Evaluation of Predictive
            <i>Cyp2C19</i>
            Genotyping Assays Relative to Measured Phenotype in a South African Cohort

Dodgen, Tyren Mark; Drögemöller, Britt I.; Wright, Galen E.B.; Warnich, Louise; Steffens, François E.; Cromarty, Allan Duncan; Alessandrini, Marco; Pepper, Michael Sean

doi:10.2217/pgs.15.80

Cited by 5 publications

(3 citation statements)

References 46 publications

(68 reference statements)

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“…We elaborated and adopted a “metabolic score” to take into account the global effect of the three polymorphisms together, according to an extensive literature linking genetic polymorphisms to functional impact 10 , 66 – 68 . For the metabolic score we translated the genotype information into a measure of phenotype using an ‘activity score’ system already adopted for CYP2D6 47 , 69 , for CYP2A6 70 and for CYP2C19 71 . The metabolic score adopted is based on the algebraic sum of the individual allele values, according to an additive model for CYP2B6 72 , 73 .…”

Section: Methodsmentioning

confidence: 99%

Human cytochrome P450 2B6 genetic variability in Botswana: a case of haplotype diversity and convergent phenotypes

Tawe

Motshoge

Ramatlho

et al. 2018

Sci Rep

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Identification of inter-individual variability for drug metabolism through cytochrome P450 2B6 (CYP2B6) enzyme is important for understanding the differences in clinical responses to malaria and HIV. This study evaluates the distribution of CYP2B6 alleles, haplotypes and inferred metabolic phenotypes among subjects with different ethnicity in Botswana. A total of 570 subjects were analyzed for CYP2B6 polymorphisms at position 516 G > T (rs3745274), 785 A > G (rs2279343) and 983 T > C (rs28399499). Samples were collected in three districts of Botswana where the population belongs to Bantu (Serowe/Palapye and Chobe) and San-related (Ghanzi) ethnicity. The three districts showed different haplotype composition according to the ethnic background but similar metabolic inferred phenotypes, with 59.12%, 34.56%, 2.10% and 4.21% of the subjects having, respectively, an extensive, intermediate, slow and rapid metabolic profile. The results hint at the possibility of a convergent adaptation of detoxifying metabolic phenotypes despite a different haplotype structure due to the different genetic background. The main implication is that, while there is substantial homogeneity of metabolic inferred phenotypes among the country, the response to drugs metabolized via CYP2B6 could be individually associated to an increased risk of treatment failure and toxicity. These are important facts since Botswana is facing malaria elimination and a very high HIV prevalence.

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Section: Methodsmentioning

confidence: 99%

Human cytochrome P450 2B6 genetic variability in Botswana: a case of haplotype diversity and convergent phenotypes

Tawe

Motshoge

Ramatlho

et al. 2018

Sci Rep

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“… 43 It spans from values 0 to 2, and >2, where AS is calculated based on an additive model counting individual alleles and haplotypes, similarly developed also for CYP2A6 , 44 CYP2B6 45 , 46 and for CYP2C19 . 47 The CYP2D6 AS distribution in world populations shows that Africans (in general) do not express particularly outlying metabolic phenotypes. 48 …”

Section: Tamoxifenmentioning

confidence: 99%

Pharmacogenetics of Breast Cancer Treatments: A Sub-Saharan Africa Perspective

Nthontho¹,

Ndlovu²,

Sharma³

et al. 2022

PGPM

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Breast cancer is the most frequent cause of cancer death in low- and middle-income countries, in particular among sub-Saharan African women, where response to available anticancer treatment therapy is often limited by the recurrent breast tumours and metastasis, ultimately resulting in decreased overall survival rate. This can also be attributed to African genomes that contain more variation than those from other parts of the world. The purpose of this review is to summarize published evidence on pharmacogenetic and pharmacokinetic aspects related to specific available treatments and the known genetic variabilities associated with metabolism and/or transport of breast cancer drugs, and treatment outcomes when possible. The emphasis is on the African genetic variation and focuses on the genes with the highest strength of evidence, with a close look on CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, CYP19A1, UGT1A4, UGT2B7, UGT2B15, SLC22A16, SLC38A7, FcγR, DPYD, ABCB1 , and SULT1A1 , which are the genes known to play major roles in the metabolism and/or elimination of the respective anti-breast cancer drugs given to the patients. The genetic variability of their metabolism could be associated with different metabolic phenotypes that may cause reduced patients’ adherence because of toxicity or sub-therapeutic doses. Finally, this knowledge enhances possible personalized treatment approaches, with the possibility of improving survival outcomes in patients with breast cancer.

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“…Đáng chú ý, kiểu hình giảm hoạt tính protein được xác định với tần số cao ở Vanuata (70% *2 và 13% *3) và Papua New Guinea (40% *2 và 30* *3) (Hsu et al, 2008;Helsby, Burns, 2012). Biến thể CYP2C19*17 cũng xuất hiện với tần số khác nhau ở các quần thể khác nhau, tần số của biến thể này là dưới 5% ở người Trung Quốc và Nhật Bản (Myrand et al, 2008;Jin et al, 2016), trong khi đó ở người châu Âu và châu Phi, biến thể này xuất hiện với tần số có thể đến gần 30% (Barysheva, Ketova, 2015;Dodgen et al, 2015).…”

Section: Gen Cyp2c19unclassified

Genetic variation of pharmacogenes

Nhung¹,

Ton²,

Hải³

et al. 2020

Vietnam J. Biotechnol.

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Patient specific response against a particular drug could be affected by various factors, in which genetic factors are the most crucial contributor. The genetic variability in pharmacogenes might result in variable drug response of individuals, which in turn can lead to unexpected treatment outcomes or even adverse drug reactions. The pharmacogenes include of genes that encode for several proteins which divided into 3 main functional categories: drug metabolizing enzymes, drug transporters and receptor-drug targets. Genetic variants of genes coding for drug metabolizing enzymes phase I (CYP450), phase II (GSTs, UGT, TPMT) as well as drug transporters (ABC, SLCO) of numerous populations in global have been extensively studied. Among these, SNPs are the major contributor behind variants of pharmacogenes along with copy number variants. Furthermore, the clinical impact on drug response of common variants belonging to several important pharmacogenes has been well understood. On the other hand, information on the variant spectrum of genes encoding for receptor-drug targets as well as their physiological effects have remained limited. In recent years, along with computational methods, next generation sequencing technologies had been developed tremendously. These high throughput methods had greatly promoted the field of pharmacogenetic research through providing ability to detect novel and rare genetic variants. The data on genetic variants of pharmacogenes would be valuable for determining the responder and non-responder to medication during treatment. These are also significant basis which play a vital role in development of the field of optimizing drug dose for individuals and personalized medicine in the future.

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Evaluation of Predictive Cyp2C19 Genotyping Assays Relative to Measured Phenotype in a South African Cohort

Cited by 5 publications

References 46 publications

Human cytochrome P450 2B6 genetic variability in Botswana: a case of haplotype diversity and convergent phenotypes

Human cytochrome P450 2B6 genetic variability in Botswana: a case of haplotype diversity and convergent phenotypes

Pharmacogenetics of Breast Cancer Treatments: A Sub-Saharan Africa Perspective

Genetic variation of pharmacogenes

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