title: A Global Health Diagnostic for Personalized Medicine in Resource-Constrained World Settings: A Simple PCR-RFLP Method for Genotyping CYP2B6 g.15582C>T and Science and Policy Relevance for Optimal Use of Antiretroviral Drug Efavirenz.
abstract: The use of pharmacogenomics (PGx) knowledge in treatment of individual patients is becoming a common phenomenon in the developed world. However, poorly resourced countries have thus far been constrained for three main reasons. First, the cost of whole genome sequencing is still considerably high in comparison to other (non-genomics) diagnostics in the developing world where both science and social dynamics create a dynamic and fragile healthcare ecosystem. Second, studies correlating genomic differences with drug pharmacokinetics and pharmacodynamics have not been consistent, and more importantly, often not indexed to impact on societal end-points, beyond clinical practice. Third, ethics regulatory frames over PGx testing require improvements based on nested accountability systems and in ways that address the user community needs. Thus, CYP2B6 is a crucial enzyme in the metabolism of antiretroviral drugs, efavirenz and nevirapine. More than 40 genetic variants have been reported, but only a few contribute to differences in plasma EFV and NVP concentrations. The most widely reported CYP2B6 variants affecting plasma drug levels include c.516G>T, c.983T>C, and to a lesser extent, g.15582C>T, which should be considered in future PGx tests. While the first two variants are easily characterized, the g.15582C>T detection has been performed primarily by sequencing, which is costly, labor intensive, and requires access to barely available expertise in the developing world. We report here on a simple, practical PCR-RFLP method with vast potentials for use in resource-constrained world regions to detect the g.15582C>T variation among South African and Cameroonian persons. The effects of CYP2B6 g.15582C>T on plasma EFV concentration were further evaluated among HIV/AIDS patients. We report no differences in the frequency of the g.15582T variant between the South African (0.08) and Cameroonian (0.06) groups, which are significantly lower than reported in Asians (0.39) and Caucasians (0.31). The g.15582C/T and T/T genotypes were associated with significantly reduced EFV levels (p=0.006). This article additionally presents the policy relevance of the PGX global health diagnostics and therefore, collectively makes an original interdisciplinary contribution to the field of integrative biology and personalized medicine in developing world. Such studies are, in fact, broadly important because resource-constrained regions exist not only in developing world but also in major geographical parts of the G20 nations and the developed countries.
authors.affiliation: 1 Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Clinical Laboratory Sciences and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
authors.forename: Jonathan
authors.initials: J
authors.lastname: Evans
authors.affiliation: 1 Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Clinical Laboratory Sciences and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
authors.forename: Marelize
authors.initials: M
authors.lastname: Swart
authors.affiliation: 1 Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Clinical Laboratory Sciences and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
authors.forename: Nyarai
authors.initials: N
authors.lastname: Soko
authors.affiliation: 1 Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Clinical Laboratory Sciences and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
authors.forename: Ambroise
authors.initials: A
authors.lastname: Wonkam
authors.affiliation: 2 Science, Technology and Innovation Studies, School of Social and Political Science, University of Edinburgh , Edinburgh, United Kingdom .
authors.forename: Farah
authors.initials: F
authors.lastname: Huzair
authors.affiliation: 1 Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Clinical Laboratory Sciences and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
authors.forename: Collet
authors.initials: C
authors.lastname: Dandara
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D057285:Precision Medicine / Q000379:methods*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz