Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: Characterization of 48 mutations and 53 alleles, their frequencies and evolution

被引:324
作者
Marez, D
Legrand, M
Sabbagh, N
LoGuidice, JM
Spire, C
Lafitte, JJ
Meyer, UA
Broly, F
机构
[1] CHRU,HOP CALMETTE,CLIN PNEUMOPHTISIOL,F-59037 LILLE,FRANCE
[2] UNIV BASEL,BIOZENTRUM,DEPT PHARMACOL,CH-4056 BASEL,SWITZERLAND
来源
PHARMACOGENETICS | 1997年 / 7卷 / 03期
关键词
CYP2D6; polymorphism; pharmacogenetics; population; SSCP;
D O I
10.1097/00008571-199706000-00004
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The polymorphic cytochrome P450 CYP2D6 is involved in the metabolism of various drugs of wide therapeutic use and is a presumed susceptibility factor for certain environmentally-induced diseases, Our aim was to define the mutations and alleles of the CYP2D6 gene and to evaluate their frequencies in the European population, Using polymerase chain reaction-single strand conformation polymorphism analysis, 672 unrelated subjects were screened for mutations in the 9 exons of the gene and their exon-intron boundaries, A total of 48 point mutations were identified, 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 the 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 subgroup, Fifty-three different alleles were characterized from the mutation pattern and by allele-specific sequencing, They are derived from three major alleles, namely the wild-type CYP2D6*1A, the functional CYP2D6*2 and the null CYP2D6*4A. Five allelic variants (CYP2D6*1A, *2, *2B, *4A and *5) account for about 87%, of all alleles, while the remaining alleles occur with a frequency of 0.1% - 2.7%. These data provide a solid basis for future epidemiological, clinical as well as interethnic studies of the CYP2D6 polymorphism and highlight that the described single strand conformation polymorphism method call be successfully used in designing such studies.
引用
收藏
页码:193 / 202
页数:10
相关论文
共 52 条
[1]   PREVALENCE OF CYP2D6 GENE DUPLICATION AND ITS REPERCUSSION ON THE OXIDATIVE PHENOTYPE IN A WHITE-POPULATION [J].
AGUNDEZ, JAG ;
LEDESMA, MC ;
LADERO, JM ;
BENITEZ, J .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1995, 57 (03) :265-269
[2]   HYDROXYLATION POLYMORPHISMS OF DEBRISOQUINE AND MEPHENYTOIN IN EUROPEAN POPULATIONS [J].
ALVAN, G ;
BECHTEL, P ;
ISELIUS, L ;
GUNDERTREMY, U .
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1990, 39 (06) :533-537
[3]   THE CYTOCHROME-P450 CYP2D6 ALLELIC VARIANT CYP2D6J AND RELATED POLYMORPHISMS IN A EUROPEAN POPULATION [J].
ARMSTRONG, M ;
FAIRBROTHER, K ;
IDLE, JR ;
DALY, AK .
PHARMACOGENETICS, 1994, 4 (02) :73-81
[4]   GEOGRAPHICAL INTERRACIAL DIFFERENCES IN POLYMORPHIC DRUG OXIDATION - CURRENT STATE OF KNOWLEDGE OF CYTOCHROMES P450 (CYP) 2D6 AND 2C19 [J].
BERTILSSON, L .
CLINICAL PHARMACOKINETICS, 1995, 29 (03) :192-209
[5]   Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis [J].
Beyeler, C ;
Armstrong, M ;
Bird, HA ;
Idle, JR ;
Daly, AK .
ANNALS OF THE RHEUMATIC DISEASES, 1996, 55 (01) :66-68
[6]   An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis [J].
Broly, F ;
Marez, D ;
Sabbagh, N ;
Legrand, M ;
Millecamps, S ;
LoGuidice, JM ;
Boone, P ;
Meyer, UA .
PHARMACOGENETICS, 1995, 5 (06) :373-384
[7]   A NONSENSE MUTATION IN THE CYTOCHROME-P450 CYP2D6 GENE IDENTIFIED IN A CAUCASIAN WITH AN ENZYME DEFICIENCY [J].
BROLY, F ;
MAREZ, D ;
LOGUIDICE, JM ;
SABBAGH, N ;
LEGRAND, M ;
BOONE, P ;
MEYER, UA .
HUMAN GENETICS, 1995, 96 (05) :601-603
[8]   DEBRISOQUINE SPARTEINE HYDROXYLATION GENOTYPE AND PHENOTYPE - ANALYSIS OF COMMON MUTATIONS AND ALLELES OF CYP2D6 IN A EUROPEAN POPULATION [J].
BROLY, F ;
GAEDIGK, A ;
HEIM, M ;
EICHELBAUM, M ;
MORIKE, K ;
MEYER, UA .
DNA AND CELL BIOLOGY, 1991, 10 (08) :545-558
[9]  
BROLY F, 1993, PHARMACOGENETICS, V3, P923
[10]   CYP2D6 GENOTYPE DETERMINATION IN THE DANISH POPULATION [J].
BROSEN, K ;
NIELSEN, PN ;
BRUSGAARD, K ;
GRAM, LF ;
SKJODT, K .
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1994, 47 (03) :221-225