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Background: Poor management of diabetes mellitus gives rise to complications such as diabetic foot (DF), which pose a host of medical and socioeconomic problems, especially in low-income countries ...

As human genomics research in Africa continues to generate large amounts of data, ethical issues arise regarding how actionable genetic information is shared with research participants. The Human Heredity and Health in Africa Consortium (H3Africa) Ethics and Community Engagement Working group acknowledged the need for such guidance, identified key issues and principles relevant to genomics research in Africa and developed a practical guideline for consideration of feeding back individual genetic results of health importance in African research projects. This included a decision flowchart, providing a logical framework to assist in decision-making and planning for human genomics research projects. Although presented in the context of the H3Africa Consortium, we believe the principles described, and the decision flowchart presented here is applicable more broadly in African genomics research.

Advanced genomics and sequencing technologies are increasingly becoming critical for global health applications such as pathogen and antimicrobial resistance (AMR) surveillance. Limited resources challenge capacity development in low- and middle-income countries (LMICs), with few countries having genomics facilities and adequately trained staff. Training research and public health experts who are directly involved in the establishment of such facilities offers an effective, but limited, solution to a growing need. Instead, training them to impart their knowledge and skills to others provides a sustainable model for scaling up the much needed capacity and capability for genomic sequencing and analysis locally with global impact. We designed and developed a Train-the-Trainer course integrating pedagogical aspects with genomic and bioinformatics activities. The course was delivered to 18 participants from 12 countries in Africa, Asia, and Latin America. A combination of teaching strategies culminating in a group project created a foundation for continued development at home institutions. Upon follow-up after 6 months, at least 40% of trainees had initiated training programs and collaborations to build capacity at local, national, and regional level. This work provides a framework for implementing a training and capacity building program for the application of genomics tools and resources in AMR surveillance.

© 2021 Moore et al., Bioinformatics training is required at every stage of a scientist’s research career. Continual bioinformatics training allows exposure to an ever-changing and growing repertoire of techniques and databases, and so biologists, computational scientists, and healthcare practitioners are all seeking learning opportunities in the use of computational resources and tools designed for data storage, retrieval, and analysis. There are abundant opportunities for accessing bioinformatics training for scientists in high-income countries (HICs), with well-equipped facilities and participants and trainers requiring minimal travel and financial costs alongside a range of general advice for developing short bioinformatics training courses [1–3]. However, regionally targeted bioinformatics training in low- and middle-income countries (LMICs) often requires more extensive local and external support, organization, and travel. Due to the limited expertise in bioinformatics in LMICs in general, most bioinformatics training requires a fair amount of collaboration with experts beyond the local community, country, or region. A common model of training, used as the basis of this article, includes a local host collaborating with local, regional, and international experts gathering to train local or regional participants. Recently, there has been a growth of capacity strengthening initiatives in LMICs, such as the Pan African Bioinformatics Network for Human Heredity and Health in Africa (H3ABioNet) Initiative [4–6], the Capacity Building for Bioinformatics in Latin America (CABANA) Project [7], the Asia Pacific BioInformatics Network (APBioNet) [8], and the Wellcome Connecting Science Courses and Conferences program [9]. One of the important strands of these initiatives is a drive to organize and deliver valuable bioinformatics training, but organizing and delivering short bioinformatics training workshops in an LMIC present a unique set of challenges. This paper attempts to build upon the sage advice for organizing bioinformatics workshops with specific guidance for organizing and delivering them in LMICs. It describes the processes to follow in organizing courses taking into consideration the low-resource setting. We should also note that LMICs are not a monolithic group and that setting, context, temporality, and specific location matters. LMICs are a complex regional grouping [10] and should be treated as such; however, we will present some common lessons that we hope will help organizers and trainers of bioinformatics training events in LMICs to navigate the often different, challenging, and rewarding experience., The authors who contributed to this manuscript are funded as follows: BM receives salary support from Wellcome Trust grants [WT108749/Z/15/Z, WT108749/Z/15/A], PC, VR, NM, AG’s salaries are funded in whole, or in part, by the NIH Common Fund H3ABioNet grant [U24HG006941], MC, SLFV, AR, PG, PCL’s salaries were partly funded by the UKRI-BBSRC ‘Capacity building for bioinformatics in Latin America’ (CABANA) grant, on behalf of the Global Challenges Research Fund [BB/P027849/1], JDLR is funded by ISCiii AES [ref. PI18/00591] at the CSIC/USAL (Spain) and by CYTED, RIABIO (Red Iberoamericana 521RT0118), AM’s salary is funded by [WT206194/Z/17/Z], GO is funded by the CABANA grant and SM is funded by the EMBL-EBI.

© 2021 Ras, Carvajal-López, Gopalasingam, Matimba, Chauke, Mulder, Guerfali, Del Angel, Reyes, Oliveira, De Las Rivas and Cristancho., In general, institutions and research groups based in Low to Middle Income Countries (LMICs) battle a number of challenges ranging from a shortage of infrastructure, lack of training facilities, and poor internet, to a lack of local expertise (Karikari et al., 2015; Tastan Bishop et al., 2015; Shaffer et al., 2019). A shortage of local experts, particularly within more specialised topics, still remains a key obstacle in developing bioinformatics research capacity within LMICs (Tastan Bishop et al., 2015; Mulder et al., 2018)., The authors who contributed to this manuscript are funded in whole, or in part, by the Wellcome Trust (WT108749/Z/15/Z), (WT108749/Z/15/A), H3ABioNet NIH grant U24HG006941, H3ABioNet NIH grant U24HG006942, CABANA—Capacity building for bioinformatics in Latin America’ (CABANA), funded by UKRI-BBSRC on behalf of the Global Challenges Research Fund (BB/P027849/1), CSIC/ USAL and EMBL-EBI.

Aim: To describe pain management regulations, prevalence of pain and pain management practices in a Zimbabwean setting. Materials & methods: A multi-methods approach was used, consisting of: policy and guideline review; review of 410 cervical cancer patient records for pain symptoms and pain management data; and semistructured interviews with oncology healthcare practitioners. Results: We found a lack of policies that are specific for cervical cancer pain management. Although prevalence of pain was 68% (n = 278), only 42% of the patient records indicated pain drugs had been prescribed. Barriers to pain management included inadequate use of pain assessment tools, inaccessibility of key drugs and limited capacity. Conclusion: Cancer pain management in Zimbabwe can be improved by tailoring assessment protocols, improving drug accessibility and strengthening healthcare systems.

A generic framework for providing participant information and implementing a tiered consent process for health genomic research in Africa can help to harness global health benefits from sharing and meta-analysis of African genomic data while simultaneously respecting and upholding the autonomy and individual choices of African research participants.

Due to the increasing incidence of diabetes in Zimbabwe, complications such as diabetic foot (DF) are anticipated. Establishing local gaps and needs in DF healthcare is paramount for tailoring management strategies.To determine the status of DF services in the healthcare system and explore awareness of DF management and practices among registered general nurses (RGNs) in Zimbabwe.A mixed-methods approach was applied. Thirty-one RGNs from 16 public health facilities in Harare, Zimbabwe attending a DF workshop were administered with a cross-sectional survey instrument and a semi-structured questionnaire. Data collected included presence/absence of DF services and podiatrists in healthcare facilities, healthcare system approaches in DF care and availability of DF training/education programs for RGNs. Analysis was performed using Stata and Nvivo software.No respondents reported availability of podiatrists. Only 1 (3%) of RGNs reported DF screening in primary care. Sixty percent (18) did not know or had never screened for DF. The RGNs reported inadequate DF educational programs/modules in primary care settings.This data highlights a need to improve DF education for RGNs at the frontline of managing PLWD. Understanding the needs for DF services may guide interventions to improve education and awareness programs that are appropriately tailored to local constraints in the health system. The non-communicable diseases director is encouraged to develop DF educational programmes for frontline health care workers.

Background High-risk human papillomavirus HPV (HR-HPV) modifies cervical cancer risk in people living with HIV, yet African populations are under-represented. We aimed to compare the frequency, multiplicity and consanguinity of HR-HPVs in HIV-negative and HIV-positive Zimbabwean women. Methods This was a cross-sectional study consisting of women with histologically confirmed cervical cancer attending Parirenyatwa Group of Hospitals in Harare, Zimbabwe. Information on HIV status was also collected for comparative analysis. Genomic DNA was extracted from 258 formalin fixed paraffin embedded tumour tissue samples, and analysed for 14 HR-HPV genotypes. Data was analysed using Graphpad Prism and STATA. Results Forty-five percent of the cohort was HIV-positive, with a median age of 51 (IQR = 42–62) years. HR-HPV positivity was detected in 96% of biospecimens analysed. HPV16 (48%), was the most prevalent genotype, followed by HPV35 (26%), HPV18 (25%), HPV58 (11%) and HPV33 (10%), irrespective of HIV status. One third of the cohort harboured a single HPV infection, and HPV16 (41%), HPV18 (21%) and HPV35 (21%) were the most prevalent. HIV status did not influence the prevalence and rate of multiple HPV infections (p>0.05). We reported significant (p Conclusion We found that HIV does not influence the frequency, multiplicity and consanguinity of HR-HPV in cervical cancer. For the first time, we report high prevalence of HPV35 among women with confirmed cervical cancer in Zimbabwe, providing additional evidence of HPV diversity in sub-Saharan Africa. The data obtained here probes the need for larger prospective studies to further elucidate HPV diversity and possibility of selective pressure on genotypes.

Precision medicine is being enabled in high-income countries by the growing availability of health data, increasing knowledge of the genetic determinants of disease and variation in response to treatment (pharmacogenomics), and the decreasing costs of data generation, which promote routine application of genomic technologies in the health sector. However, there is uncertainty about the feasibility of applying precision medicine approaches in low- and middle-income countries, due to the lack of population-specific knowledge, skills, and resources. The Human Heredity and Health in Africa (H3Africa) initiative was established to drive new research into the genetic and environmental basis for human diseases of relevance to Africans as well as to build capacity for genomic research on the continent. Precision medicine requires this capacity, in addition to reference data on local populations, and skills to analyze and interpret genomic data from the bedside. The H3Africa consortium is collectively processing samples and data for over 70,000 participants across the continent, accompanied in most cases by rich clinical information on a variety of non-communicable and infectious diseases. These projects are increasingly providing novel insights into the genetic basis of diseases in indigenous populations, insights that have the potential to drive the development of new diagnostics and treatments. The consortium has also invested significant resources into establishing high-quality biorepositories in Africa, a bioinformatic network, and a strong training program that has developed skills in genomic data analysis and interpretation among bioinformaticians, wet-lab researchers, and health-care professionals. Here, we describe the current perspectives of the H3Africa consortium and how it can contribute to making precision medicine in Africa a reality.

Biobanks and human genomics applications are key for understanding health, disease and heredity in Africa and globally. Growing interest in these technologies calls for strengthening relevant legal, ethical and policy systems to address knowledge disparities and ensure protection of society, while supporting advancement of science. In Zimbabwe there is limited understanding of ethical, legal, and societal issues (ELSI) for biobanking and genomics. The Genomics Inheritance Law Ethics and Society (GILES) initiative was established in 2015 to explore the current status and gaps in the ethical and legal frameworks, knowledge among various stakeholders, and to establish capacity for addressing ELSI of biobanking and genomics as applied in biomedical and population research, and healthcare. A multi-methods approach was applied including document reviews, focus group discussions and in-depth interviews among health and research professionals, and community members in six provinces comprising urban, peri-urban and rural areas. Emerging findings indicates a need for updating guidelines and policies for addressing ELSI in biobanking and genomics research in Zimbabwe. Emerging terminologies such as biobanking and genomics lack clarity suggesting a need for increased awareness and educational tools for health professionals, research scientists and community members. Common concerns relating to consent processes, sample and data use and sharing, particularly where there is trans-national flow of biospecimens and data, call for nationally tailored ELSI frameworks aligned to regional and international initiatives. This paper describes the strategy undertaken for the development and implementation of the GILES project and discusses the importance of such an initiative for characterisation of ELSI of human biobanking and genomics in Zimbabwe and Africa. Conducting this explorative study among a wide range of stakeholders over a countrywide geographical regions, established one of the most comprehensive studies for ELSI of human biobanking and genomics in Africa.

The growing need for biobanks in health research presents an opportunity for building capacity in developing countries. In Zimbabwe, there is limited knowledge and awareness about biobanking. As such we report the proceedings of a biobanking course, which included research scientists, healthcare professionals, and regulatory authorities as a start to developing a framework for biobanking practice. The aim was to educate stakeholders about biobanking and to understand the current and future regulatory and infrastructure requirements for biobanking. Using an inclusive stakeholder approach, we sought to articulate the strengths, weaknesses, opportunities, and threats. This report highlights a practical method to providing basic education to stakeholders, building awareness and consensus about building capacity for biobanking in a developing country.

Aims: To investigate the prevalence of p53 codon 72 polymorphism in Zimbabwean women and risk of cervical cancer Study Design: Case-control study Place and Duration of Study: Parirenyatwa Referral Hospital in Harare in between January and December 2014. Methodology: Genomic DNA from cervical cancer patients and women without cancer was extracted from whole blood and genotyping of the p53 codon 72 polymorphism was performed using the polymerase chain reaction followed by restriction fragment length polymorphism method. Results: The frequencies of the Arg/Arg; Arg/Pro and Pro/Pro genotypes in cervical cancer patients Short Research Article Kouamou et al.; IJTDH, 15(3): 1-6, 2016; Article no.IJTDH.24676 2 were reported as 15.07%, 43.84% and 41.10% respectively. An unconditional logistic regression model was used to calculate odds ratios (ORs) with a corresponding 95% confidence interval [95%CI] as measure of risk and association between the p53 polymorphism and the development of cervical cancer. The p53 Arg/Arg was found to be at increased risk for the development of cervical cancer (OR= 1.78). However its association with the development of cervical cancer was not statistically significant (p-value= 0.29; 95% CI, 0.54-6.12). Conclusion: The prevalence of the Arg/Arg genotype in our study was low in women with cervical cancer. The genotype was poorly associated with the disease.

Research practices should be ethical and transparent, prioritising patient benefits and provision of health carehealthcare, and respecting participant autonomy.Priority should be given to research studies with the potential for immediate translated patient benefits based on realistic interventions appropriate to an African context. Institutional Ethics Review Boards should be supported to ensure high-quality, rapid review of research proposals. Informed consent models should reflect research risk level and the heightened vulnerability of the study population during a health crisis. Consideration should be made for patients who are too ill to give consent, and inclusion of data from deceased patients. Participant information must be accessible and relevant to participants, in local languages, and include clear, realistic descriptions of potential benefits and risks. Community engagement using appropriate media channels can be effective in providing information and counter dissemination of false information. Funders and journal editors can provide additional checks and balances to ensure funded and published research from Africa is ethical, patient-centric, relevant and transparent.

Human papillomavirus (HPV) is an essential but not a sufficient cervical cancer etiological factor. Cancer promoters, such as host genetic mutations, significantly modulate therapeutic responses and susceptibility. In cervical cancer, of interest have been viral clearing genes and HPV oncoprotein targets, for which conflicting data have been reported among different populations. This expert analysis evaluates cervical cancer genetic susceptibility biomarkers studied in African populations. Notably, the past decade has seen Africa as a hotbed of biomarker and precision medicine innovations, thus potentially informing worldwide biomarker development strategies. We conducted a critical literature search in PubMed/MEDLINE, Google Scholar, and Scopus databases for case-control studies reporting on cervical cancer genetic polymorphisms among Africans. We found that seven African countries conducted cervical cancer molecular epidemiology studies in one of Casp8, p53, CCR2, FASL, HLA, IL10, TGF-beta, and TNF-alpha genes. This analysis reveals a remarkable gap in cervical cancer molecular epidemiology among Africans, whereas cervical cancer continues to disproportionately have an impact on African populations. Genome-wide association, whole exome- and whole-genome sequencing studies confirmed the contribution of candidate genes in cervical cancer. With such advances and omics technologies, the role of genetic susceptibility biomarkers can be exploited to develop novel interventions to improve current screening, diagnostic and prognostic methods worldwide. Exploring these genetic variations is crucial because African populations are genetically diverse and some variants or their combined effects are yet to be discovered and translated into tangible clinical applications. Thus, translational medicine and flourishing system sciences in Africa warrant further emphasis in the coming decade.

Information related to knowledge, attitudes, and practices of people with diabetes is especially important in resource-limited settings such as Zimbabwe, where medications to treat diabetes are costly and capacity to treat complications is limited, making observance of appropriate self-care practices that may delay or prevent complications vital to patient and public health. As a start to understanding the level of knowledge of diabetes eye complications, attitudes towards self-care practices, and utilization of available health care resources among diabetes patients, we conducted face-to-face interviews with 189 diabetes patients (133 female, 56 male, mean age 62.7 years) attending a referral hospital in Zimbabwe’s second largest city. A structured questionnaire was administered to each patient to document knowledge, attitudes, and practices that had 13, 11, and 12 questions in each section respectively. Knowledge results revealed the total knowledge score of diabetes and associated eye complications is associated with patients' self-report of seeing clearly or not, indicating patients not seeing all the time have a higher score then patients self-reporting they do see clearly all the time, x2=24.5815, df=11, p=0.0105. Attitude results revealed 74% of participants viewed consulting a pharmacist as a very important health care step compared to 96% who viewed consulting a physician as a very important health care step. Results indicating patients with diabetes who see clearly have less knowledge about diabetes and related eye complications suggests that reinforcing self-care steps should be directed towards this group. At the same time, patient attitude results suggest this gap could be filled by emphasizing the role of pharmacists in fostering good diabetes self-care practices and providing education for individuals with diabetes, especially early in the course of disease before vision impairment may occur. Disclosure M. Sithole: None. A. Matimba: None. R. Woodward: None.

International audience; Genomics is the study of the genetic material that constitutes the genomes of organisms. This genetic material can be sequenced and it provides a powerful tool for the study of human, plant and animal evolutionary history and diseases. Genomics research is becoming increasingly commonplace due to significant advances in and reducing costs of technologies such as sequencing. This has led to new challenges including increasing cost and complexity of data. There is, therefore, an increasing need for computing infrastructure and skills to manage, store, analyze and interpret the data. In addition, there is a significant cost associated with recruitment of participants and collection and processing of biological samples, particularly for large human genetics studies on specific diseases. As a result, researchers are often reluctant to share the data due to the effort and associated cost. In Africa, where researchers are most commonly at the study recruitment, determination of phenotypes and collection of biological samples end of the genomic research spectrum, rather than the generation of genomic data, data sharing without adequate safeguards for the interests of the primary data generators is a concern. There are substantial ethical considerations in the sharing of human genomics data. The broad consent for data sharing preferred by genomics researchers and funders does not necessarily align with the expectations of researchers, research participants, legal authorities and bioethicists. In Africa, this is complicated by concerns about comprehension of genomics research studies, quality of research ethics reviews and understanding of the implications of broad consent, secondary analyses of shared data, return of results and incidental findings. Additional challenges with genomics research in Africa include the inability to transfer, store, process and analyze large-scale genomics data on the continent, because this requires highly specialized skills and expensive computing infrastructure which are often unavailable. Recently initiatives such as H3Africa and H3ABioNet which aim to build capacity for large-scale genomics projects in Africa have emerged. Here we describe such initiatives, including the challenges faced in the generation, analysis and sharing of genomic data and how these challenges are being overcome.

The potential of pharmacogenomics (PGx) to positively impact health outcomes and quality of healthcare is well-established. However, the application of available evidence into clinical practice is still limited due to limited knowledge among healthcare professionals, including pharmacists. As a start towards building capacity for PGx education, we assessed knowledge, attitudes, and perceptions about PGx among practising pharmacists and pharmacy students. A cross-sectional study was conducted among pharmacists and undergraduate pharmacy students selected using a convenient sampling method—a 37-question survey instrument was used to obtain information regarding PGx among the participants. Out of a total of 131 participants, 56% of respondents showed fair-to-good PGx knowledge. Respondents’ self-reported assessment indicated that 88% had average and above knowledge scores in PGx. Practising pharmacists in Zimbabwe have positive attitudes towards PGx and would support its application to improve treatments. However, there were concerns about security and discrimination when genomics data is used by those who do not understand its meaning. Participants agreed that they would play a leading role in PGx testing if provided with appropriate training. The interest in PGx is challenged by their limited knowledge and understanding of genetics, suggesting a need to update curricula for pharmacy students and for continuing health education programmes.

Introduction Despite the wide-spread availability of cervical cancer prevention and screening programs in developed countries, the morbidity and mortality rates of cervical cancer in Zimbabwe are still very high. Limited resources as well as the high HIV prevalence are contributors to the high burden of cervical cancer. This paper aims to analyse the policies, frameworks and current practices in the management of cervical cancer in Zimbabwe. Methods A review of national documents and published literature on cervical cancer prevention, screening, treatment and knowledge in Zimbabwe was done. Informal interviews were conducted to assess the practices of cervical cancer management. Results Through strategic collaboration, a pilot for the HPV vaccination program is underway. The VIAC national cervical cancer screening program is being adopted into the current healthcare system. With regards to the treatment of precancerous lesions we found that the "see and treat" program has been implemented in colposcopy clinics. In addition, there are two multidisciplinary cancer treatment clinics installed in two central public hospitals. The general knowledge and understanding of cervical cancer is poor in Zimbabwe. Conclusion Limitations in resources, infrastructure, manpower, delays in treatment and patient knowledge play a role in the high morbidity and mortality of cervical cancer in Zimbabwe. The Ministry of Health needs to increase funding to expedite the availability of HPV vaccine and screening programs. Community engagement initiatives to raise awareness on cervical cancer should be established to provide education on how to prevent the development of cervical cancer, as well as promote screening for early detection.

Background.The burden of communicable and non-communicable diseases in Sub-Saharan Africa poses a challenge in achieving quality healthcare. Although therapeutic drugs have generally improved health, their efficacy differs from individual to individual. Variability in treatment response is mainly because of genetic variants that affect the pharmacokinetics and pharmacodynamics of drugs.Method.The intersection of disease burden and therapeutic intervention is reviewed, and the status of pharmacogenomics knowledge in African populations is explored.Results.The most commonly studied variants with pharmacogenomics relevance are discussed, especially in genes coding for enzymes that affect the response to drugs used for HIV, malaria, sickle cell disease and cardiovascular diseases.Conclusions.The genetically diverse African population is likely to benefit from a pharmacogenomics-based healthcare approach, especially with respect to reduction of drug side effects, and separation of responders and non-responders leading to optimized drug choices and doses for each patient.

A report on the Second H3Africa Ethics Consultation Meeting, which was held in Livingstone, Zambia on 11 May 2015. The meeting demonstrated considerable evolution by African Research Ethics Committees on thinking about broad consent as a consent option for genomics research and biobanking. The meeting concluded with a call for broader engagement with policy makers across the continent in order to help these recognise the need for guidance and regulation where these do not exist and to explore harmonisation where appropriate and possible.

Pharmacogenomics has the potential of transforming clinical research and improving healthcare in sub-Saharan Africa (SSA). The role of African genome diversity and the opportunities for pharmacogenomics research are highlighted and will enable discovery of novel genetic mechanisms and validation of established markers. African genomics and biobank consortia will play an important role in building capacity for pharmacogenomics in SSA.

Objective Responses to therapies, either with regard to toxicities or efficacy, are expected to involve complex relationships of gene products within the same molecular pathway or functional gene set. Therefore, pathways or gene sets, as opposed to single genes, may better reflect the true underlying biology and may be more appropriate units for analysis of pharmacogenomic studies. Application of such methods to pharmacogenomic studies may enable the detection of more subtle effects of multiple genes in the same pathway that may be missed by assessing each gene individually. Methods A gene set analysis of 3821 gene sets is presented assessing the association between basal messenger RNA expression and drug cytotoxicity using ethnically defined human lymphoblastoid cell lines for two classes of drugs: pyrimidines [gemcitabine (dFdC) and arabinoside] and purines [6-thioguanine and 6-mercaptopurine]. Results The gene set nucleoside-diphosphatase activity was found to be significantly associated with both dFdC and arabinoside, whereas gene set γ-aminobutyric acid catabolic process was associated with dFdC and 6-thioguanine. These gene sets were significantly associated with the phenotype even after adjusting for multiple testing. In addition, five associated gene sets were found in common between the pyrimidines and two gene sets for the purines (3',5'-cyclic-AMP phosphodiesterase activity and γ-aminobutyric acid catabolic process) with a P value of less than 0.0001. Functional validation was attempted with four genes each in gene sets for thiopurine and pyrimidine antimetabolites. All four genes selected from the pyrimidine gene sets (PSME3, CANT1, ENTPD6, ADRM1) were validated, but only one (PDE4D) was validated for the thiopurine gene sets. Conclusion In summary, results from the gene set analysis of pyrimidine and purine therapies, used often in the treatment of various cancers, provide novel insight into the relationship between genomic variation and drug response.

Thiopurine drugs such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat acute lymphoblastic leukemia of childhood. To test the hypothesis that variation in the expression of genes within the “thiopurine pathway” might influence 6-MP and 6-TG sensitivity, we generated basal gene expression profiles and IC50 values for both of these thiopurine drugs using a model system consisting of 194 Human Variation Panel lymphoblastoid cell lines. Association analysis showed that thiopurine S-methyltransferase, ecto-5′-nucleotidase (NT5E), and multidrug resistance protein 4 (ABCC4) expression were correlated with thiopurine cytotoxicity. Those observations suggested the possible existence of a “thiopurine cellular circulation” involving nucleotide efflux by ABCC4, hydrolysis of thiopurine nucleotide monophosphates outside of the cell by NT5E, and subsequent transport of thiopurine nucleosides back into the cell by nucleoside transporters. The existence of this cellular circulation was confirmed by a series of functional experiments performed with cultured cells stably or transiently transfected with ABCC4 and/or NT5E. Because of the central role of NT5E in this cellular circulation, the NT5E gene was resequenced using 287 DNA samples from three ethnic groups, with the identification of 68 single nucleotide polymorphisms (SNPs), 46 of which were novel. Several SNPs in the 5′-flanking region of NT5E were highly correlated with expression, rs9450278 having the lowest p value (p = 2.4 × 10−10, R = −0.376). The thiopurine cellular circulation and genetic polymorphisms for genes encoding the proteins involved should be incorporated into future studies of thiopurine drug therapy and effect.

Africa is the ultimate source of modern humans and as such harbors more genetic variation than any other continent. For this reason, studies of the patterns of genetic variation in African populations are crucial to understanding how genes affect phenotypic variation, including disease predisposition. In addition, the patterns of extant genetic variation in Africa are important for understanding how genetic variation affects infectious diseases that are a major problem in Africa, such as malaria, tuberculosis, schistosomiasis, and HIV/AIDS. Therefore, elucidating the role that genetic susceptibility to infectious diseases plays is critical to improving the health of people in Africa. It is also of note that recent and ongoing social and cultural changes in sub-Saharan Africa have increased the prevalence of non-communicable diseases that will also require genetic analyses to improve disease prevention and treatment. In this review we give special attention to many of the past and ongoing studies, emphasizing those in Sub-Saharan Africans that address the role of genetic variation in human disease.

Tele-ophthalmology using portable retinal imaging technology, mobile phone and Internet connectivity offers a solution to improve access to diabetic retinopathy (DR) screening services in sub-Saharan African (SSA) countries where the burden of diabetes is increasing and there is limited access to eye care services and specialists. The Zimbabwe Retinopathy Telemedicine Project (ZRTP) established routine DR screening at a hospital-based diabetic clinic in the urban capital city, Harare. A handheld ‘point and shoot’ digital camera operated by a trained nurse was used to acquire retina images of 203 diabetic patients. A secured ‘store-and forward’ approach was set up and used for sharing and transfer of images to a retinal specialist at a remote site for reading. This method enabled detection of non-macular DR (11%), diabetic macular oedema (5%), cataract (5%) and glaucoma (6%) among the patients screened. ZRTP demonstrated the utility of tele-ophthalmology for routine retinal screening for diabetic patients in Zimbabwe who have limited access to eye care services. In addition, ZRTP showed how tele-ophthalmology services can provide an empirical framework for providing patient education, and a platform for research in the detection of DR. This approach could be used as a model to address the DR challenges in other countries in SSA.

Aim: We investigated candidate genes associated with thiopurine metabolism and clinical response in childhood acute lymphoblastic leukemia. Materials & methods: We performed genome-wide SNP association studies of 6-thioguanine and 6-mercaptopurine cytotoxicity using lymphoblastoid cell lines. We then genotyped the top SNPs associated with lymphoblastoid cell line cytotoxicity, together with tagSNPs for genes in the ‘thiopurine pathway’ (686 total SNPs), in DNA from 589 Caucasian UK ALL97 patients. Functional validation studies were performed by siRNA knockdown in cancer cell lines. Results: SNPs in the thiopurine pathway genes ABCC4, ABCC5, IMPDH1, ITPA, SLC28A3 and XDH, and SNPs located within or near ATP6AP2, FRMD4B, GNG2, KCNMA1 and NME1, were associated with clinical response and measures of thiopurine metabolism. Functional validation showed shifts in cytotoxicity for these genes. Conclusion: The clinical response to thiopurines may be regulated by variation in known thiopurine pathway genes and additional novel genes outside of the thiopurine pathway. Original submitted 31 July 2013; Revision submitted 4 November 2013

The developed world has made significant advances in translating pharmacogenetics/genomics research into medical solutions that aim to personalize treatment that is based on a patients’ genetic status. Africa, on the other hand, has lagged behind in these advances, but recent developments are showing great potential for pharmacogenomics research and clinical applications on the continent. The genetic variability of African populations is proving an invaluable tool for understanding susceptibility and/or resistance to infectious diseases or noncommunicable diseases and the search for biomarkers for drug safety and efficacy. Studies on the polymorphism of genes that code for drug-metabolizing enzymes (CYP2B6, 2C9, 2C19, 2D6, FMO, NAT2, GSTT and GSTM) in nine major African ethnic groups (Yoruba, Ibo, Hausa, Kikuyu, Masaai, San, Luo, Venda, and Shona) showed genetic clustering of these populations distinct from that of Asian and of Caucasian populations. Clinical studies on the effect of the CYP2B6G516T variant on efavirenz concentrations were predictive of a dose reduction to a third of the standard dose in patient homozygous of the variant. This could have significant effects on the safe and efficacious use of this drug in Africa where 20% of the people are homozygous for this variant compared to about 5% in Caucasian and Oriental populations. We also found that CYP2C9 variants associated with dose optimization of warfarin in Caucasians are very rare in African populations. This has implication on the utility of commercial genetic diagnostic kits in use in Europe, which might not be applicable in African populations. Molecular evolution studies on the nine major ethnic groups and in comparison with data on Caucasian and Oriental populations using the Illumina chip with 600 K SNPs confirmed the genetic diversity of African populations and their distinct difference from other non-African populations. Though only a few genome-wide association studies (GWAS) have been done on common infectious diseases in Africa (malaria, TB, and HIV), interest in the scientific community to conduct such studies on noncommunicable disease in Africa will provide the scientific and technological impetus for genomic medicine research in Africa.

Aims: To investigate intra- and inter-ethnic differences in three widespread (E158K, V257M and E308G) and two African-specific (D132H and L360P) flavin-containing monooxygenase 3 (FMO3) polymorphisms. Materials & methods: Allele frequencies were determined by TaqMan® allelic discrimination assay in 2152 healthy volunteers from Europe (Swedes, Italians and Turks), East Asia (Japanese) and sub-Saharan Africa (nine ethnic groups covering eastern, southern and western regions), followed by haplotype and linkage analysis. Results: Significant subpopulation differences (p < 0.001) in allele frequencies were found for E158K, V257M and E308G in Europeans and regional differences (p < 0.01) for D132H among Africans. No carrier of P360 was identified. Cis-linkage between G308 and K158 was confirmed with the compound variant (K158/G308) being found in a high proportion (12.0–38.3%) of non-African subjects, but rarely (1.3%) among Africans. Conclusions: Distribution of functionally relevant FMO3 polymorphisms varies not only between ethnicities but also within. The K158/G308 variant may have potential clinical importance primarily in non-African populations due to its low prevalence in Africa.

We have used maximum-likelihood models of codon substitution to investigate the role of adaptive evolution in the evolution of cytochrome P450 (CYP) sequences. Evidence for the operation of adaptive evolution in the evolution of rat CYP2C, rabbit CYP2C, rat CYP2D, human CYP3A and rabbit CYP4A was observed. The absence of signal in rat CYP2B, rat CYP3A, human CYP2C and monkey CYP2C suggests that the adaptive evolution did not operate in the evolution of these cytochromes. Our results show identical adaptive evolution patterns for rabbit (lagomorpha) and rat (rodentia) CYP2C. The absence of signal for adaptive evolution in primate CYP2C suggests that the identical rat and rabbit CYP2C patterns arose in the last common ancestor of rodentia and lagomorpha. Furthermore, we have found statistically significant association of sites under adaptive evolution and Gotoh's substrate recognition sites in rat and rabbit CYP2C (5%), human CYP3A and rat CYP2D (10%). From these correlations, the given substrate-dependent nature of differences in CYP substrate-specificity profiles and differences in cytochrome active-site residues, we hypothesize that the most likely role of adaptive evolution in the evolution of cytochrome P450 substrate specificities was to fix mutations that permitted an increased number of binding modes (thereby expanding the substrate repertoire). The pattern of adaptive evolution observed in this work is consistent with results from microsomal studies in which CYP2C isoforms are responsible for most of the metabolism of foreign compounds in rat and rabbit, and CYP3A isoforms play the same role in humans.

Pharmacogenetics and genomics research has experienced great advances over the past decade as witnessed by the completion of the human genome in 2003 (www.genome.gov/HGP). The field has been driven by the belief that understanding the human genome, that of pathogens, and interindividual genetic variability would result in radical advances in medicine. Anticipated measurable end points include increased targets for which drug discovery campaigns could be initiated, increased understanding of human susceptibility to disease and variability in drug response hence development of diagnostic tools to realize individualized treatment where drugs would be given to patients in whom they are predicted to work and at doses predicted to be safe.1 Toward the realization of this biomedical paradigm, Biobanking and Pharmacogenetics Databasing have become well established in developed countries (www.biobanks.se, www.icelandbio.com, www.ukbiobank.ac.uk). Little has, however, been done in developing countries.2 Starting with a workshop organized by the African Institute of Biomedical Science and Technology (www.aibst.com) in 2003 on Pharmacogenetics of Drug Metabolism in Nairobi, Kenya, a number of African scientists initiated a consortium for the biobanking and pharmacogenetics databasing of African populations. We here report the results of the first phase of this initiative that has seen research groups from five different African countries with collaborative support from leading experts in Europe and America establish a biobank of blood and DNA from nine ethnic groups from across the African continent. The biobank of anonymous samples has been used to establish baseline frequency distribution of SNPs of genes important in drug metabolism, hence the initiation of a pharmacogenetics database (http://www.aibst.com/biobank.html).