Cell Biochem Funct.

2007 Feb 21;

Frequency of single nucleotide polymorphisms of

CYP2D6 in the Czech population.
Buzková H, Pechandová K, Slanař O, Perlík F.

Clinical Pharmacology Unit, Department of Pharmacology, First Faculty of Medicine,

Charles University, Prague, Czech Republic.

CYP2D6 is a member of cytochrome P450 enzymes that metabolise over 25% of

commonly used drugs. Genetic polymorphisms can cause insufficient drug efficacy at
usually administered doses or can be the cause of adverse drug reaction. CYP2D6
genotyping can be used to predict CYP2D6 phenotype and thereby explain some
abnormalities in drug response and thus optimize pharmacotherapy. The aim of this
study was to investigate the frequency of functionally important variant alleles of the
CYP2D6 gene throughout the Czech population to predict the prevalence of ultra-
rapid and poor metabolizer phenotypes. The DNA of 223 unrelated, healthy volunteers
was analysed to detect the presence of CYP2D6*6, *5, *4, *3 and gene duplication.
The variant allele frequencies in our population were 0.22%, 3.14%, 22.87%, 1.12%
and 3.14% for CYP2D6*6, CYP2D6*5, CYP2D6*4, CYP2D6*3 and CYP2D6*MxN,
respectively. Fifteen subjects carried two variant alleles leading to predicted poor type
of metabolism, 84 subjects were heterozygous extensive metabolizers (het-EM). The
full-text contains detailed comparison with European white populations. The
distribution of variant alleles complies with the Hardy-Weinberg equilibrium. The
frequencies of functional variant alleles of CYP2D6 in Czech population are in
concordance with other Caucasian populations.

1: Cell Biochem Funct. 2006 Sep-Oct;24(5):381-5.

Characterization of variant alleles of cytochrome CYP2D6 in a
Spanish population.
Menoyo A, del Rio E, Baiget M.

Servei de Genètica, Hospital de la santa Creu i Sant Pau, Barcelona, Spain.

The CYP2D6 gene codes for a P450 monooxygenase which is involved in the
biotransformation of a large number of commonly prescribed drugs. Adverse drug
effects and therapeutic failure can be related to abnormal CYP2D6 activity. We
investigated the allele and genotype frequencies of cytochrome P4502D6 in a Spanish
population to predict the prevalence of ultra-rapid and poor metabolizer phenotypes in
our population and to design a feasible CYP2D6 genotyping protocol. The study
included 105 healthy unrelated Spanish Caucasian volunteers. CYP2D6 genotyping
was performed by a combination of long-PCR, direct sequencing and allele-specific
real-time PCR. The frequency of the wild-type CYP2D6*1 allele was 31%. The alleles
coding for slightly (CYP2D6*2) or moderately (*9 and *10) reduced activity showed
frequencies of 40.47, 2.38 and 1.90%, respectively. Frequencies of defective alleles
*3, *4, *5 and *6 were 0.95, 13.8, 3.33 and 0.95%, respectively. The defective
CYP2D6 alleles *7, *8, *12, *14, *15 and *21 were not found. Duplicated CYP2D6
alleles were detected at a frequency of 4.27%. Our protocol allows the identification of
 the four inactive CYP2D6 alleles (*3, *4, *5 and *6) and the detection of alleles with
CYP2D6 *1, CYP2D6 *2 and CYP2D6*4 gene duplications. Testing for this reduced
CYP2D6 allele set would facilitate its use in clinical practice by assisting in the
development of individualized pharmacotherapy

Clin Pharmacol Ther. 1999 Aug;66(2):185-92.

Low frequency of defective alleles of cytochrome P450

enzymes 2C19 and 2D6 in the Turkish population.
Aynacioglu AS, Sachse C, Bozkurt A, Kortunay S, Nacak M, Schröder T,
Kayaalp SO, Roots I, Brockmöller J.

Institute of Clinical Pharmacology, University Clinic Charité, Humboldt University,

Berlin, Germany.

BACKGROUND AND OBJECTIVES: The genetically polymorphic cytochrome

P450 enzymes 2Cl9 (CYP2Cl9) and 2D6 (CYP2D6) contribute to the metabolism of
about 30% of all drugs. For analysis of the ethnic-related differences in drug
disposition and as a preparation for routine genotyping, we examined CYP2C19 and
CYP2D6 mutations in a large Turkish population. Methods: CYP2C19 and CYP2D6
alleles were determined with use of genomic deoxyribonucleic acid from 404
unrelated Turkish individuals. CYP2C19 alleles *1 to *5 and CYP2D6 alleles *1 to
*12, and *14, *15, and *17 were measured by polymerase chain reaction-restriction
fragment length polymorphism assays. RESULTS: From 404 subjects genotyped for
CYP2C19, allele frequencies of CYP2C19*1 (wt), CYP2C19*2 (ml), and
CYP2C19*3 (m2) were 0.88, 0.12, and 0.004, respectively; mutations m3 and m4
were not found. Four individuals (1.0%) were predicted to be poor metabolizers
(CYP2C19*2/*2), a significantly lower frequency compared to Middle European
populations. Among 404 subjects genotyped for CYP2D6, most frequent alleles were
CYP2D6*1 (allele frequency 0.37), *2 (0.35), *4 (0.11), *10 (0.06), duplications
*1x2, *2x2, or *4x2 (0.06), *5 (0.01), and *17(0.01). Overall, six subjects (1.49%)
were predicted to be CYP2D6 poor metabolizers, and 35 subjects (8.66%) were
predicted to be ultrarapid metabolizers as a result of CYP2D6 gene duplications.
CONCLUSION: Obviously, within Europe there is a north-south gradient, with
decreasing frequency of poor metabolizers of CYP2C19 and CYP2D6 to the south and
a corresponding increase of ultrarapid metabolizers of CYP2D6. As in other white
groups, only CYP2C19*2 plays a relevant role for the CYP2C19 poor metabolizer
phenotype. The mutational spectrum of CYP2D6 indicated partial ethnic relationships
to Asian and African populations.

Pharmacol Res. 2004 Aug;50(2):195-200.

Allele and genotype frequencies of CYP2C9, CYP2C19 and

CYP2D6 in an Italian population.
Scordo MG, Caputi AP, D'Arrigo C, Fava G, Spina E.
 Department of Experimental and Clinical Medicine and Pharmacology, Section of
Pharmacology, University of Messina, Torre Biologica, Policlinico Universitario, Via
Consolare Valeria-Gazzi, 98125 Messina, Italy.

The polymorphic cytochrome P450 isoenzymes (CYPs) 2C9, 2C19 and 2D6
metabolise many important drugs, as well as other xenobiotics. Their polymorphism
gives rise to important interindividual and interethnic variability in the metabolism and
disposition of several therapeutic agents and may cause differences in the clinical
response to these drugs. In this study, we determined the genotype profile of a random
Italian population in order to compare the CYP2C9, CYP2C19 and CYP2D6 allele
frequencies among Italians with previous findings in other Caucasian populations.
Frequencies for the major CYP2C9, CYP2C19 and CYP2D6 mutated alleles and
genotypes have been evaluated in 360 unrelated healthy Italian volunteers (210 males
and 150 females, aged 19-52 years). Genotyping has been carried out on peripheral
leukocytes DNA by molecular biology techniques (PCR, RFLP, long-PCR). CYP2C9,
CYP2C19 and CYP2D6 allele and genotype frequencies resulted in equilibrium with
the Hardy-Weinberg equation. One hundred and fourteen subjects (31.7%) carried one
and 23 subjects (6.4%) carried two CYP2C9 mutated alleles. Sixty-eight (18.9%)
volunteers were found to be heterozygous and six (1.7%) homozygous for the
CYP2C19*2, while no CYP2C19*3 was detected in the evaluated population.
Volunteers could be divided into four CYP2D6 genotypes groups: 192 subjects
(53.3%) with no mutated alleles (homozygous extensive metabolisers, EM), 126
(35.0%) with one mutated allele (heterozygous EM), 12 (3.4%) with two mutated
alleles (poor metabolisers, PM) and 30 (8.3%) with extracopies of a functional gene
(ultrarapid metabolisers, UM). Frequencies of both CYP2C9 and CYP2C19 allelic
variants, as well as CYP2D6 detrimental alleles, in Italian subjects were similar to
those of other Caucasian populations. Conversely, the prevalence of CYP2D6 gene
duplication among Italians resulted very high, confirming the higher frequency of
CYP2D6 UM in the Mediterranean area compared to Northern Europe.

Eur J Clin Pharmacol. 2005 Aug;61(7):491-7. Epub 2005 Jul 16.

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and

CYP2C8 in the Faroese population.
Halling J, Petersen MS, Damkier P, Nielsen F, Grandjean P, Weihe P, Lundgren
S, Lundblad MS, Brøsen K.

Clinical Pharmacology, Faculty of Health Sciences, Institute of Public Health,

University of Southern Denmark, Winslovparken 19, 5000 Odense C, Denmark.
jhalling@health.sdu.dk

OBJECTIVE: The purpose of the study was to study the distribution of poor and
extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and
CYP2C9 among 312 randomly selected Faroese.METHODS AND RESULTS: The
participants were phenotyped for CYP2D6 with the use of sparteine. The distribution
of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and
14.5% (n=44; 95% CI: 10.7--18.9%) of the subjects were phenotyped as poor
metabolizers. The frequency of poor metabolizers was higher (P=0.0002; chi(2) test)
among the Faroese than in other European populations (7.4%). Genotype analyses for
the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time polymerase
chain reaction (PCR) (TaqMan, Foster City, CA, USA), and we found 14.6% (n=45)
(95% CI: 10.8--19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in
the Faroese population. The subjects were phenotyped for CYP2C19 with the use of
mephenytoin and 10 subjects, i.e., 3.2% (95% CI: 1.6--5.9%) were phenotyped as poor
metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by
means of PCR analysis, and 2.9% (n=9) (95% CI: 1.3-5.4%) of the Faroese were
found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2
genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8%
(95% CI: 6.7--11.4%) and 5.3% (95% CI: 3.7--7.4%), respectively, while the
CYP2C8*3 allele frequency was 6.9% (95% CI: 5.0--9.2%). Real-time PCR
(TaqMan) was used for both CYP2C9 and CYP2C8 genotype
analyses.CONCLUSION: The frequency of CYP2D6 poor metabolizers is twofold
higher among the Faroese population than other Caucasians, while the frequencies of
Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity
are the same as seen in other Caucasian populations. A possible consequence might be
a higher incidence of side effects among Faroese patients taking pharmaceuticals that
are CYP2D6 substrates.