Pharmacogenomics
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6 Rajman, I, Knapp, L, Morgan, T and Masimirembwa, C (2017). Implications of African allele frequency variation in CYP450 genes for drug safety, efficacy and the future of drug development. EBioMedicine. ISSN 2352-3964 (Volume 17, March 2017, Pages 67-74).
http://www.sciencedirect.com/ science/article/pii/S235239641 7300762. 7 He, Z, Chen, X, Yang, Y and Zhou, S (July 2016). A Comparison of Non-Human Primate Cytochrome P450 2D Members and the Implication in Drug Discovery. Current Drug Metabolism. Volume 17, Number 6, July 2016, pp. 520-527(8).
http://www.ingentaconnect.co m/contentone/ben/cdm/2016/0 0000017/00000006/art00003. 8 Pan, S, Xue, D, Li, Z, Zhou, Z et al (2016). Computational Identification of the Paralogs and Orthologs of Human Cytochrome P450 Superfamily and the Implication in Drug Discovery. Int. J. Mol. Sci. 2016, 17(7), 1020; doi:10.3390/ijms17071020.
http://www.mdpi.com/ 1422-0067/17/7/1020/htm.
problem to solve, particularly as the results of more public genome projects and population stud- ies become available and as institutions find new ways to share samples. Future efforts will focus on characterising CYP2D6 variation among popula- tions that have been under-represented in studies so far.
Of course, once the catalogue of CYP2D6 alleles is complete, it will take many studies to detail the phe- notypic effect of each possible variant. This will not be easy, but having associated enzyme activity phe- notypes with known alleles in the past, at least we are familiar with the methods required for this task. Another important step will be determining how closely the natural CYP2D6 variation in humans is mirrored by animal models used for evaluating new compounds. Several investigations have already compared the human gene to its ortholog in other species. Last year, a team of scientists reviewed analyses of CYP2D genes in non-human primates7. They found material differences in how various species metabolised certain drugs, which may be reflective of divergent gene sequences. “Further studies are warranted to elucidate the structural and functional features of CYP2D mem- bers in non-human primates and thus offer a solid base for the application of these animals in drug discovery,” the scientists recommended in the paper. In a separate publication, scientists used computational analysis to identify and interrogate genes related to the cytochrome P450 family in
organisms ranging from plants to fish to mammals 8. They found a high level of conservation for most of the genes, suggesting in their report that an improved understanding “of the evolutionary rela- tionships and functional implications of the human CYP superfamily” would be helpful for drug discovery.
A longstanding challenge in pharmacogenomics has been the lack of consistent results across stud- ies, leading some in the field to question the clinical utility of trying to associate traits such as CYP2D6 genotype with drug selection or dosing. However, it is quite possible that these studies have not been as robust as expected; after all, if 20% of partici- pants had their CYP2D6 genotype misclassified – as the Mount Sinai work suggests is likely – that could explain why results were inconsistent. Future studies and clinical trials might produce more reli- able and clinically meaningful results by incorpo- rating SMRT sequencing for a high-resolution view of the CYP2D6 locus in participants. This has major implications for success rates in matching the safest and most effective drug, at the right dose, to the right person.
DDW 28 Drug Discovery World Summer 2017
Dr Jenny Ekholm is a Senior Scientist specialising in human biomedical applications at PacBio. She has more than 10 years’ experience in human genetics, applied techniques, statistical analysis and laboratory management. She earned her PhD in human/medical genetics at the University of Helsinki and completed a postdoctoral fellowship at UCLA.
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