Figure 1. Human lymphoblastoid cells selected based on the SNP genotypes as indicated in the labels show different response to anastrozole treatment. Cells were treated with indicated anastrozole concentrations and MTS assays were performed to determine the cell survival.
Figure 2. In anastrozole resistant ER+ cell line, addition of E2 could sensitize cells to anastrozole in a dose dependent fashion.
The Perera laboratory focuses on pharmacogenomics (using a patient's genome to predict drug response) in minority populations. Working in this translation research space requires both clinical expertise as well as the use of high-throughput basic science approaches. Our goal is to bring the benefits of precision medicine to all US populations.
The Perera lab recruited patient populations from around the world. The data collection includes genomic (DNA), transcriptomic (mRNA), pharmacokinetic and clinical data. We then integrate these different data sources to understand genetic drivers of drug response (e.g. genetic predictors of adverse events) as well as disease. By studying minority populations the lab has discovered genetic risk variants that may benefit the implementation of precision medicine in African Americans and others.
ACCOuNT (African American Cardiovascular pharmacogenomics CONsorTium)
AA: African American, Dashed arrow show potential synergies, while solid arrows show planned interactions.
Debbie Nickerson is a professor of Genome Sciences at the University of Washington School of Medicine, Seattle, Washington, and runs the Northwest Genomics Center in Seattle. In collaboration with researchers accorss the country, the NHLBI Large-Scale DNA Sequencing Project, mines genetic data gathered from the NHLBI-funded population studies of heart, lung, and blood diseases. The Nickerson Lab is interested in the identification and typing of common sequence variations in the human genome known as single nucleotide polymorphisms (SNPs). By identifying SNPs they hope to gain an understanding of the patterns of sequence variation in human genome and to improve approaches for association mapping of common human diseases. They are also developing and testing novel SNP and haplotype-based approaches for association mapping in humans, and exploring the relationships that may exist between genotype and trait expression at the RNA and protein levels in humans.
NHLBI GO Exome Sequencing Project (ESP)
Our October featured Investigator, Debbie Nickerson, along with Phil Green, Jay Shendure, are the three PIs heading the SeattleGO group in the NHLBI GO ESP. The other groups participating and collaborating are:
- Broad GO - Broad Institute of MIT and Harvard, Cambridge, MA
- WHISP GO - Ohio State University Medical Center, Columbus, OH
- Lung GO - University of Washington, Seattle, WA
- WashU GO - Washington University, St. Louis, MO
- Heart GO - University of Virginia Health System, Charlottesville, VA
- ChargeS GO - University of Texas Health Sciences Center at Houston
Associate Professor of Pharmacogenetics and Clinical Pharmacist at the Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center
Jesse Swen, PharmD, PhD is an associate professor of pharmacogenetics and clinical pharmacist at the Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center. He is a staff member of the laboratory section of the hospital pharmacy, with most of his time devoted to the pharmacogenetics laboratory. His research efforts are in 2 areas. First, he is interested in finding genomic biomarkers for the response to pharmacotherapy in oncology. He is particularly interested in unravelling genetic mechanisms behind the response to antiangiogenic drugs. Second, he is interested in the clinical implementation of pharmacogenomics. He is one of the primary investigators of the “Ubiquitous Pharmacogenomics” project (www.upgx.eu). This project aims to implement pharmacogenetics across 7 European sites by genotyping 8,000 patients. Dr. Swen has published multiple papers on the identification of barriers for clinical implementation of pharmacogenomics and the development of approaches to overcome them. In addition he has (co)authored pharmacogenomics guidelines and is an active member of the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium.
Dr. Monte holds appointments in the Department of Emergency Medicine, the School of Pharmacy, and the Center for Bioinformatics and Personalized Medicine at the University of Colorado . He is a founding member of the University of Colorado Pharmacogenomic Implementation Committee and has been integral in implementation of efficient electronic medical record alerts across the University of Colorado Health System. His research utilizes systems biology to integrate pharmacogenetics, metabolomics, and drug metabolizing enzyme phenotyping to improve drug effectiveness and safety. He focuses on CYP2D6 and drugs utilized for emergent conditions. Dr. Monte received the Translational Scholar Award in Pharmacogenomics and Personalized Medicine through NIGMS in addition to numerous other foundation and institutional grants for this work. He has become a leader in personalized medicine in the specialties of emergency medicine and medical toxicology.
An Integrated Approach to Personalized Medicine
Her research interests center on translational research in pharmacogenomics for personalization of pediatric analgesia. Dr.Chidambaran received the Translational Scholar Career Award in Pharmacogenomics and Personalized Medicine (NICHD) to identify and characterize genetic and phenotypic predictors of morphine induced respiratory depression in postsurgical children, as well as to study gene-gene and gene-environmental interactions affecting morphine pharmacokinetics and pharmacodynamics. She was awarded the Young Investigator Award – 1st place by the Society of Pediatric Anesthesia for two consecutive years (2010 and 2011) for her findings on ABCB1 effects on morphine induced respiratory depression and PK/PD optimization of propofol dosing in morbidly obese adolescents. She received an Outstanding Research Award (2016) from the Society of Pediatric Pain Medicine for her presentation on FAAH variant effects on morphine induced depression of hypercarbic ventilatory response in adolescents after spinal fusion. Her honors include competitive institutional grants including a “Center of Pediatric Genomics” award, and being the first pediatric anesthesiologist to receive the Safety Scientist Career Development Award from the Anesthesia Patient Safety Foundation.
Morphine pharmacogenomics to predict risk of respiratory depression in children
Experimental MIRD entails using hypercapnia (rebreathing 5% carbon dioxide) to measure baseline minute ventilation response and depression in the response after morphine dose. The first aim is to test the hypothesis that Caucasian race (genetically defined using ancestry information markers using a Genome Wide Association Study array) and female sex contribute to MIRD risk. The second aim addresses the contribution of specific genetic variants and their interactions ( ATP binding cassette ABCB1, Fatty Acid Amide Hydrolase/FAAH and Mu-opioid receptor /OPRM1) to inter-patient variability in MIRD. Analysis is done using logistic regression after population stratification using known clinical predictors like morphine doses, hyperoxemia, pain scores, co-administration of sedatives and significant variables from Aim 1 as covariates. Furthermore, this project explores associations with MIRD for variants in select genes involved in the opioid-MIRD and morphine pharmacokinetic (PK) pathway using a discordant phenotype approach to maximize identification of associations. Morphine concentration data is analyzed using non-linear modeling to evaluate genetic effects on PK/PD.
We reported association for μ1 opioid receptor OPRM1 A118G SNP and clinical respiratory depression in our population. This variant results in decreased μ-receptor binding potential in the brain and increases morphine requirement. Multivariable logistic regression showed that the risk of MIRD in patients with AA genotype was significantly higher (odds ratio 5.6, 95% CI: 1.4–37.2, P=0.030). Presence of G allele was associated with higher pain scores (effect size 0.73, P=0.045). (attached figure). We also published our findings of associations of ABCC3 variants with postoperative MIRD and morphine pharmacokinetics in children. The ATP binding Cassette gene ABCC3 which is a hepatic efflux transporter of morphine metabolites, was found to affect morphine 3 and 6 glucuronide formation clearances. This supports findings in a tonsillectomy population which is under study at our institution, where ABCC3 variant is associated with MIRD. This is the first study to report association of ABCC3 variants with opioid-related RD, and morphine metabolite formation (in two independent surgical cohorts). Moreover, we identified a region of FAAH variants in the region +/- 5kb of the FAAH gene with regulatory function, associated with depression of the hypercarbic response after morphine administration, and post-operative vomiting. Patients with clinical respiratory depression also had depressed hypercarbic responses, which indicated our genetic associations can identify subclinical respiratory depression. This manuscript is under preparation. These findings bring us closer to my goal of understanding predictors of MIRD in children, and personalization of opioid analgesia to improve opioid safety.
Michelle Whirl-Carrillo, PhD is the Associate Director of PharmGKB and Senior Research Scientist in the Department of Genetics at Stanford University. She manages the team of scientific curators and developers at PharmGKB, and works with the Director to set priorities and direction for the project. She is interested in breaking down barriers to the routine clinical use of pharmacogenomics through education and raising awareness of the field. Her work includes finding new pharmacogenomics knowledge to incorporate into PharmGKB and developing criteria to assess that knowledge, including information curated from the literature and drug labels. She worked with the CPIC (Clinical Pharmacogenetics Implementation Consortium) leadership to help develop the standards used to score evidence and weigh dosing recommendations, and has co-authored several CPIC guidelines. She has worked on a variety of projects focused on standardizing representation of pharmacogenomics information. Currently, she is working with PharmGKB, CPIC and the ClinGen PGx working group to incorporate pharmacogenomics associations into ClinVar, an NCBI resource that catalogs genomic variation affecting human health.
Associate Director of PharmGKB
PGRN Group: PharmGKB
- annotate genetic variants and gene-drug-disease relationships via literature reviews.
- summarize important pharmacogenomic genes, associations between genetic variants and drugs, and drug pathways.
- curate FDA drug labels containing pharmacogenomic information.
- enable consortia examining important questions in pharmacogenomics.
- curate and participate in writing pharmacogenomic-based drug dosing guidelines.
- contribute to clinical implementation projects for pharmacogenomics through collaborations.
- publish pharmacogenomic-based drug dosing guidelines, very important pharmacogene summaries and drug-centered pharmacokinetic and pharmacodynamic pathways.
James M. Hoffman PharmD, MS is an Associate Member in Pharmaceutical Sciences and the Chief Patient Safety Officer at St. Jude Children’s Research Hospital in Memphis, Tennessee. His career has focused on evaluating and improving complex medication use systems, and he currently provides leadership of patient safety activities across St. Jude. His research focuses on advancing pharmacogenetics as a proactive medication safety strategy, including St. Jude’s implementation effort and nationally through the Clinical Pharmacogenetic Implementation Consortium (CPIC). Through these efforts he works to accelerate implementation of research discoveries in pharmacogenomics into the clinic through the development and dissemination of model practices and clinical practice guidelines. He has experience developing and refining clinical decision support for pharmacogenetics in electronic health records, which informs his leadership of the CPIC Informatics group with colleagues from Mayo Clinic and Stanford.
Informatics and the Term Standardization Project (CPIC)
Recently, the CPIC Informatics working group led the CPIC term standardization project. Terms used to describe pharmacogene allele functions and clinical phenotypes have not to date been standardized across laboratory reports or across CPIC guidelines. To maximize utility of pharmacogenetic test results and to fully implement CPIC guidelines, it is desirable to standardize these terms. To achieve as much harmonization as possible, particularly for purposes of clinical reporting, CPIC developed consensus across pharmacogenetics experts and clinicians to determine the best terms to use for CPIC level A and level B pharmacogenes. Where possible, the goal was to agree upon uniform terms that can apply to more than one pharmacogene for terms used to characterize 1) allele functional status and 2) presumed phenotype (generally based on diplotypes). CPIC used a modified Delphi method, which is a structured approach to determine consensus through iterative surveys of an expert panel. Survey participants represented a wide range of genetic and professional organizations. After five surveys of pharmacogenetic experts, consensus was reached. A full description, including results, can be found at https://cpicpgx.org/resources/. While these standardized terms will be incorporated into all new CPIC guidelines and updates, we expect these terms to have broad uptake in the clinic as they are adopted by other organizations (e.g. clinical laboratories, LOINC, IOM’s DIGITizE, Association for Molecular Pathology, etc).
Personalized medicine offers the hope that we can tailor treatment to a person's unique genetic background. To that end, we can now quickly and cheaply sequence a patient. However, rare variation abounds in humans, posing a formidable challenge: how do we interpret the sequencing data that is returned for a particular patient?
I am using genome engineering techniques and developing new technologies to address this question. In particular, I'm leveraging Cas9-based genome editing for large-scale functional characterization of genetic variants in human cells. Using these methods, my goal is to make comprehensive protein sequence-function maps that could be used to interpret any variant in a protein of interest. Pharmacogenes are an exciting focus of this research, as many patients carry variants in these genes that have unknown effects. Using our approach, we can understand how variants we’ve already seen affect protein function and make predictions about what drugs and doses would be appropriate for each new variant that is identifiede. I'm also interested in methods for investigating non-coding variants and multiplexing variants to better map genotypes to phenotypes.
Interpreting variation in VKOR, a critical pharmacogene (F-CAP)
My laboratory function at the intersection of a variety of disciplines which include zebrafish development, drug discovery, and cardiovascular biology. Our research can be divided into 2 broad areas. The first area involves chemical biology of vertebrate development, which entails discovery of small molecules that selectively modulate signaling pathways involved in embryogenesis. We have thus far discovered potent and highly selective chemical modifiers of bone morphogenetic protein (BMP), Wnt, Hedgehog, and lipid signaling pathways, among others. Several of our compounds are first-in-class molecules with substantial therapeutic potential in rare and common diseases, including heterotopic ossification, cancers, atherosclerosis and heart failure. Thus, our chemical biological exploration is leading to new opportunities for innovative therapeutic programs. In the second, we are exploring the potential of patient-derived induced pluripotent stem cells (iPSC) to study and treat human heart diseases. We use human iPSCs as renewable cell sources for examining the fundamental cell biology and physiology of normal and diseased human cardiomyocytes. Finally, we collaborate with bioengineers to develop human iPSC-derived heart tissues as a platform for drug discovery and evaluation.
A new paradigm for identifying patients and drugs at risk for QT prolongation (IPoDA)
QT interval prolongation and arrhythmias have been a major cause for drug relabeling and withdrawals. However, only a small minority of patients exposed to culprit drugs develops the ADR, and the fundamental determinants of this individual sensitivity remain unexplained. In this project we will derive cardiomyocytes from individual patients whose drug-response phenotypes we have established. We will compare cells from those with drug induced long QT syndrome (diLQTS) to those who have been drug-tolerant both at baseline and with exposure to drugs known to elicit this ADR, including HERG blockers as well as those inhibiting PI3-kinase, a new pathway to diLQTS we have recently delineated.
PGRN Hub & the Featured Investigator