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

Marez, Delphine; Legrand, M.; Sabbagh, N; Lo-Guidice, Jean-Marc; Spire, Catherine; Jj, Lafitte; Meyer, Ursina; Broly, Franck

doi:10.1097/00008571-199706000-00004

Cited by 343 publications

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“…Allele frequencies were similar to those found in large sample studies (Marez et al 1997;Sachse et al 1997). Among the 36 subjects there were 11 genotypes, which are listed in Table 2.…”

Section: Resultssupporting

confidence: 87%

“…We classified the most common CYP2D6 alleles according to predicted metabolic activity: extensive (*1), intermediate (*2, *10), or null (*3, *4A, *5) based on published genotype-phenotype comparisons (Marez et al 1997;Sachse et al 1997). Subjects were classified as having a genotype resulting in extensive drug metabolism (two extensive metabolic alleles or an extensive metabolic allele and an intermediate metabolic allele), or a genotype resulting in impaired drug metabolism (two intermediate metabolic alleles, one null allele, or two null alleles).…”

Section: Methodsmentioning

confidence: 99%

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CYP2D6 Genotyping with Oligonucleotide Microarrays and Nortriptyline Concentrations in Geriatric Depression

Murphy

Pollock

Kirshner

et al. 2001

Neuropsychopharmacology

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“…Allele frequencies were similar to those found in large sample studies (Marez et al 1997;Sachse et al 1997). Among the 36 subjects there were 11 genotypes, which are listed in Table 2.…”

Section: Resultssupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

CYP2D6 Genotyping with Oligonucleotide Microarrays and Nortriptyline Concentrations in Geriatric Depression

Murphy

Pollock

Kirshner

et al. 2001

Neuropsychopharmacology

View full text Add to dashboard Cite

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“…Our findings corroborate a recent report stating that psychiatric patients genotyped homozygous or heterozygous for CYP2C19 and CYP2D6 null alleles (CYP2C19*2, and CYP2D6*3, *4, *5 and *6) were hospitalized for a longer time during treatment with psychotropic medication, as compared with subjects without these alleles. 44 The allele frequencies and prevalence of 'abnormal' CYP2D6 genotypes (that is, without functional alleles or with an elevated number of functional alleles) that we found were in agreement with the figures previously reported for Western populations, 13,22,34,35,45,46 and depressed patients in specialized psychiatric hospitals, 47,48 respectively.…”

Section: Discussionsupporting

confidence: 90%

Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients

et al. 2007

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The inactivation and clearance of the tricyclic antidepressant imipramine is dependent on CYP2D6 activity. First, CYP2C19 converts imipramine into the active metabolite desipramine, which is then inactivated by CYP2D6. This retrospective single center study aimed to prove whether CYP2C19 and ample CYP2D6 genotyping (taking into consideration four null alleles and three decreased-activity alleles) could be used to predict imipramine and desipramine plasma concentrations in depressed patients, and whether genotype-based drug dose recommendations might assist in the early management of imipramine pharmacotherapy. In 181 subjects with major depressive disorder, drug doses were recorded, imipramine and desipramine plasma concentrations were monitored and CYP2C19 (*2) and CYP2D6 genotype (*3, *4, *5, *6, *9, *10, *41 and gene duplication) were obtained, yielding graded allele-specific CYP2D6 patient groups. Desipramine and imipramine þ desipramine plasma concentration per drug dose unit, imipramine dose at steady state, and imipramine dose requirement significantly depended on CYP2D6 genotype (Kruskal-Wallis test, P < 0.0001). Mean (7s.d.) drug dose requirements were 131 (7109), 155 (770), 217 (795), 245 (7125), 326 (7213), and 509 (7292) mg imipramine/day in carriers of 0, 0.5, 1, 1.5, 2, and > 2 active CYP2D6 genes, respectively. Our protocol for CYP2D6 genotyping will thus importantly aid in the prediction of imipramine metabolism, allowing for the use of an adjusted starting dose and faster achievement of predefined imipramine þ desipramine plasma levels in all genetic patient subgroups. Therefore, therapeutic efficacy and efficiency may be improved, the number of adverse drug reactions decreased, and hospital stay reduced.

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“…The DNA sequence encoding the enzyme has been localized to the 4.3-kb, nine-exon cytochrome P450 2D6 (CYP2D6) gene found at chromosome 22q13.1. To date more than 48 mutations and 53 alleles of CYP2D6 have been characterized in European populations [1]. The poor metabolizer (PM) phenotype follows an autosomal recessive pattern of inheritance [2].…”

Section: Introductionmentioning

confidence: 99%

“…ki.se/CYPalleles/CYP2D6.htm): C100T (Pro34Ser), C1023T (Thr107Ile), G1846A (splicing defect), 1863 ϩ9-bp repeat (172-174FRP rep), A2549del (frameshift), 2613-2615AGAdel (Lys281del), and C2850T (Arg296Cys). These polymorphisms can be used to distinguish between CYP2D6*2 [3], CYP2D6*3 [25], CYP2D6*4 [26], CYP2D6*9 [27], CYP2D6*10 [28], CYP2D6*17 [29], and CYP2D6*30 [1]. CYP2D6*3 and *4 alleles either fail to produce enzymes or produce defective ones with no activity.…”

mentioning

confidence: 99%

High-throughput analysis of informative CYP2D6 compound haplotypes

et al. 2003

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We describe a high-throughput protocol for detecting key polymorphisms in the drug-metabolizing enzyme gene CYP2D6 and a number of linked microsatellites that is both fast and relatively inexpensive to perform. This approach employs GeneScan technology to enable a researcher to determine rapidly the status of seven simple nucleotide polymorphisms in CYP2D6 and also to assay repeat number variation at five closely linked dinucleotide microsatellite loci. The method requires only three PCRs and two GeneScan runs per sample. We anticipate that this will be of value to researchers in three different ways: (1) rapid discrimination of common CYP2D6 alleles, (2) high-resolution haplotyping for association studies involving chromosome 22q13.1 using microsatellite variation, and (3) generation of compound haplotypes for investigating the evolution of CYP2D6 variation. We also report compound haplotype frequencies for an Ashkenazi Jewish and a British sample. © 2003 Elsevier Science (USA). All rights reserved.Keywords: CYP2D6; Pharmacogenetics; Genotyping; Haplotype; Microsatellites; SNPs; Jews; British; Population; Variation It is now clear that much of the observed variation in drug efficacy and safety has a hereditary basis, arising from polymorphisms in genes coding for drug-metabolizing enzymes (DMEs). The frequency of DME alleles can vary greatly between different human populations, and this has implications for both medical and evolutionary studies. Consequently, there has been growing academic and commercial interest in the extent, nature, and causes of DME variation. However, it is currently unknown to what extent interpopulation variability is due to selection, drift, or other processes. Studies seeking to elucidate this have been held back by the absence of efficient low-cost high-throughput procedures for characterizing variability at the molecular level in and around DME loci. Ultimately, the identification of the molecular basis of pharmacogenetically relevant variation combined with the technology to screen individuals for the presence of specific alleles allows for the prediction of drug response and individualized treatment.Polymorphism in debrisoquine/sparteine oxidation is arguably the most highly studied pharmacogenetic trait. The DNA sequence encoding the enzyme has been localized to the 4.3-kb, nine-exon cytochrome P450 2D6 (CYP2D6) gene found at chromosome 22q13.1. To date more than 48 mutations and 53 alleles of CYP2D6 have been characterized in European populations [1]. The poor metabolizer (PM) phenotype follows an autosomal recessive pattern of inheritance [2]. An allele duplication consisting of multiple functional copies of CYP2D6 confers the ultrarapid metabolizer (URM) phenotype [3]. Individuals who demonstrate normal levels of CYP2D6 activity are referred to as extensive metabolizers. Intermediate metabolizers (IMs) typically produce lower than normal levels of functional enzyme.Medical interest in CYP2D6 polymorphism arises because the CYP2D6 enzyme has been found to process more t...

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

Cited by 343 publications

References 0 publications

CYP2D6 Genotyping with Oligonucleotide Microarrays and Nortriptyline Concentrations in Geriatric Depression

CYP2D6 Genotyping with Oligonucleotide Microarrays and Nortriptyline Concentrations in Geriatric Depression

Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients

High-throughput analysis of informative CYP2D6 compound haplotypes

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