br Discussion Our study provides a comprehensive review

Discussion Our study provides a comprehensive review and statistical analysis of CYP frequency data in global populations including Africa. We have demonstrated that genetic variation is greater in African populations than in Asian and Caucasian populations, and therefore that Africa cannot be treated as a single entity in drug research and development. PCA identified allelic variants showing a marked difference in distribution in African populations which may be of clinical significance and are discussed below. Moreover, our literature review identified reports of polymorphisms in CYP genes that have not been described in populations outside of Africa.
Conclusions In summary, our review of the published literature on CYP polymorphisms has clearly demonstrated and confirmed that genetic variation is greater in African populations than in Asian and Caucasian populations. The African continent cannot, therefore, be treated as a single entity in drug research and development, nor can African-American populations be considered an adequate proxy for pharmacogenetic differences across Africa. By use of PCA, we identified allelic variants showing a marked difference in distribution in African populations; however, more research is required to confirm these distributions and to identify populations at a potentially greater risk of drug-induced adverse events or drug inefficacy. We also identified CYP pgi2 that may be unique to Africa or for which data in African populations are limited, and regions where further data need to be collected. Here, we focused on CYP alleles, but it is likely that polymorphisms in other enzymes and transporters contribute to the diversity in drug response observed in Africa. Furthermore, the potential effect of genetic variability on drug pharmacodynamics, and the subsequent effect on drug responses in Africa, were not addressed in this study. There are also challenges in translating research findings from the laboratory to the clinical environment. The involvement of clinicians in genomic research will facilitate this translation process, helping to ensure that patients are treated with efficacious doses of therapeutic drugs. The involvement of groups such as H3Africa, AGVP and the proposed consortium of pharmaceutical companies could help to implement these changes, with an aim of reducing the burden of disease and adverse drug reactions in Africa.
Funding Funding for this review was provided by Novartis Pharma AG for the study design, literature searches, data collection, data analysis, data interpretation and editorial assistance for the development of the manuscript.
Conflicts of Interest
Author Contributions
Acknowledgments
Introduction Mitochondrial (mt) disorders represent an expanding group of diseases characterized by wide variability in clinical presentation and course (Turnbull and Rustin, 2015). Our understanding of these pathologies remains limited despite the elucidation of a huge number of the underlying gene defects. With a few exceptions (e.g. primary CoQ10 deficiency), no therapy can currently be offered to the patients and hardly any clinical trial has led to reliable and convincing conclusions (Koopman et al., 2016). This depends in part from the difficulty to collect sufficiently large cohorts of patients with a homogeneous genetic defect and similar clinical presentation. In complete flower context, the use of animal models may provide a clue for identifying and testing therapies. However, in spite of extensive studies particularly on murine models, very few candidate drugs have shown some positive effects in subsequent human trials (Hackam and Redelmeier, 2006). A number of reasons have been advocated to account for this failure, and one of them may be disparity of clinical phenotypes between humans and mice (Rice, 2012). In addition, the extreme variability in clinical presentation and course is observed even within the same family, which suggests a relevant, albeit still unclear, role of additional genetic, epigenetic and environmental factors in the natural history of these conditions (Jain et al., 2016). Accordingly, the genetic background should be taken into account in modelling specific mt diseases (Benit et al., 2010 #4255). For instance, studies on mouse models are usually carried out on highly selected, inbred, isogenic individuals. This may be useful in the elucidation of disease mechanism or in investigating the function of a disease gene, but is inadequate to test drug efficacy in a clinically relevant (and hence heterogeneous) setting. In addition to these genetic considerations, the nursing conditions, such as cage constraint, reduced exercise, idleness, and ad libitum feeding, and the improper conception and execution of some studies (Couzin-Frankel, 2013), all concur to explain why so many murine models fail to yield convincing results in pre-clinical studies.