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 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.