The importance of including African populations in pharmacogenetics studies of warfarin response.

Tweetable abstract Warfarin will remain in use for a long time to come, thus inclusion of African populations in pharmacogenomics is essential to be able to identify all possible biomarkers that are potential predictors for warfarin drug response.

Tweetable abstract Warfarin will remain in use for a long time to come, thus inclusion of African populations in pharmacogenomics is essential to be able to identify all possible biomarkers that are potential predictors for warfarin drug response.

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.

Profiling of warfarin pharmacokinetics-associated genetic variants: Black Africans portray unique genetic markers important for an African specific warfarin pharmacogenetics-dosing algorithm.

BACKGROUND: Warfarin dose variability observed in patients is attributed to variation in genes involved in the warfarin metabolic pathway. Genetic variation in CYP2C9 and VKORC1 has been the traditional focus in evaluating warfarin dose variability, with little focus on other genes. OBJECTIVE: We set out to evaluate 27 single nucleotide polymorphisms (SNPs) in the CYP2C cluster loci and 8 genes (VKORC1, ABCB1, CYP2C9, CYP2C19, CYP2C8, CYP1A2, CYP3A4, and CYP3A5) involved in pharmacokinetics of warfarin. PATIENTS/METHODS: 503 participants were recruited among black Africans and Mixed Ancestry population groups, from South Africa and Zimbabwe, and a blood sample taken for DNA. Clinical parameters were obtained from patient medical records, and these were correlated with genetic variation. RESULTS: Among black Africans, the SNPs CYP2C rs12777823G>A, CYP2C9 c.449G>A (*8), CYP2C9 c.1003C>T (*11) and CYP2C8 c.805A>T (*2) were significantly associated with warfarin maintenance dose. Conversely, CYP2C9 c.430C>T (*2), CYP2C8 c.792C>G (*4) and VKORC1 g.-1639G>A were significantly associated with maintenance dose among the Mixed Ancestry. The presence of CYP2C8*2 and CYP3A5*6 alleles was associated with increased mean warfarin maintenance dose, whereas CYP2C9*8 allele was associated with reduced warfarin maintenance dose. CONCLUSION: African populations present with a diversity of variants that are important in predicting pharmacogenetics-based warfarin dosing in addition to those reported in CYP2C9 and VKORC1. It is therefore important, to include African populations in pharmacogenomics studies to be able to identify all possible biomarkers that are potential predictors for drug response.

Childhood Obesity Risk in Relationship to Perilipin 1 (PLIN1) Gene Regulation by Circulating microRNAs.

Childhood obesity is a growing public health burden in many countries. The lipid perilipin 1 (PLIN1) gene is involved in regulation of lipolysis, and thus represents a viable candidate mechanism for obesity genetics research in children. In addition, the regulation of candidate gene expression by circulating microRNAs (miRNAs) offers a new research venue for diagnostic innovation. We report new findings on associations among circulating miRNAs, regulation of the PLIN1 gene, and susceptibility to childhood obesity. In a sample of 135 unrelated subjects, 35 children with obesity (between ages 3 and 13) and 100 healthy controls (between ages 4 and 16), we examined the expression levels of four candidate miRNAs (hsa-miR-4777-3p, hsa-miR-642b-3p, hsa-miR-3671-1, and hsa-miR-551b-2) targeting the PLIN1 as measured by real-time polymerase chain reaction in whole blood samples. We found that the full genetic model, including the four candidate miRNAs and the PLIN1 gene, explained a statistically significant 12.7% of the variance in childhood obesity risk (p = 0.0034). The four miRNAs together explained 10.1% of the risk (p = 0.008). The percentage of variation in childhood obesity risk explained by hsa-miR-642b-3p and age was 19%. In accordance with biological polarity of the observed association, for example, hsa-miR-642b-3p was upregulated, while the PLIN1 expression decreased in obese participants compared to healthy controls. To the best of our knowledge, this is the first clinical association study of these candidate miRNAs targeting the PLIN1 in childhood obesity. These data offer new molecular leads for future clinical biomarker and diagnostic discovery for childhood obesity.

The Genetics of Warfarin Dose-Response Variability in Africans: An Expert Perspective on Past, Present, and Future.

Coumarins such as warfarin are prescribed for prevention and treatment of thromboembolic disorders. Warfarin remains the most widely prescribed and an anticoagulant of choice in Africa. Warfarin use is, however, limited by interindividual variability in pharmacokinetics and a narrow therapeutic index. The difference in patients' pharmacodynamic responses to warfarin has been attributed to genetic variation in warfarin metabolism and molecular targets (e.g., CYP2C9 and VKORC1) and host-environment interactions. This expert review offers a synthesis of human genetics studies in Africans with respect to pharmacogenetics-informed warfarin dosing. We identify areas that need future research attention or could benefit from harnessing existing pharmacogenetics knowledge toward rational and optimal therapeutics with warfarin in African patients. A literature search was conducted until January 2019. A total of 343 articles were retrieved from nine African countries: Botswana, Ethiopia, Egypt, Ghana, Kenya, South Africa, Sudan, Tanzania, and Mozambique. We found 19 studies on genetics of warfarin treatment specifically among Africans. Genes examined included CYP2C9, VKORC1, CYP4F2, APOE, CALU, GGCX, and EPHX1. CYP2C9*2 and *3 alleles were highly frequent among Egyptians, while rare in other African populations. CYP2C9*5, *8, *9, and *11, and VKORC1 Asp36Tyr genetic variants explained warfarin variability in Africans better, compared to CYP2C9*2 and *3. In Africa, there is limited pharmacogenetics data on warfarin. Therefore, future research and funding commitments should be prioritized to ensure safe and effective use of warfarin in Africa. Lessons learned in Africa from the science of pharmacogenetics would inform rational therapeutics in hematology, cardiology, and surgical specialties worldwide.

Warfarin Dose and CYP2C Gene Cluster: An African Ancestral-Specific Variant Is a Strong Predictor of Dose in Black South African Patients.

Warfarin is a widely prescribed anticoagulant with a narrow therapeutic index. The rs12777823G>A single-nucleotide polymorphism (SNP) in the CYP2C gene cluster has been shown to influence optimal warfarin doses in African Americans. We report here effects of rs12777823G>A SNP on warfarin dose requirements in two South African population groups, black Africans (BA) and mixed ancestry (MA). A total of 425 participants on warfarin treatment were enrolled in the study. The age group of the studied population ranged between 44 and 66 years, with 69% females enrolled. Genetic characterization of the rs12777823G>A was done using the TaqMan SNP genotyping assay. To further compare effects of rs12777823G>A to those of other SNPs, VKORC1 g.-1639G>A and 4 SNPs in CYP2C9 gene (i.e., CYP2C9 c.430C>T, c.1075A>C, c.449G>A, and c.1003C>T) were analyzed. The rs12777823A variant allele frequencies were 0.28 and 0.25 in the BA and MA, respectively. The rs12777823A/A genotype was associated with significantly (p = 0.002) reduced mean warfarin dosage (27 ± 5.3 mg/week) compared with the G/G genotype (45 ± 16.1 mg/week) among BA, but not among the MA. The rs12777823G>A is located in a nongenomic region, suggesting that this SNP might be in linkage disequilibrium with another, likely causal SNP that is present in BA only. Given ongoing worldwide efforts to identify clinically relevant human genetic variation impacting on optimal warfarin dose selection, the African ancestry-specific genetic variant in the CYP2C cluster and others warrant further research and consideration in development of future warfarin dosing algorithms for precision medicine guidelines.