Instructor in Medicine, Harvard Medical School
Associate Physician, Brigham and Women's Hospital
The primary focus of Dr Tantisira's research efforts, have been in the pharmacogenetics of asthma therapeutics. With a focus on the pharmacogenetics of the beta-agonist and corticosteroid pathways and have made significant progress, they have identified genes that influence bronchodilator response in asthmatics, corticosteroid response over time as manifested by changes in FEV1, differences in airways hyperresponsiveness in patients on corticosteroids, and prediction of who will be hospitalized while on inhaled steroids
I have pursued research in pharmacogenomics over the past twenty years, first with a focus on molecular genetics of target genes, and then increasingly broadening into a genomics approach, including chemogenomics and systems biology. My research focuses on genetic variability in drug response and disease risk. We study regulatory polymorphisms that affect gene expression, RNA processing, and translation, playing a main role in inter-individual differences in disease and therapy. Since 2002 at OSU College of Medicine, I have developed a Center for Pharmacogenomics, tying together multiple research groups at OSU and beyond. Previously support by an NIH GMS U01 project “Regulatory variants in Drug Therapy”, under the umbrella of the Pharmacogenomics Research Network, has fostered functional genomics core laboratory with next-gen sequencing, collaborations in bioinformatics, mathematical modeling, and clinical sciences. I anticipate that genomic medicine and in particular pharmacogenomics is at the cusp of taking a quantum leap towards clinical implementation, because the tools available to us have expanded dramatically. More recently through a growing collaboration with Dr. Schlesinger and the Center of Microbial Interface Biology, my group has developed an extensive research program to understand the genomics of M.tb infection of human macrophages, with focus on the innate immune system – containing numerous genes under strong evolutionary selection and targets of numerous drugs, in a broad spectrum of disorders. A further personal goal is to translate our results into robust biomarker panels predictive of drug response, with much potential to advance personalized therapeutics, and thereby, improve therapy of complex disorders with tangible benefits to society.
Understanding each gene locus or gene cluster as an integrated regulatory: exampleCHRNA5-CHRNA3- CHRNB4 nicotinic receptor gene cluster
Approach. We have develop an R package (K. Hartman) to canvass multiple databases including GTEx, dbGaP, ENCODE, 1,000 genomes project, etc, to extract LD, eQTLs, GWAS hits, and chromatin annotations, applicable to hundreds of genes at a time. This was applied to the nicotinic gene cluster to determine the main LD blocks and candidate variants associated with expression in body tissues and GWAS hits (3).
Results. In a first step, we have identified the main haplotype blocks and three SNPs, the regulatory variants rs880395 and rs1948, plus the known nonsynonymous CHRNA5 rs16969968, a known risk variant in nicotine dependence. Importantly, rs880395 affects the RNA expression of CHRNA3 and 5, and of an antisense RNA, while rs1948 affects specifically CHRNA3 only in the basal ganglia – a region important to nicotine dependence. The predominant LD structure in the gene cluster enables assignment of haplotypes and diplotypes with high confidence in a majority a study cohort. These results document the interactive nature of variants in this gene locus, modified in a tissue specific manner critical for determining influence on specific target traits.
Analysis of a GWAS cohort with nicotine dependence confirmed the known influence of the nsSNP alone, but haplotype and diplotype analyses reveal significant modulation of the influence of rs16969968 on nicotine dependence.
Conclusion. The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor gene cluster represents a local regulome that should be considered for its overall influence on complex traits such as nicotine dependence. Operating via DNA looping over long distances, each regulatory variant can modify expression of multiple genes in an interactive fashion. We are now systematically expanding our approach to multiple gene loci and gene clusters, including cardiovascular and CNS disorder gene candidates, and genes in the innate immune system, which is under strong evolutionary constraints.
- Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. D. Wang, Y. Guo, S.A. Wrighton, G.E. Cooke, W. Sadee. Pharmacogenomics J 11: 274-286 (2011). PMID 20386561
- D. Wang, M.J. Poi, X. Sun, A. Gaedigk, J.S. Leeder, W. Sadee. Common CYP2D6 Polymorphisms Affecting Alternative Splicing and Transcription: Long-range Haplotypes with Two Regulatory Variants Modulate CYP2D6 Activity. Hum.Mol.Gen. 23: 268-278 (2014). PMID:23985325.
- E.S. Barrie, K. Hartmann, S.-H. Lee, J.T. Frater, M. Seweryn, D. Wang, W. Sadee. The CHRNA5/CHRNA3/CHRNB4 nicotinic receptor regulome: genomic architecture, regulatory variants, and clinical associations. Human Mutation, in print (2016). PMID:27758088, doi: 10.1002/humu.23135. https://www.ncbi.nlm.nih.gov/pubmed/27758088
Chair, Department of Biomedical and Translational Informatics
Chief Research Informatics Officer
Geisinger Health System
Dr. Marylyn Ritchie, PhD is a Professor and Chair in the Department of Biomedical and Translational Informatics at Geisinger Health System. Dr. Ritchie is a statistical and computational geneticist with a focus on understanding genetic architecture of complex human disease. She has expertise in developing novel bioinformatics tools for complex analysis of big data in genetics, genomics, and clinical databases, in particular in the area of Pharmacogenomics. Dr. Ritchie has received several awards and honors including selection as a Genome Technology Rising Young Investigator in 2006, an Alfred P. Sloan Research Fellow in 2010, a KAVLI Frontiers of Science fellow by the National Academy of Science from 2011-2014, and she was named one of the most highly cited researchers in her field by Thomas Reuters in 2014. Dr. Ritchie has extensive experience in all aspects of genetic epidemiology and translational bioinformatics as it relates to human genomics. She also has extensive expertise in dealing with big data and complex analysis including GWAS, next-generation sequencing, CNVs, data integration of meta-dimensional omics data, Phenome-wide Association Studies (PheWAS), and development of data visualization approaches.
Dr. Wang has developed a research program with a focus on the use of high throughput genomic technology, joined with a cell-based model system which she developed that consists of 300 lymphoblastoid cell lines (LCLs) with extensive high through put genomic data to study mechanisms of cancer biology and therapy, including both chemotherapy and radiation therapy. Her research has also focused on understanding regulation of the PI3K-AKT as well as AMPK pathways and their impact on response to drug therapy. As a Co-PI, she led the functional genomics activities within the Mayo-NIH Pharmacogenomics Research Network (PGRN) grant that included the PGx of breast cancer. Her program has been deeply involved in characterizing GWAS signals related to response to endocrine therapy and chemotherapy of breast cancer. She is also leading a program that is developing patient derived xenografts (PDX) using breast cancer and prostate biopsy samples collected from prospective clinical trials at Mayo. In summary, her program is applying high throughput omics technology together with functional genomics using cell lines and animal models to help identify and characterize biomarkers associated with therapy resistance, information that allow further development of alternative therapeutic strategies to help individualized therapy for cancer patients.
Professor of Molecular Pharmacology and Experimental Therapeutics
Precision Medicine of Aromatase Inhibitors In Post-Menopausal Women With ER+ Breast Cancer
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.
PGRN Hub & the Featured Investigator