POLYMORPHISM OF THE CYTOCHROME-P450 CYP2D6 GENE IN A EUROPEAN POPULATION - CHARACTERIZATION OF 48 MUTATIONS AND 53 ALLELES, THEIR FREQUENCIES AND EVOLUTION

The polymorphic cytochrome P450 CYP2D6 is involved in the metabolism o f various drugs of wide therapeutic use and is a presumed susceptibili ty factor for certain environmentally-induced diseases, Our aim was to define the mutations and alleles of the CYP2D6 gene and to evaluate t heir frequencies in the European population, Using polymerase chain re action-single strand conformation polymorphism analysis, 672 unrelated subjects were screened for mutations in the 9 exons of the gene and t heir exon-intron boundaries, A total of 48 point mutations were identi fied, of which 29 were novel, Mutations 1749 G --> C, 2938 C --> T and 4268 G --> C represented 52.6% 34.3% and 52.9%, of the mutations in t he total population, respectively, Of the eight detrimental mutations detected, the 1934 G --> A, the 1795 Tdel and the 2637 Adel accounted for 65.8% 6.2%, and 4.8% respectively, within the poor metabolizer sub group, Fifty-three different alleles were characterized from the mutat ion pattern and by allele-specific sequencing, They are derived from t hree major alleles, namely the wild-type CYP2D61A, the functional CYP 2D62 and the null CYP2D6*4A. Five allelic variants (CYP2D6*1A, *2, *2 B, 4A and *5) account for about 87%, of all alleles, while the remain ing alleles occur with a frequency of 0.1% - 2.7%. These data provide a solid basis for future epidemiological, clinical as well as intereth nic studies of the CYP2D6 polymorphism and highlight that the describe d single strand conformation polymorphism method call be successfully used in designing such studies.