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A novel intronic mutation, 2988G>A, with high predictivity for impaired dunction of cytochrome P450 2D6 in white subjects
Author(s) -
Raimundo Sebastian,
Toscano Claudia,
Klein Kathrin,
Fischer Joachim,
Griese ErnstUlrich,
Eichelbaum Michel,
Schwab Matthias,
Zanger Ulrich M.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.04.009
Subject(s) - genetics , biology , genotyping , allele , genotype , cyp2d6 , population , allele frequency , gene , medicine , environmental health
Background Individuals with the cytochrome P450 (CYP) 2D6 intermediate metabolizer (IM) phenotype have low residual enzyme activity and compose about 10% to 15% of white populations. Their identification is clinically relevant but remains unsatisfactory because of incomplete characterization of the major allele involved, termed CYP2D6*41 (−1584C, R296C, S486T). Methods To search for novel mutations, resequencing of the entire CYP2D6 gene was performed in selected individuals. Genotype‐phenotype correlation analysis was done in a population sample of 308 white subjects phenotyped with sparteine and previously genotyped for all major alleles. Results A total of 16 novel polymorphic positions were identified, of which 7 were located within 2.4 kilobases of previously uncharacterized 2D7–2D6 intergenic sequence and 9 were located within intronic regions. The novel mutation 2988G>A in intron 6 appeared to be specifically associated with the IM phenotype. Further analysis in the population sample demonstrated that 2988G>A was strongly linked to allele *41 but not to any other alleles including *1 , *2 , *2×N , *4 , *6 , *7 , *8 , *9 , *10 , and *35 . The overall frequency of the novel polymorphism was 8.4% in the normal white population. Compared with conventionally determined *41 , 2988G>A was shown to have improved predictivity for the IM phenotype. With 2988G>A being taken into account, alleles *1 , *2 , and *35 (−1584G, V11M, R296C, S486T) were found to be phenotypically equivalent. Conclusions CYP2D6 genotyping can be considerably simplified by using 2988G>A as a marker for *41 and by omitting genotyping for the functionally equivalent alleles *2 and *35 . Clinical Pharmacology & Therapeutics (2004) 76 , 128–138; doi: 10.1016/j.clpt.2004.04.009