Featured project: Exploring Statin Pleiotropic Effects within a Very Large EHR Cohort
Statins (HMG-CoA reductase inhibitors), among the most widely prescribed agents worldwide for prevention of cardiovascular diseases, produce substantial pleiotropic effects. Pleiotropic effects are unanticipated outcomes other than those for which the drug was originally developed, either therapeutic (beneficial) or detrimental (adverse drug reactions). Statin pleiotropic effects are unanticipatedly broad, including increasing the risk of developing type 2 diabetes mellitus (T2DM), decreasing cancer-related mortality, and reducing dementia. Many effects are still not determined. In addition, individual responses to statins are highly variable. In this project, we investigate statin pleiotropic effects using whole de-identified electronic health records (EHRs) of >2.5 million patients at Vanderbilt, including >100,000 statin recipients. We will evaluate genetic predictors of statin pleiotropic effects as well.
Collen Masimirembwa is a pioneer of pharmacogenetics research in Africa and continues to champion its development to clinical applications. He conducted the first molecular genetic studies in African populations in the early 90s leading to the discovery of the African specific CYP2D6 genetic variant, CYP2D6*17. Over the past 25 years he has endeavored to integrated pharmacogenetics in the drug discovery and development value chain with a particular interest in understanding the genomic diversity of African populations and its implications for drug safety and efficacy. He has published over 90 original papers on the metabolism & pharmacokinetics of antiparasitic drugs and on the population genetic polymorphism of ADME genes in Africa. This has allowed him to combine pharmacokinetics modeling & simulation and molecular structural & functional studies of genetic variation of ADME to bridge basic genetic polymorphism research to clinical applications. This research has led to the award-winning pharmacogenetics test and dosing algorithm for the safe use of the antiretroviral drug, efavirenz (EFV). The product, GeneDoseÒ-EFV is now under commercial development.
To build capacity for pharmacogenomics research in Africa Collen has used his institute and extensive international network of collaborators to train Masters and PhD students in Africa, who are, in their various settings conducting basic and translational pharmacogenetics research. This has culminated in an EDCTP (European and Developing Countries Clinical Trial Partnership) training grant to initiate a 2-year Master’s degree in Genomic Medicine and Molecular Diagnostics, whose first intake will be in January 2019. Towards this, Collen is appealing for support from the international pharmacogenetics community to assist with mentorship and opportunities for research project attachment for students of this MSc program through AiBST’s Virtual Global Faculty program (contact him at email@example.com).
The Huang laboratory’s main research focus is translational pharmacogenomics with particular interest in the pharmacogenomics of anti-cancer agents. By systematically evaluating human genome and its relationships to drug response and toxicity, our goal is to develop clinically useful models that predict risks for adverse drug reactions and non-response prior to administration of chemotherapy. With her broad training background, Dr. Huang assembles and leads a multi-disciplinary team that consists of computational biologist, geneticist, physician, molecular biologist and biostatistician to tackle a series of serious problems in cancer research. These include the lack of mechanistic understanding of genomic regulation of cancer phenotypes; the lack of reproducible predictive biomarkers for cancer therapeutic agents; and the lack of effective treatment for many hard to treat cancers.
Bridging pre-clinical drug screening with patient genomic profiles in order to accurately predict patient response to therapy.
By leveraging new data and improved methods, the Huang lab has shown that gene expression based models derived from very large panels of cancer cell lines could directly inform clinical response to drugs. Furthermore, using an HDAC inhibitor as an example, they elucidated the polygenic architecture of drug response by comparing and contrasting the predicted power derived from a single gene, a pathway, or all genes in the genome. In this case, they clearly demonstrated the superior power of prediction when applying a machine learning method in deriving polygenic predictors of drug response. More recently, they described a novel statistical approach that improves the success rate of biomarker discovery by conditioning on shared drug sensitivity features among many drugs. Their work showed that despite a controversial history, drug screening in large panels of cell lines is more useful than was previously appreciated. Recently, they integrated data from large clinical cancer studies (e.g. The Cancer Genome Atlas (TCGA)) with data from pre-clinical disease models to impute drug sensitivity in patient data sets. These newly imputed drug sensitivity phenotypes enable large sequencing studies such as TCGA to be effectively used for pharmacogenomics discovery, which has previously been a severe limitation of these data.
He has made significant contributions to the field of pharmacogenomics including the identification of a gene that is involved in cardiomyopathy and congestive heart failure after cancer treatment (Aminkeng F et al, Nature Genetics. 2015 Sep; 47(9):1079-84.). He is the recipient of a number of fellowships including the Canadian Institutes of Health Research, Michael Smith Foundation for Health Research and the British Columbia Children Hospital Research Institute Bertram Hoffmeister Postdoctoral Fellowships. He has also been recognized for a distinguish academic and scientific career through a number of career awards including the Canadian Society of Pharmacology and Therapeutics Boehringer Ingelheim Postdoctoral Award in Pharmacology, the British Columbia Children Hospital Research Institute award for outstanding achievement by a postdoctoral fellow, the Golden Helix Top Prize and the Canadian Society of Pharmacology and Therapeutics Publication Award. He currently serves on the Editorial Board of the Journal of Population Therapeutics and Clinical Pharmacology and is a member of the Canadian Society of Pharmacology and Therapeutics Scientific Program Committee.
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