D6*2, median MR values were consistently higher in black Americans than in white subjects, indicating that other unidentified factors also contribute to lower CYP2D6 activity in black Americans.


CONCLUSIONS
The lower CYP2D6 activity observed in a black American population is in part attributable to the presence of variant alleles that occur at a higher frequency in this population than in white subjects. Additional studies are required to ascertain the pharmacokinetic and pharmacodynamic consequences of these pharmacogenetic data in black Americans.
Gaedigk
Andrea
A
Division of Pediatric Clinical Pharmacology and Medical Toxicology, Children's Mercy Hospital and Clinics, Kansas City, MO 64108 USA. agaedigk@cmh.edu
Bradford
L DiAnne
LD
Marcucci
Kenda A
KA
Leeder
J Steven
JS
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D000996:Antitussive Agents; D044383:Black People / Q000235:genetics*; D019556:COS Cells; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D017931:DNA Primers; D003915:Dextromethorphan; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D014481:United States; D044465:White People; D001741:Black or African American
D000996:Antitussive Agents; D017931:DNA Primers; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6