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.

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.

The COVID-19 Pandemic and Explaining Outcomes in Africa: Could Genomic Variation Add to the Debate?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, emanated from the Wuhan Province in China and rapidly spread across the globe causing extensive morbidity and mortality rate, and affecting the global economy and livelihoods. Contrary to early predictions of "body bags" across Africa, the African COVID-19 pandemic was marked by apparent low case numbers and an overall mortality rate when compared with the other geographical regions. Factors used to describe this unexpected pattern included a younger population, a swifter and more effective national health policy, limited testing capacities, and the possibility of inadequate reporting of the cases, among others. However, despite genomics contributing to interindividual variations in many diseases across the world, there are inadequate genomic and multiomics data on COVID-19 in Africa that prevent richer transdisciplinary discussions on the contribution of genomics to the spread of COVID-19 pandemic. To invite future debates on comparative studies of COVID-19 genomics and the pandemic spread around the world regions, this expert review evaluates the reported frequency distribution of genetic variants in candidate genes that are likely to affect COVID-19 infection dynamics/disease outcomes. We propose here that genomic variation should be considered among the many factors determining the COVID-19 infection and its outcomes in African populations and across the world.

Warfarin Pharmacogenomics for Precision Medicine in Real-Life Clinical Practice in Southern Africa: Harnessing 73 Variants in 29 Pharmacogenes.

Pharmacogenomics is universally relevant for worldwide modern therapeutics and yet needs further development in resource-limited countries. While there is an abundance of genetic association studies in controlled medical settings, there is a paucity of studies with a naturalistic design in real-life clinical practice in patients with comorbidities and under multiple drug treatment regimens. African patients are often burdened with communicable and noncommunicable comorbidities, yet the application of pharmacogenomics in African clinical settings remains limited. Using warfarin as a model, this study aims at minimizing gaps in precision/personalized medicine research in African clinical practice. We present, therefore, pharmacogenomic profiles of a cohort of 503 black Africans (n = 252) and Mixed Ancestry (n = 251) patients from Southern Africa, on warfarin and co-prescribed drugs in a naturalized noncontrolled environment. Seventy-three (n = 73) single nucleotide polymorphisms (SNPs) in 29 pharmacogenes were characterized using a combination of allelic discrimination, Sanger sequencing, restriction fragment length polymorphism, and Sequenom Mass Array. The common comorbidities were hypertension (43-46%), heart failure (39-45%), diabetes mellitus (18%), arrhythmia (25%), and HIV infection (15%). Accordingly, the most common co-prescribed drugs were antihypertensives, antiarrhythmic drugs, antidiabetics, and antiretroviral therapy. We observed marked variation in major pharmacogenes both at interethnic levels and within African subpopulations. The Mixed Ancestry group presented a profile of genetic variants reflecting their European, Asian, and African admixture. Precision medicine requires that African populations begin to capture their own pharmacogenetic SNPs as they cannot always infer with absolute certainty from Asian and European populations. In the current historical moment of the COVID-19 pandemic, we also underscore that the spectrum of drugs interacting with warfarin will likely increase, given the systemic and cardiovascular effects of COVID-19, and the anticipated influx of COVID-19 medicines in the near future. This observational clinical pharmacogenomics study of warfarin, together with past precision medicine research, collectively, lends strong support for incorporation of pharmacogenetic profiling in clinical settings in African patients for effective and safe administration of therapeutics.

Priority setting in otolaryngology practices in Zimbabwe.

PURPOSE OF REVIEW: This article describes priority setting in otorhinolaryngology healthcare services in Zimbabwe. It aims to initiate discussion on priority setting among otorhinolaryngologists working in African countries. RECENT FINDINGS: The WHO reports that most developed countries have formal processes in place for the collection and analysis of information that is used in priority setting in healthcare services. However, many resource-limited nations lack well-defined processes for priority setting. Information surrounding priority setting in otorhinolaryngology in particular is scarce. SUMMARY: Priority setting refers to the distribution of limited resources among competing programmes and patient or patient groups in an equitable and just manner. A dearth of information on priority setting in otorhinolaryngology exists. This silence is more pronounced in African settings. Despite the myriad of challenges facing many African countries, formal guidelines for priority setting are rare. Priority setting therefore is often haphazard and unplanned. We therefore recommend agility in bringing together otorhinolaryngology stakeholders in an effort to initiate dialogue and come up with formal processes that will collect information that will lead to provision of guidelines in priority setting.

Human papillomavirus types causing recurrent respiratory papillomatosis in Zimbabwe.

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) caused by human papillomavirus (HPV) is preventable through vaccination. This study was motivated by the recent thrust of the Zimbabwean government to reduce incidence of HPV related cervical cancer in Zimbabwe through vaccination against HPV. We therefore set out to type HPV genotypes causing RRP in Zimbabwe. We also describe for the first time, the demographics of Zimbabwean RRP patients, the characteristics of patients with different HPV types and possible risk factors of HPV infection in our setting. METHODS: We conducted a prospective, hospital based study were patients were recruited from two national otorhinolaryngology hospitals in Zimbabwe. All patients diagnosed with RRP during a twenty four month period were included in the study. A questionnaire was administered per patient to collect both demographic and clinical variables. HPV DNA was extracted from formalin fixed paraffin embedded laryngeal tissue. The extracted HPV DNA was amplified using polymerase chain reaction and next generation sequencing was used to genotype the HPV types. RESULTS: A total of 52 patients all aged 14 years and under were recruited into the study. Only Juvenile onset RRP cases were observed over the two year period and 64% of the patients were HPV positive. HPV types 6 and 11 were the dominant types observed constituting 85% of all HPV types. The remaining 15% constituted of HPV 16 and HPV 18. 27% of the patients had coinfection with at least two different HPV types. There were no statistically significant differences between the characteristics of HPV positive and HPV negative patients. No statistically significant risk factors were observed. CONCLUSION: HPV types 6 and 11 were the predominant genotypes causing RRP in Zimbabwe. Thus the use of quadrivalent or even nonavalent HPV vaccines may play an important role in the prevention and management of RRP in Zimbabwe.

A cost effective RFLP method to genotype Solute carrier organic anion 1B1 (SLCO1B1) c.1929A>C (p.Leu643Phe, rs34671512); a variant with potential effect on rosuvastatin pharmacokinetics.

OBJECTIVE: This study describes a restriction fragment polymorphism protocol for rapidly screening the polymorphism SLCO1B1 c.1929A>C in genomic DNA samples. The polymorphism SLCO1B1 c.1929A>C has been associated with increased activity resulting in increased hepatic uptake of drugs. Currently SLCO1B1 c.1929A>C is genotyped using direct sequencing techniques and 5' nuclease based assays which can be cost prohibiting in resource limited settings. The aim of this study therefore was to design and validate a cost effective RFLP for genotyping the SLCO1B1 c.1929A>C polymorphism. This study was designed to investigate the effect of the polymorphism SLCO1B1 c.1929A>C on interindividual variability in rosuvastatin pharmacokinetics in healthy volunteers of African descent. RESULTS: We describe a restriction fragment length polymorphism method to genotype SLCO1B1 c.1929A>C polymorphism using the restriction enzyme Ase1. A student's t test with Welch correction was used to establish association between the SLCO1B1 c.1929A>C variant and rosuvastatin exposure. The frequency of the SLCO1B1 c.1929C allele amongst Zimbabweans was 6%. The SLCO1B1 c.1929C allele was associated with a 75% reduction (P < 0.001) in rosuvastatin exposure when compared to individuals carrying the wild type SLCO1B1 c.1929A allele. Polymorphism c.1929A>C may therefore play a significant role in rosuvastatin response. The RFLP method is quick and cost effective.

Pharmacogenomics of Rosuvastatin: A Glocal (Global+Local) African Perspective and Expert Review on a Statin Drug.

The incidence of cardiovascular diseases (CVDs) in African populations residing in the African continent is on the rise fueled by both a steady increase in CVD risk factors and comorbidities such as human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), tuberculosis, and parasitic diseases such as bilharzia. Statins are recommended together with lifestyle changes in the treatment of hypercholesterolemia and overall reduction of cardiovascular events. Rosuvastatin in particular is an attractive candidate in the management of CVDs in African populations often plagued with multimorbidities owing to both its potency and low drug-to-drug interaction potential. In this expert review, we describe the pharmacogenetics of rosuvastatin and how it may instrumentally affect the African populations. We describe polymorphisms in the candidate genes, ABCG2, SLCO1B1, CYP2C9, APOE, PCSK9, LDLR, LPA, and HMGCR, and their role in the potency and safety of rosuvastatin therapy. We report on qualitative and quantitative differences in the distribution of genetic variants that affect efficacy and toxicity of rosuvastatin. These differences are observed across world populations (Caucasian, European, and Asian) as well as within African populations. Finally, we advocate for extensive pharmacogenetic studies in African populations that take into account the genetic diversity of intra-African ethnic groups and the genetic differences between African populations and other global populations, with a collaborative and collective aim to provide effective and safe use of rosuvastatin in management of CVD in Africa. Our key thesis presented in this innovation field analysis is that rosuvastatin precision medicine can serve as a veritable Glocal (Global and Local) model to offer pharmacogenetic-guided optimal therapeutics for the public in both developing and developed regions of the world.

Differences in genetic variants in lopinavir disposition among HIV-infected Bantu Africans.

INTRODUCTION: Variability in lopinavir (LPV) plasma concentration among patients could be due to genetic polymorphisms. This study set to evaluate significance of variants in CYP3A4/5, SLCO1B1 and ABCC2 on LPV plasma concentration among African HIV-positive patients. MATERIALS & METHODS: Eighty-six HIV-positive participants on ritonavir (LPV/r) were genetically characterized and LPV plasma concentration determined. RESULTS & DISCUSSION: LPV plasma concentrations differed >188-fold (range 0.0206-38.6 µg/ml). Both CYP3A4*22 and SLCO1B1 rs4149056G (c.521C) were not observed in this cohort. CYP3A4*1B, CYP3A5*3, CYP3A5*6 and ABCC2 c.1249G>A which have been associated with LPV plasma concentration, showed no significant association. CONCLUSION: These findings highlight the need to include African groups in genomics research to identify variants of pharmacogenomics significance.

Hypothesis: Do miRNAs Targeting the Leucine-Rich Repeat Kinase 2 Gene (LRRK2) Influence Parkinson's Disease Susceptibility?

Parkinson's disease (PD) is a frequently occurring neurodegenerative motor disorder adversely impacting global health. There is a paucity of biomarkers and diagnostics that can forecast susceptibility to PD. A new research frontier for PD pathophysiology is the study of variations in microRNA (miRNA) expression whereby miRNAs serve as "upstream regulators" of gene expression in relation to functioning of the dopamine neuronal pathways. Leucine-Rich Repeat Kinase 2 (LRRK2) is a frequently studied gene in PD. Little is known about the ways in which expression of miRNAs targeting LRKK2 impact PD susceptibility. In a sample of 204 unrelated subjects (102 persons with PD and 102 healthy controls), we report here candidate miRNA expression in whole blood samples as measured by real-time PCR (hsa-miR-4671-3p, hsa-miR-335-3p, hsa-miR-561-3p, hsa-miR-579-3p, and hsa-miR-3143) that target LRRK2. Using step-wise logistic regression, and controlling for covariates such as age, gender, PD disease severity, concomitant medications, and co-morbidity, we found that the combination of has-miR-335-3p, has-miR-561-3p, and has-miR-579-3p account for 50% of the variation in regards to PD susceptibility (p<0.0001). Notably, the hsa-miR-561-3p expression was the most robust predictor of PD in both univariate and multivariate analyses (p<0.001). Moreover, the biological direction (polarity) of the association was plausible in that the candidate miRNAs displayed a diminished expression in patients. This is consistent with the hypothesis that decreased levels of miRNAs targeting LRRK2 might result in a gain of function for LRRK2, and by extension, loss of neuronal viability. To the best of our knowledge, this is the first clinical association study of the above candidate miRNAs' expression in PD using peripheral samples. These observations may guide future clinical diagnostics research on PD.