Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

Scantamburlo, Giada; Tziolia, Konstantina; Zopf, Michaela; Bernardinelli, Emanuele; Soyal, Selma M.; Civello, Davide Antonio; Vanoni, Simone; Dossena, Silvia; Patsch, Wolfgang; Patrinos, George P.; Paulmichl, Markus; Nofziger, Charity

doi:10.1159/000484380

Cited by 14 publications

(16 citation statements)

References 29 publications

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“…For the other eight samples, misclassification due to allele dropout was the most probable cause of the discrepancies. In this study, a frequency of 0.01% of misclassification was shown, whereas previous publications show higher frequencies of misclassification (0.27% in 365 patients, Scantamburlo et al [29] and 0.44% in 30.769 genotypes, Blais et al [24]). A difference in discrepant results between the two genotyping centres was identified and might be explained by the different genotyping techniques used in each centre, as the call rate and accuracy of the techniques can be different.…”

Section: Accepted Manuscriptcontrasting

confidence: 77%

Confirmation practice in pharmacogenetic testing; how good is good enough?

Lunenburg

Guchelaar

Schaik

et al. 2019

Clinica Chimica Acta

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Pharmacogenetic testing is increasingly implemented in routine diagnostics. However, quality control measures, in particular confirmation practices e.g. the use of two independent genotyping techniques, are subject of debate and there are no clear guidelines. The aim of the current paper is to discuss the current practice in confirmation testing in the field of pharmacogenetics and draw attention to this situation. DPYD genotyping is used as a case example to highlight the importance of assigning the correct genotype. Current confirmation practices in laboratories are explored through a survey. Substantial heterogeneity was observed with 54% of the laboratories applying different forms of confirmation practice. Finally, we evaluated over 10 years of genotyping results from two large genotyping facilities, which both use a second, independent genotyping technique.Discrepancies between tests were identified in 9 patients (0.01%), possibly due to allele dropout. We feel that a second, independent technique is useful for genetic tests with a high clinical impact, such as DPYD testing. Guidelines can help to align confirmatory laboratory practices for pharmacogenetics, which may need to be specified per gene and test. ACCEPTED MANUSCRIPT

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Section: Accepted Manuscriptcontrasting

confidence: 77%

Confirmation practice in pharmacogenetic testing; how good is good enough?

Lunenburg

Guchelaar

Schaik

et al. 2019

Clinica Chimica Acta

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“…Another limitation is that we inferred CYP2D6 metabolizer status from the CYP2D6 genotype. There has been a series of publications describing situations where the commercially available TaqMan assays, also used here in the OpenArray format, have not worked as expected and have been redesigned (26–29). Most significantly, one assay variant detecting CYP single nucleotide polymorphisms (SNPs) (*15 allele; C_32407245_40) suffers from interference from the sequence of the pseudogene CYP2D7 to the extent that these results were not included in the analysis (27).…”

Section: Discussionmentioning

confidence: 99%

CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum

Pett

Bradley

Okebe

et al. 2019

Antimicrob Agents Chemother

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Single-dose primaquine (PQ) clears mature gametocytes and reduces the transmission of Plasmodium falciparum after artemisinin combination therapy. Genetic variation in CYP2D6, the gene producing the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6), influences plasma concentrations of PQ and its metabolites and is associated with PQ treatment failure in Plasmodium vivax malaria. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa (n = 1,076), we were able to genotype CYP2D6 for 774 samples (72%). We determined whether genetic variation in CYP2D6 has implications for PQ efficacy in individuals with gametocytes at the time of PQ administration (n = 554) and for safety in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals treated with PQ (n = 110). Individuals with a genetically inferred CYP2D6 poor/intermediate metabolizer status had a higher gametocyte prevalence on day 7 or 10 after PQ than those with an extensive/ultrarapid CYP2D6 metabolizer status (odds ratio [OR] = 1.79 [95% confidence interval {CI}, 1.10, 2.90]; P = 0.018). The mean minimum hemoglobin concentrations during follow-up for G6PD-deficient individuals were 11.8 g/dl for CYP2D6 extensive/ultrarapid metabolizers and 12.1 g/dl for CYP2D6 poor/intermediate metabolizers (P = 0. 803). CYP2D6 genetically inferred metabolizer status was also not associated with anemia following PQ treatment (P = 0.331). We conclude that CYP2D6 poor/intermediate metabolizer status may be associated with prolonged gametocyte carriage after treatment with single-low-dose PQ but not with treatment safety.

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“…We searched in PubMed and Google Scholar from 1996 to 2017 using the combination of keywords such as CYP2D6 , allele, and frequency plus the name of each country in the Middle East region. All studies reported CYP2D6 allele and genotype frequencies in different Middle Eastern countries including Saudi Arabia,[1314] Egypt,[15161718192021] United Arab Emirates (UAE),[2223] Iran,[24252627] Jordan,[28] Syria,[29] and Turkey[30313233343536373839404142434445] performed on healthy unrelated controls or patient samples were reviewed in this article. Overview of the studies evaluated in this review is listed in Table 1, showing the number of studies in each geographic region, number and type of samples (healthy or patients), list of alleles considered, and their frequency in each study.…”

Section: Introductionmentioning

confidence: 99%

Distribution of CYP2D6 polymorphism in the Middle Eastern region

et al. 2019

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Cytochrome P450 2D6 (CYP2D6) is an important drug-metabolizing enzyme involved in the pharmacokinetic metabolism of drugs. CYP2D6 gene is highly polymorphic, and the combination of its different alleles yields different phenotypes including extensive metabolizer (EM), intermediate metabolizer (IM), poor metabolizer (PM), and ultrarapid metabolizer (UM). Genotyping of the important alleles for this gene in different ethnicities is of particular importance for assessing the efficacy of various drugs. In this study, we reviewed the CYP2D6 allele and phenotype frequencies predicted from the genotypes of CYP2D6 in the Middle East area. Regardless of different ethnicities, the CYP2D6 *41 allele frequency was shown to be higher than that of other reduced functional alleles. In addition, CYP2D6 *4 was the most frequent nonfunctional allele in all studied populations in the Middle East. Taken together, our findings illustrated that the frequencies of PM or IM alleles and different genotypes harboring these alleles are relatively high in the Middle Eastern countries. Therefore, the study of CYP2D6 alleles for each patient to detect those that are at risk is of great importance to prevent adverse drug reactions through individualization therapy.

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Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

Cited by 14 publications

References 29 publications

Confirmation practice in pharmacogenetic testing; how good is good enough?

Confirmation practice in pharmacogenetic testing; how good is good enough?

CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum

Distribution of CYP2D6 polymorphism in the Middle Eastern region

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