Population genetic polymorphisms of pharmacogenes in Zimbabwe, a potential guide for the safe and efficacious use of medicines in people of African ancestry

Abstract

Objective Pharmacogenomics (PGx) is a clinically significant factor in the safe and efficacious use of medicines. While PGx knowledge is abundant for other populations, there are scarce PGx data on African populations and is little knowledge on drug-gene interactions for medicines used to treat diseases common in Africa. The aim of this study was to use a customdesigned open array to genotype clinically actionable variants in a Zimbabwean population. This study also identified some of the commonly used drugs in Zimbabwe and the associated genes involved in their metabolism.Methods A custom-designed open array that covers 120 genetic variants was used to genotype 522 black Zimbabwean healthy volunteers using TaqMan-based single nucleotide polymorphism genotyping. Data were also accessed from Essential Drugs' List in Zimbabwe (EDLIZ), and the medicines were grouped into the associated biomarker groups based on their metabolism. We also estimated the national drug procurement levels for medicines that could benefit from PGx-guided use based on the data obtained from the national authorities in Zimbabwe. ResultsThe results demonstrate the applicability of an open-array chip in simultaneously determining multiple genetic variants in an individual, thus significantly reducing cost and time to generate PGx data. There were significantly high frequencies of African-specific variants, such as the CYP2D6*17 and *29 variants and the CYP2B6*18 variant. The data obtained showed that the Zimbabwean population exhibits PGx variations in genes important for the safe and efficacious use of drugs approved by the EDLIZ and are procured at significantly large amounts annually. The study has established a cohort of genotyped healthy volunteers that can be accessed and used in the conduct of clinical pharmacogenetic studies for drugs entering a market of people of predominantly African ancestry. ConclusionOur study demonstrated the potential benefit of integrating PGx in Zimbabwe for the safe and efficacious use of drugs that are commonly used.

Cardiotoxicity and pharmacogenetics of doxorubicin in black Zimbabwean breast cancer patients

“…In this study we could not verify clinical risk factors to be significant risk factors for developing DIC, of which previous studies have identified hypertension, female sex, age, cumulative anthracycline dose, as risk factors for DIC 3,14,27 . It may be possible that the small sample size in our study could have reduced the statistical power to demonstrate the significance of association of the clinical risk factors with DIC 12,[28][29][30][31][32][33] If we considered doxorubicin cumulative dose, we observe that there was no clear association between cumulative doxorubicin dose and cardiotoxicity (p = 0.357), which is not as expected 11,12,18,[34][35][36][37][38] . However, the high frequency (60.7%) of the cardioprotective variant could have influenced this dose relationship in our study.…”

Pharmacogenetics and Adverse Events in the Use of Fluoropyrimidine in a Cohort of Cancer Patients on Standard of Care Treatment in Zimbabwe

“…Variant c.2846A>T is also a rare variant present across the general populations, American (0.30%), European (0.70%), South Asian (0.10%), African (0.08%) and Zimbabwe (0.29%). The frequency of the Hap B3 variant is high in the European (2.39%) and South Asian (1.90%) populations but low in other populations, American (0.60%) and African (0.08%) [15,26,27].…”

Investigation of the Differences in the Pharmacokinetics of CYP2D6 Substrates, Desipramine, and Dextromethorphan in Healthy African Subjects Carrying the Allelic Variants CYP2D6*17 and CYP2D6*29, When Compared with Normal Metabolizers

“…PCR on the GenoPharm OpenArray panel following the manufacturer's protocol to detect normal and mutated alleles for CYP2D6. 26 Genotype calls were generated with the TaqMan Genotyper Software. The CYP2D6 copy number was determined using the Applied Biosystems TaqMan copy number variation (CNV) assays targeting exon 9 (assay ID: Hs00010001_cn) and the TaqMan copy number reference assay (ribonuclease P) as the reference gene.…”

“…DNA was extracted from 200 μL of peripheral whole blood using the MagMAX DNA Multi‐Sample Ultra 2.0 Kit (ThermoFisher Scientific). Genotyping for CYP2D6 was performed using multiplex TaqMan PCR on the GenoPharm OpenArray panel following the manufacturer's protocol to detect normal and mutated alleles for CYP2D6 26 . Genotype calls were generated with the TaqMan Genotyper Software.…”