Genetic basis for differences in debrisoquin polymorphism between a spanish and other white populations

Agúndez, José A. G.; Martı́nez, Carmen; Ledesma, María C.; Ladona, Margarita G.; Ladero, José M.; Benı́tez, Julio

doi:10.1038/clpt.1994.50

Cited by 44 publications

(32 citation statements)

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“…In Caucasians the frequency of allele *4 is 19% whereas in the present study it was found to be 14%. 3,9 Allele *5 has been found at frequencies between 2 and 4% in Caucasians, 3,10 which resembles our findings (3.3%). In our sample these four alleles (*3, *4, *5 and *6) accounted for 100% of CYP2D6 defective alleles.…”

Section: Discussionsupporting

confidence: 91%

Characterization of variant alleles of cytochrome CYP2D6 in a Spanish population

Menoyo

Río

Baiget

2006

Cell Biochem. Funct.

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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.

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Section: Discussionsupporting

confidence: 91%

Characterization of variant alleles of cytochrome CYP2D6 in a Spanish population

Menoyo

Río

Baiget

2006

Cell Biochem. Funct.

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“…The prevalence of these allelic variants is similar to that found in the general Spanish population [47,48], This genetic polymorphism has been studied in other neurological disorders. It is widely admit ted that carriers of the genotype CYP2D6*1/CYP2D6*4 show increased risk for PD [7][8][9].…”

Section: Discussionsupporting

confidence: 50%

<i>CYP2D6</i>Polymorphism Is Not Associated with Essential Tremor

et al. 1997

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Recent reports have shown an association between cytochrome P450IID6 (CYP2D6) polymorphism and Parkinson''s disease. We investigated the association between this polymorphism and the risk for developing essential tremor (ET). Leukocytic DNA from 91 unrelated ET patients and a control group of 258 unrelated healthy individuals was studied for the occurrence of eight different CYP2D6 allelic variants by using allele-specific PCR amplification Xbal and .EroRI-RFLP''s analyses. The prevalence for these allelic variants in the ET and control groups were, respectively: CYP2D6*1 76.9 and 78.7%, CYP2D6*2 0.5 and 0.2%, CYP2D6*3 0 and 1%, CYP2D6*4 12.1 and 12.2%, CYP2D6*5 1.6 and 1.7%, CYP2D6*9 4.4 and 2.9%, CYP2D6*2x2 4.4 and 3.2%. The prevalence of subjects with absent CYP2D6 activity (those carrying two defect genes) was 1.1 and 3.1% in ET and control groups, respectively. Both groups studied were in Hardy-Weinberg equilibrium. These results indicate that mutations at the CYP2D6 gene do not seem to be a major factor in determining susceptibility to ET, and reinforces the view that ET and parkinsonism are distinct conditions.

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“…The findings indicate that CYP2D6*5 in most cases is combined with the CYP2D6*1 allelic variant in the other chromosome. The frequency of CYP2D6 variants at the complementary gene in the subgroup of carriers of CYP2D6*5 was similar to the CYP2D6 allele frequency among unrelated Spaniard noncarriers of CYP2D6*5 (6,8 ). We therefore observed no association between CYP2D6*5 and mutations in the complementary gene.…”

Section: Resultsmentioning

confidence: 47%

“…Genomic DNA was purified from peripheral leukocytes and kept in sterile plastic vials at 4°C until analysis. We performed the CYP2D6 genotyping analysis by mutation-specific PCR, long PCR, and restriction mapping with the enzymes EcoRI and XbaI as described elsewhere (8,(13)(14)(15)(16). For the sequencing analyses of exons 1-9 and the 3Јflanking region of CYP2D8P, we conducted a series of 12 PCR amplification reactions spanning areas of ϳ0.5 kb between the positions Ϫ25 (CYP2D8P) and Ϫ276 (the 3Ј intergenic region of CYP2D8P).…”

Section: Methodsmentioning

confidence: 99%

Identification of Subtypes of CYP2D Gene Rearrangements among Carriers of CYP2D6 Gene Deletion and Duplication

Ledesma

Agúndez

2005

Clinical Chemistry

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Background: Cytochrome P450 2D6 (CYP2D6) is one of the best-known polymorphic drug-metabolizing enzymes. Rapidly evolving genotyping techniques permit the identification of single-nucleotide polymorphisms (SNPs) and thereby a prediction of individual metabolic capacities for CYP2D6 substrates. A considerable part of interindividual variability in CYP2D6 enzyme activity, however, is not related to SNPs but to gene deletions and duplications. Currently used genotyping methods assume that these gene rearrangements are homogeneous. Methods: We analyzed the interindividual variability in CYP2D6 gene arrangements in genomic DNA from 740 Caucasian individuals by allele-specific PCR to identify common SNPs of the CYP2D6 gene that correspond to the variant alleles CYP2D6*3, *4, and *9. We investigated the presence and variability of CYP2D6*5 (gene deletion), CYP2D6x2 (gene duplication), and CYP2D6xn (gene amplification) by EcoRI and XbaI restriction fragment length polymorphism analyses and by long PCR plus KpnI and BamHI digestion. The presence of new mutations at the CYP2D locus was analyzed by sequencing. Results: CYP2D6 gene rearrangements were present in >12% of individuals. Variability in the rearrangements regarding both gene deletion and gene duplication existed, and one of the unusual arrangements led to incorrect phenotype prediction. The frequency for carriers of unusual gene rearrangements was <0.3% (95% confidence interval, 0%-0.6%) in the population studied. Conclusions: Heterogeneity in CYP2D6 gene rearrangement exists, but the allele frequency indicates that the risk for an erroneous phenotype prediction related to

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Genetic basis for differences in debrisoquin polymorphism between a spanish and other white populations

Cited by 44 publications

References 0 publications

Characterization of variant alleles of cytochrome CYP2D6 in a Spanish population

Characterization of variant alleles of cytochrome CYP2D6 in a Spanish population

<i>CYP2D6</i>Polymorphism Is Not Associated with Essential Tremor

Identification of Subtypes of CYP2D Gene Rearrangements among Carriers of CYP2D6 Gene Deletion and Duplication

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