Resolving Discordant
            <i>CYP2D6</i>
            Genotyping Results in Thai Subjects: Platform Limitations and Novel Haplotypes

Hongkaew, Yaowaluck; Wang, Wendy Y.; Gaedigk, Roger; Sukasem, Chonlaphat; Gaedigk, Andrea

doi:10.2217/pgs-2021-0013

Cited by 10 publications

(7 citation statements)

References 37 publications

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“…This, however, can be problematic, as rare population-specific variants may not be adequately identified. As a result, a patient’s predicted CYP2D6 metabolizer status, which is typically used for drug and/or dosing recommendations, may not be accurate [ 41 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…From this sample set (n = 211), 96 samples were randomly selected and subjected to Illumina high-throughput sequencing. First, XL-PCR amplicons (6.7 kb) were generated with a CYP2D6 -specific forward (5′-TCACCCCCAGCGGACTTATCAACC-3′) and reverse (5′-CGACTGAGCCCTGGGAGGTAGGTAG-3′) primer set [ 46 , 47 ]. This XL-PCR amplicon is referred to here, and in previous publications, as Fragment A. XL-PCR products were sheared on a Covaris ® instrument to an estimated size of 300 bp.…”

Section: Methodsmentioning

confidence: 99%

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CYP2D6 Gene Resequencing in the Malagasy, a Population at the Crossroads between Asia and Africa: A Pilot Study

et al. 2022

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Background: Plasmodium vivax malaria is endemic in Madagascar, where populations have genetic inheritance from Southeast Asia and East Africa. Primaquine, a drug of choice for vivax malaria, is metabolized principally via CYP2D6. CYP2D6 variation was characterized by locus-specific gene sequencing and was compared with TaqMan™ genotype data. Materials & methods: Long-range PCR amplicons were generated from 96 Malagasy samples and subjected to next-generation sequencing. Results: The authors observed high concordance between TaqMan™-based CYP2D6 genotype calls and the base calls from sequencing. In addition, there are new variants and haplotypes present in the Malagasy. Conclusion: Sequencing unique admixed populations provides more detailed and accurate insights regarding CYP2D6 variability, which may help optimize primaquine treatment across human genetic diversity.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

CYP2D6 Gene Resequencing in the Malagasy, a Population at the Crossroads between Asia and Africa: A Pilot Study

et al. 2022

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“…It was suggested that the CYP2D6*10 frequency was overestimated in the past because the available platforms were unable to detect structural variants. Luminex, MassArray, and TaqMan platforms cannot detect the CYP2D6-2D7 hybrid of *36 , leading to an erroneous assignment of CYP2D*36+*10 as *10 [ 34 , 54 ]. In the current study, we performed long-range PCR with a *36 -specific primer set described by Soyama et al .…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 2D6 (CYP2D6) and glucose-6-phosphate dehydrogenase (G6PD) genetic variations in Thai vivax malaria patients: Implications for 8-aminoquinoline radical cure

et al. 2022

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Background Primaquine and tafenoquine are the only licensed drugs that effectively kill the hypnozoite stage and are used to prevent Plasmodium vivax malaria relapse. However, both primaquine and tafenoquine can cause acute hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient people with varying degrees of severity depending on G6PD variants. Additionally, primaquine efficacy against malaria parasites was decreased in individuals with impaired cytochrome P450 2D6 (CYP2D6) activity due to genetic polymorphisms. This study aimed to characterize G6PD and CYP2D6 genetic variations in vivax malaria patients from Yala province, a malaria-endemic area along the Thai–Malaysian border, and determine the biochemical properties of identified G6PD variants. Methodology/Principle findings Multiplexed high-resolution melting assay and DNA sequencing detected five G6PD variants, including G6PD Kaiping, G6PD Vanua Lava, G6PD Coimbra, G6PD Mahidol, and G6PD Kerala-Kalyan. Biochemical and structural characterization revealed that G6PD Coimbra markedly reduced catalytic activity and structural stability, indicating a high susceptibility to drug-induced hemolysis. While Kerala-Kalyan had minor effects, it is possible to develop mild adverse effects when receiving radical treatment. CYP2D6 genotyping was performed using long-range PCR and DNA sequencing, and the phenotypes were predicted using the combination of allelic variants. Decreased and no-function alleles were detected at frequencies of 53.4% and 14.2%, respectively. The most common alleles were CYP2D*36+*10 (25.6%), *10 (23.9%), and *1 (22.2%). Additionally, 51.1% of the intermediate metabolizers showed CYP2D6*10/*36+*10 as the predominant genotype (15.9%). Conclusions/Significance Our findings provide insights about genetic variations of G6PD and CYP2D6 in 88 vivax malaria patients from Yala, which may influence the safety and effectiveness of radical treatment. Optimization of 8-aminoquinoline administration may be required for safe and effective treatment in the studied population, which could be a significant challenge in achieving the goal of eliminating malaria.

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“…Samples with CNVs detected by XL-PCR were subjected to droplet digital PCR (ddPCR) to quantitatively measure copy number. ddPCR was performed as previously described [ 27 , 31 ] using TaqMan™-based copy number assays (Thermo Fischer, Waltham, MA, USA) with the following modification and published by Wen et al [ 32 ]: intron 6 copy number was interrogated as a single assay and copy number of the 5′UTR, and exon 9 targets were duplexed in an amplitude-based single reaction. Droplets were generated, thermal cycled, and read using the Bio-Rad QX200 AutoDG Droplet Digital PCR System (Bio-Rad Laboratories, Hercules, CA, USA) per manufacturer protocol.…”

Section: Methodsmentioning

confidence: 99%

Characterization of Novel CYP2D6 Alleles across Sub-Saharan African Populations

Wang

Twesigomwe

Nofziger³

et al. 2022

JPM

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The CYP2D6 gene has been widely studied to characterize variants and/or star alleles, which account for a significant portion of variability in drug responses observed within and between populations. However, African populations remain under-represented in these studies. The increasing availability of high coverage genomes from African populations has provided the opportunity to fill this knowledge gap. In this study, we characterized computationally predicted novel CYP2D6 star alleles in 30 African subjects for whom DNA samples were available from the Coriell Institute. CYP2D6 genotyping and resequencing was performed using a variety of commercially available and laboratory-developed tests in a collaborative effort involving three laboratories. Fourteen novel CYP2D6 alleles and multiple novel suballeles were identified. This work adds to the growing catalogue of validated African ancestry CYP2D6 allelic variation in pharmacogenomic databases, thus laying the foundation for future functional studies and improving the accuracy of CYP2D6 genotyping, phenotype prediction, and the refinement of clinical pharmacogenomic implementation guidelines in African and global settings.

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Resolving Discordant CYP2D6 Genotyping Results in Thai Subjects: Platform Limitations and Novel Haplotypes

Cited by 10 publications

References 37 publications

CYP2D6 Gene Resequencing in the Malagasy, a Population at the Crossroads between Asia and Africa: A Pilot Study

CYP2D6 Gene Resequencing in the Malagasy, a Population at the Crossroads between Asia and Africa: A Pilot Study

Cytochrome P450 2D6 (CYP2D6) and glucose-6-phosphate dehydrogenase (G6PD) genetic variations in Thai vivax malaria patients: Implications for 8-aminoquinoline radical cure

Characterization of Novel CYP2D6 Alleles across Sub-Saharan African Populations

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