A novel intronic mutation, 2988G>A, with high predictivity for impaired function of cytochrome P450 2D6 in white subjects

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(star)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 (star)41 but not to any other alleles including (star)1, (star)2, (star)2xN, (star)4, (star)6, (star)7, (star)8, (star)9, (star)10, and (star)35. The overall frequency of the novel polymorphism was 8.4% in the normal white population. Compared with conventionally determined (star)41, 2988G>A was shown to have improved predictivity for the IM phenotype. With 2988G>A being taken into account, alleles (star)1, (star)2, and (star)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 (star)41 and by omitting genotyping for the functionally equivalent alleles (star)2 and (star)35.