Major Genetic Drivers of Statin Treatment Response in African Populations and Pharmacogenetics of Dyslipidemia Through a One Health Lens.

A One Health lens is increasingly significant to address the intertwined challenges in planetary health concerned with the health of humans, nonhuman animals, plants, and ecosystems. A One Health approach can benefit the public health systems in Africa that are overburdened by noncommunicable, infectious, and environmental diseases. Notably, the COVID-19 pandemic revealed the previously overlooked two-fold importance of pharmacogenetics (PGx), for individually tailored treatment of noncommunicable diseases and environmental pathogens. For example, dyslipidemia, a common cardiometabolic risk factor, has been identified as an independent COVID-19 severity risk factor. Observational data suggest that patients with COVID-19 infection receiving lipid-lowering therapy may have better outcomes. However, among African patients, the response to these drugs varies from patient to patient, pointing to the possible contribution of genetic variation in important pharmacogenes. The PGx of lipid-lowering therapies may underlie differences in treatment responses observed among dyslipidemia patients as well as patients comorbid with COVID-19 and dyslipidemia. Genetic variations in APOE, ABCB1, CETP, CYP2C9, CYP3A4, CYP3A5, HMGCR, LDLR, NPC1L1, and SLCO1B1 genes affect the pharmacogenomics of statins, and they have individually been linked to differential responses to dyslipidemia and COVID-19 treatment. African populations are underrepresented in PGx research. This leads to poor accounting of additional diverse genetic variants that could be important in understanding interindividual and between-population variations in therapeutic responses to dyslipidemia and COVID-19. This expert review examines and synthesizes the salient and priority PGx variations, as seen through a One Health lens in Africa, to improve and inform personalized medicine in both dyslipidemia and COVID-19.

Towards Evidence-Based Implementation of Pharmacogenomics in Southern Africa: Comorbidities and Polypharmacy Profiles across Diseases.

Pharmacogenomics may improve patient care by guiding drug selection and dosing; however, this requires prior knowledge of the pharmacogenomics of drugs commonly used in a specific setting. The aim of this study was to identify a preliminary set of pharmacogenetic variants important in Southern Africa. We describe comorbidities in 3997 patients from Malawi, South Africa, and Zimbabwe. These patient cohorts were included in pharmacogenomic studies of anticoagulation, dyslipidemia, hypertension, HIV and breast cancer. The 20 topmost prescribed drugs in this population were identified. Using the literature, a list of pharmacogenes vital in the response to the top 20 drugs was constructed leading to drug-gene pairs potentially informative in translation of pharmacogenomics. The most reported morbidity was hypertension (58.4%), making antihypertensives the most prescribed drugs, particularly amlodipine. Dyslipidemia occurred in 31.5% of the participants, and statins were the most frequently prescribed as cholesterol-lowering drugs. HIV was reported in 20.3% of the study participants, with lamivudine/stavudine/efavirenz being the most prescribed antiretroviral combination. Based on these data, pharmacogenes of immediate interest in Southern African populations include ABCB1, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLC22A1, SLCO1B1 and UGT1A1. Variants in these genes are a good starting point for pharmacogenomic translation programs in Southern Africa.

Pharmacogenomics of Hypertension in Africa: Paving the Way for a Pharmacogenetic-Based Approach for the Treatment of Hypertension in Africans.

In Africa, the burden of hypertension has been rising at an alarming rate for the last two decades and is a major cause for cardiovascular disease (CVD) mortality and morbidity. Hypertension is characterised by elevated blood pressure (BP) ≥ 140/90 mmHg. Current hypertension guidelines recommend the use of antihypertensives belonging to the following classes: calcium channel blockers (CCB), angiotensin converting inhibitors (ACEI), angiotensin receptor blockers (ARB), diuretics, ß-blockers, and mineralocorticoid receptor antagonists (MRAs), to manage hypertension. Still, a considerable number of hypertensives in Africa have their BP uncontrolled due to poor drug response and remain at the risk of CVD events. Genetic factors are a major contributing factor, accounting for 20% to 80% of individual variability in therapy and poor response. Poor response to antihypertensive drug therapy is characterised by elevated BPs and occurrence of adverse drug reactions (ADRs). As a result, there have been numerous studies which have examined the role of genetic variation and its influence on antihypertensive drug response. These studies are predominantly carried out in non-African populations, including Europeans and Asians, with few or no Africans participating. It is important to note that the greatest genetic diversity is observed in African populations as well as the highest prevalence of hypertension. As a result, this warrants a need to focus on how genetic variation affects response to therapeutic interventions used to manage hypertension in African populations. In this paper, we discuss the implications of genetic diversity in CYP11B2, GRK4, NEDD4L, NPPA, SCNN1B, UMOD, CYP411, WNK, CYP3A4/5, ACE, ADBR1/2, GNB3, NOS3, B2, BEST3, SLC25A31, LRRC15 genes, and chromosome 12q loci on hypertension susceptibility and response to antihypertensive therapy. We show that African populations are poorly explored genetically, and for the few characterised genes, they exhibit qualitative and quantitative differences in the profile of pharmacogene variants when compared to other ethnic groups. We conclude by proposing prioritization of pharmacogenetics research in Africa and possible adoption of pharmacogenetic-guided therapies for hypertension in African patients. Finally, we outline the implications, challenges, and opportunities these studies present for populations of non-European descent.