CYP2D6 phenotype-genotype relationships in African-Americans and Caucasians in Los Angeles

CYP2D6 genotyping (CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*13, CYP2D6*16 allel es and gene duplications) was previously performed on 1053 Caucasian and Af rican-American lung cancer cases and control individuals and no significant difference in allele frequencies between cases and control individuals det ected. We have carried out additional genotyping (CYP2D6*6, CYP2D6*7, CYP2D 6*8, CYP2D6*9, CYP2D6*10, CYP2D6*17 alleles) and debrisoquine phenotyping o n subgroups from this study to assess phenotype-genotype relationships. Afr ican-Americans showed significant differences from Caucasians with respect to frequency of defective CPP2D6 alleles, particularly CYP2D6*4 and CYP2D6* 5, The CYP2D6*17 allele occurred at a frequency of 0.26 among 87 African-Am ericans and appeared to explain higher average metabolic ratios among Afric an-Americans compared with Caucasians. CYP2D6*6, CYP2D6*8, CYP2D6*9 and CYP 2D6*10 were rare in both ethnic groups but explained approximately 40% of h igher than expected metabolic ratios among extensive metabolizers. Among in dividuals phenotyped with debrisoquine, 32 out of 359 were in the poor meta bolizer range with 24 of these (75%) also showing two defective CYP2D6 alle les, Additional single strand conformational polymorphism analysis screenin g of samples showing large phenotype - genotype discrepancies resulted in t he detection of three novel polymorphisms. If subjects taking potentially i nterfering drugs were excluded, this additional screening enabled the posit ive identification of 88% of phenotypic poor metabolizers by genotyping, Th is sensitivity was comparable with that of phenotyping, which identified 90 % of those with two defective alleles as poor metabolizers, Pharmacogenetic s 8:529-541. (C) 1998 Lippincott Williams & Wilkins.