Limited Association of the 2988g&gt;a Single Nucleotide Polymorphism with CYP2D6*41 in Black Subjects

Gaedigk, Andrea; Ndjountché, Liliane; Leeder, J. Steven; Bradford, L. DiAnne

doi:10.1016/j.clpt.2004.10.014

Cited by 24 publications

(16 citation statements)

References 5 publications

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“…is difference was probably due to the limited number of subjects analyzed in [11]. Particularly, We found the presence of CYP2D6 * 2A, * 2L, and * 2 M suballeles only, where CYP2D6 * 2L (2.2%) and * 2 M (1.6%) were previously described in a South African population [27,28]. Moreover, we detected the presence of two new haplotypes, SH3 in 1.6% of the subjects, and SH4, presenting novel SNP 3948T>G, in 0.2% of the subjects (Table 4).…”

Section: Resultsmentioning

confidence: 80%

“…In our population, we found the presence of suballeles, CYP2D6 * 2L and * 2 M, previously found in a South African population [27,28] with signi�cant frequencies (2.2% and 1.6% resp.) and, moreover, the presence of one novel SNP, 3948T>G, and two new haplotypes, SH3 and SH4, that we categorized as variants of CYP2D6 * 2 M. Furthermore, we found two novel SNPs, -948C>A, and 3176C>T, and two new haplotypes, SH1 and SH2, that we categorized as a CYP2D6 * 2 M- * 41 hybrid.…”

Section: Discussionmentioning

confidence: 76%

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Analysis of CYP2D6 Allele Frequencies and Identification of Novel SNPs and Sequence Variations in Sardinians

et al. 2013

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e CYP2D6 enzyme is involved in the metabolism of many commonly prescribed drugs. e presence of polymorphisms in the CYP2D6 gene may modulate the enzyme level and activity affecting individual responses, to pharmacological treatment in drug level, response and adverse reactions. Aims. is study aimed to analyze the determination of allele frequencies in Sardinians and the comparison to frequencies found in the Caucasian Population. Methods and Materials. We used a Long PCR strategy coupled to direct genomic DNA sequencing analysis. An ampli�cation allele-speci�c was carried out to infer the correct allelic phase. e TaqMan Gene Copy Number Assay (Applied Biosystems) was used to verify the presence of gene deletions/multiplications. Results and Conclusions. Our results indicated that CYP2D6 allele frequencies in Sardinians differed from those previously detected in the Caucasian Population. Moreover, three new SNPs and four novel haplotypes were identi�ed.

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Section: Resultsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 76%

Analysis of CYP2D6 Allele Frequencies and Identification of Novel SNPs and Sequence Variations in Sardinians

et al. 2013

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“…Nine CYP2D6*2 alleles were miss-called as *41 , resulting in an over estimation of CYP2D6*41 / *41 homozygotes [41]. The AmpliChip-derived frequency of CYP2D6*41 among our Black subjects was therefore higher when compared to similar cohorts [35], in which the CYP2D6*41 allele was detected by its key SNP (2988 G>A).…”

Section: Discussionmentioning

confidence: 96%

Introduction of the AmpliChip CYP450 Test to a South African cohort: a platform comparative prospective cohort study

et al. 2013

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BackgroundAdverse drug reactions and lack of therapeutic efficacy associated with currently prescribed pharmacotherapeutics may be attributed, in part, to inter-individual variability in drug metabolism. Studies on the pharmacogenetics of Cytochrome P450 (CYP) enzymes offer insight into this variability. The objective of this study was to compare the AmpliChip CYP450 Test® (AmpliChip) to alternative genotyping platforms for phenotype prediction of CYP2C19 and CYP2D6 in a representative cohort of the South African population.MethodsAmpliChip was used to screen for thirty-three CYP2D6 and three CYP2C19 alleles in two different cohorts. As a comparison cohort 2 was then genotyped using a CYP2D6 specific long range PCR with sequencing (CYP2D6 XL-PCR + Sequencing) platform and a PCR-RFLP platform for seven CYP2C19 alleles.ResultsEven though there was a low success rate for the AmpliChip, allele frequencies for both CYP2D6 and CYP2C19 were very similar between the two different cohorts. The CYP2D6 XL-PCR + Sequencing platform detected CYP2D6*5 more reliably and could correctly distinguish between CYP2D6*2 and *41 in the Black African individuals. Alleles not covered by the AmpliChip were identified and four novel CYP2D6 alleles were also detected. CYP2C19 PCR-RFLP identified CYP2C19*9,*15, *17 and *27 in the Black African individuals, with *2, *17 and *27 being relatively frequent in the cohort. Eliminating mismatches and identifying additional alleles will contribute to improving phenotype prediction for both enzymes. Phenotype prediction differed between platforms for both genes.ConclusionComprehensive genotyping of CYP2D6 and CYP2C19 with the platforms used in this study, would be more appropriate than AmpliChip for phenotypic prediction in the South African population. Pharmacogenetically important novel alleles may remain undiscovered when using assays that are designed according to Caucasian specific variation, unless alternate strategies are utilised.

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“…The recent report of the *36xn allele in Asians, the *41xn and a probable *9xn serve as good examples to illustrate this point. [26][27][28] An interesting observation is that the same CYP2D6 allele seems to be almost always duplicated. One exception to this general rule is the recently reported CYP2D6 tandem allele *36-*10B (GenBank accession #DQ211353).…”

Section: Discussionmentioning

confidence: 99%

“…It is unclear if the CYP2D6*2A and CYP2D6*41 alleles really exhibit significant differences in CYP2D6 activity or if the differences that have been observed reflect additional parameters that are poorly understood at present. 26 One of the key problems thus far in the study and interpretation of CYP2D6 genotypes is the poor appreciation of the mechanistic reasons for differences between alleles. If an allele results in a general depression of CYP2D6 enzyme expression, one anticipates that this would lead to a global decrease in the metabolism of all substrates whenever this allele is expressed.…”

Section: Discussionmentioning

confidence: 99%

CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing

et al. 2006

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AmpliChip CYP450 prototype microarray assay, along with allele-specific-PCR and PCR restriction fragment length polymorphism methods. No significant difference was noted between controls and psychiatric patients in any CYP2D6 allele frequencies. Three subjects were genotyped as poor metabolizers (1.4%; 0.0-2.9%, 95% confidence intervals (CI)), and 10 were classified as ultrarapid metabolizers (4.5%; 1.8-7.2%, 95% CI). A new CYP2D6 allele (*58) and two new duplicated CYP2D6 alleles (*17xn and *2Lxn) not previously reported were also identified. The frequency of the CYP2D6 overexpression in African-Americans may represent a greater therapeutic challenge than its deficiency based on these results. The most common alleles found in African-Americans including CYP2D6*1, *17 and *41 need to be investigated more closely for race-specific allelic variations and the mechanism responsible for differences in allele function more closely examined. The diversity of CYP2D6 alleles suggests that nucleotide arrays or similar methods are needed to efficiently test for the most prominent/ relevant CYP2D6 alleles in humans.

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Limited Association of the 2988g>a Single Nucleotide Polymorphism with CYP2D6*41 in Black Subjects

Cited by 24 publications

References 5 publications

Analysis of CYP2D6 Allele Frequencies and Identification of Novel SNPs and Sequence Variations in Sardinians

Analysis of CYP2D6 Allele Frequencies and Identification of Novel SNPs and Sequence Variations in Sardinians

Introduction of the AmpliChip CYP450 Test to a South African cohort: a platform comparative prospective cohort study

CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing

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