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

• Published in: Clinical pharmacology and therapeutics Vol. 76; no. 2; p. 128
• Main Authors: Raimundo, Sebastian, Toscano, Claudia, Klein, Kathrin, Fischer, Joachim, Griese, Ernst-Ulrich, Eichelbaum, Michel, Schwab, Matthias, Zanger, Ulrich M
• Format: Journal Article
• Language: English
• Published: United States 01.08.2004
• Subjects: Adult; Analysis of Variance; Base Sequence; Cohort Studies; Cytochrome P-450 CYP2D6 - genetics; DNA Primers - analysis; European Continental Ancestry Group - genetics; Female; Genetic Testing; Genetic Variation; Genetics, Population; Genotype; Germany; Humans; Male; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Probability; Sensitivity and Specificity; Statistics, Nonparametric; Germany
• ISSN: 0009-9236
• DOI: 10.1016/j.clpt.2004.04.009

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). 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. 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, *2xN, *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. 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.