Pharmacogenomic Research in South Africa: Lessons Learned and Future Opportunities in the Rainbow Nation

South Africa, like many other developing countries, stands to benefit from novel diagnostics and drugs developed by pharmacogenomics guidance due to high prevalence of disease burden in the region. This includes both communicable (e.g., HIV/AIDS and tuberculosis) and non-communicable (e.g., diabetes and cardiovascular) diseases. For example, although only 0.7% of the world’s population lives in South Africa, the country carries 17% of the global HIV/AIDS burden and 5% of the global tuberculosis burden. Nobel Peace Prize Laureate Archbishop Emeritus Desmond Tutu has coined the term Rainbow Nation, referring to a land of wealth in its many diverse peoples and cultures. It is now timely and necessary to reflect on how best to approach new genomics biotechnologies in a manner that carefully considers the public health needs and extant disease burden in the region. The aim of this paper is to document and review the advances in pharmacogenomics in South Africa and importantly, to evaluate the direction that future research should take. Previous research has shown that the populations in South Africa exhibit unique allele frequencies and novel genetic variation in pharmacogenetically relevant genes, often differing from other African and global populations. The high level of genetic diversity, low linkage disequilibrium and the presence of rare variants in these populations question the feasibility of the use of current commercially available genotyping platforms, and may partially account for genotype-phenotype discordance observed in past studies. However, the employment of high throughput technologies for genomic research, within the context of large clinical trials, combined with interdisciplinary studies and appropriate regulatory guidelines, should aid in acceleration of pharmacogenomic discoveries in high priority therapeutic areas in South Africa. Finally, we suggest that projects such as the H3Africa Initiative, the SAHGP and PGENI should play an integral role in the coordination of genomic research in South Africa, but also other African countries, by providing infrastructure and capital to local researchers, as well as providing aid in addressing the computational and statistical bottlenecks encountered at present

H3Africa and the African life sciences ecosystem: building sustainable innovation

Interest in genomics research in African populations is experiencing exponential growth. This enthusiasm stems in part from the recognition that the genomic diversity of African populations is a window of opportunity for innovations in postgenomics medicine, ecology, and evolutionary biology. The recently launched H3Africa initiative, for example, captures the energy and momentum of this interest. This interdisciplinary socio-technical analysis highlights the challenges that have beset previous genomics research activities in Africa, and looking ahead, suggests constructive ways H3Africa and similar large scale science efforts could usefully chart a new era of genomics and life sciences research in Africa that is locally productive and globally competitive. As independent African scholars and social scientists, we propose that any serious global omics science effort, including H3Africa, aiming to build genomics research capacity and capability in Africa, needs to fund the establishment of biobanks and the genomic analyses platforms within Africa. Equally they need to prioritize community engagement and bioinformatics capability an d the training of African scientists on these platform s. Historically , the financial, technological, and skills imbalance between Africa and developed countries has created exploitative frameworks of collaboration where African researchers have become merely facilitators of Western funded and conceived research agendas involving offshore expatriation of samples. Not surprisingly, very little funding was allocated to infrastructure and human capital development in the past. Moving forward, capacity building should materialize throughout the entire knowledge co-production trajectory: idea generation (e.g., brainstorming workshops for innovative hypotheses development by African scientists), data generation (e.g., genome sequencing), an d high-through put data analysis an d contextualization . Additionally, building skills for political science scholarship that questions the unchecked assumptions of the innovation performers be they funders, scientists, and social scientists, would enable collective innovation that is truly sustainable, ethical, and robust

Chromosome 22q11 in a Xhosa schizophrenia population

Chromosome 22q11 aberrations substantially increase the risk for developing schizophrenia. Although micro-deletions in this region have been extensively investigated in different populations across the world, little is known of their prevalence in African subjects with schizophrenia. We screened 110 African Xhosa-speaking participants with schizophrenia for the presence of micro-deletions. As further verification for the presence or absence of 22q11 microdeletions, we screened 238 Xhosa schizophrenia patients and 240 healthy Xhosa individuals from a larger schizophrenia candidate 22q11 gene study using molecular analyses. Data from molecular and cytogenetic analyses confirmed the absence of 22q11 microdeletions in the Xhosa schizophrenia samples. Although the absence of chromosome 22q11 micro-deletions in this group of patients does not exclude the possibility that it may occur in Xhosa schizophrenia patients, we concluded an extremely low prevalence. Our findings suggest that unique susceptibility loci may be present in this group

Evaluation of predictive CYP2C19 genotyping assays relative to measured phenotype in a South African cohort

AIM : To align predicted and measured CYP2C19 phenotype in a South African cohort. MATERIALS AND METHODS : Genotyping of CYP2C19*2, *3, *9, *15, *17, *27 and *28 was performed using PCR-RFLP, and an Activity Score (AS) system was used to predict phenotype.True phenotype was measured using plasma concentrations of omeprazole and its metabolite 5’-hydroxyomperazole. RESULTS : Partial genotype-phenotype discrepancies were reported, and an adapted AS system was developed, which showed a marked improvement in phenotype prediction. Results highlight the need for a more comprehensive CYP2C19 genotyping approach to improve prediction of omeprazole metabolism. CONCLUSION : Evidence for the utility of a CYP2C19 AS system is provided, for which the accuracy can be further improved by means of comprehensive genotyping and substrate specific modification.Departments of Pharmacology and Immunology, University of Pretoria; the National Research Foundation of South Africa (NRF) grant numbers FA2006032700005 and TK2006051500005; the National Health Laboratory Services of South Africa (NHLS); the South African Medical Research Council (SAMRC) Extramural Unit for Inflammation and Immunity, and Ampath Laboratories, South Africa.http://www.futuremedicine.com/loi/pgs2016-08-31hb201

Identification of a novel functional deletion variant in the 5'-UTR of the DJ-1 gene

<p>Abstract</p> <p>Background</p> <p>DJ-1 forms part of the neuronal cellular defence mechanism against oxidative insults, due to its ability to undergo self-oxidation. Oxidative stress has been implicated in the pathogenesis of central nervous system damage in different neurodegenerative disorders including Alzheimer's disease and Parkinson's disease (PD). Various mutations in the <it>DJ-1 </it>(<it>PARK7</it>) gene have been shown to cause the autosomal recessive form of PD. In the present study South African PD patients were screened for mutations in <it>DJ-1 </it>and we aimed to investigate the functional significance of a novel 16 bp deletion variant identified in one patient.</p> <p>Methods</p> <p>The possible effect of the deletion on promoter activity was investigated using a Dual-Luciferase Reporter assay. The <it>DJ-1 </it>5'-UTR region containing the sequence flanking the 16 bp deletion was cloned into a pGL4.10-Basic luciferase-reporter vector and transfected into HEK293 and BE(2)-M17 neuroblastoma cells. Promoter activity under hydrogen peroxide-induced oxidative stress conditions was also investigated. Computational (<it>in silico</it>) <it>cis</it>-regulatory analysis of <it>DJ-1 </it>promoter sequence was performed using the transcription factor-binding site database, TRANSFAC via the PATCH™ and rVISTA platforms.</p> <p>Results</p> <p>A novel 16 bp deletion variant (g.-6_+10del) was identified in <it>DJ-1 </it>which spans the transcription start site and is situated 93 bp 3' from a Sp1 site. The deletion caused a reduction in luciferase activity of approximately 47% in HEK293 cells and 60% in BE(2)-M17 cells compared to the wild-type (<it>P </it>< 0.0001), indicating the importance of the 16 bp sequence in transcription regulation. The activity of both constructs was up-regulated during oxidative stress. Bioinformatic analysis revealed putative binding sites for three transcription factors AhR, ARNT, HIF-1 within the 16 bp sequence. The frequency of the g.-6_+10del variant was determined to be 0.7% in South African PD patients (2 heterozygotes in 148 individuals).</p> <p>Conclusion</p> <p>This is the first report of a functional <it>DJ-1 </it>promoter variant, which has the potential to influence transcript stability or translation efficiency. Further work is necessary to determine the extent to which the g.-6_+10del variant affects the normal function of the <it>DJ-1 </it>promoter and whether this variant confers a risk for PD.</p

An appeal to the global health community for a tripartite innovation: an ‘‘Essential Diagnostics List,’’ ‘‘Health in All Policies,’’ and ‘‘See-Through 21st Century Science and Ethics"

Diagnostics spanning a wide range of new biotechnologies, including proteomics, metabolomics, and nanotechnology, are emerging as companion tests to innovative medicines. In this Opinion, we present the rationale for promulgating an ‘‘Essential Diagnostics List.’’ Additionally, we explain the ways in which adopting a vision for ‘‘Health in All Policies’’ could link essential diagnostics with robust and timely societal outcomes such as sustainable development, human rights, gender parity, and alleviation of poverty. We do so in three ways. First, we propose the need for a new, ‘‘see through’’ taxonomy for knowledge-based innovation as we transition from the material industries (e.g., textiles, plastic, cement, glass) dominant in the 20th century to the anticipated knowledge industry of the 21st century. If knowledge is the currency of the present century, then it is sensible to adopt an approach that thoroughly examines scientific knowledge, starting with the production aims, methods, quality, distribution, access, and the ends it purports to serve. Second, we explain that this knowledge trajectory focus on innovation is crucial and applicable across all sectors, including public, private, or public–private partnerships, as it underscores the fact that scientific knowledge is a co-product of technology, human values, and social systems. By making the value systems embedded in scientific design and knowledge co-production transparent, we all stand to benefit from sustainable and transparent science. Third, we appeal to the global health community to consider the necessary qualities of good governance for 21st century organizations that will embark on developing essential diagnostics. These have importance not only for science and knowledge based innovation, but also for the ways in which we can build open, healthy, and peaceful civil societies today and for future generations

The DNA sequence analysis of polymorphic markers for improved high resolution mapping of important gene loci

Thesis (Ph.D.) -- University of Stellenbosch, 1993.One copy microfiche.Full text to be digitised and attached to bibliographic record