Start Date: 6/9/1998 8:00 AM
End Date: 6/10/1998 4:30 PM
Executive Summary
The working group recommended that NIGMS stimulate research in the area of pharmacogenetics/pharmacogenomics by: 1.) soliciting grant applications to examine the fundamental mechanisms underlying individual variations in drug responses, and 2.) establishing a resource database of polymorphic variants for proteins known to be essential in determining individual responses to drugs. The group emphasized the importance of relating a phenotype for a drug response to a genotype, in order to determine the functionally important sequence variants.
Background
On June 9 and 10, 1998, NIGMS convened a working group at NIH to assess the current state of the field of pharmacogenetics, and to identify ways in which the science might be advanced by taking advantage of recent developments in genomics. Its goal was to identify scientific areas of opportunity for the field. The working group included scientists who have contributed to our understanding of pharmacogenetic variation in the pathways of drug metabolism, drug transport, and drug receptors, as well as those involved in population genetics, molecular biology, genomics, and information science. Participants were included from academia, industry, and the federal government. Staff from various institutes across the NIH were also in attendance. The roster and list of attendees is included. Following is a report of the group's discussions and recommendations.
Pharmacogenetics can be defined as the effect of inheritance on individual variations in responses to drugs and xenobiotics. Pharmacogenetic variation may involve individual differences in therapeutic efficacy or adverse drug reactions. Historically, an inherited variation was often seen initially as a result of the clinical observation of an unusual response to drug therapy in an individual (e.g., prolonged apnea after succinylcholine, which results from a genetically atypical form of butyrylcholinesterase). It was also identified by the observation of large, inherited differences in the pharmacokinetic characteristics of a drug within a population (e.g., bimodal frequency distribution of peak plasma concentrations of isoniazid, which results from a genetic polymorphism for N-acetyltransferase). More recently, striking advances in the techniques of molecular biology and genomics have spurred further discoveries in the field of pharmacogenetics. Functionally significant pharmacogenetic polymorphisms have now been identified for many of the enzymes that catalyze drug biotransformations, as well as for target receptors and enzymes that determine drug responses.
The sequence of the entire human genome will likely be available in the near future. Advances are occurring daily in our appreciation of the extent of genetic variation, including but not limited to single nucleotide polymorphisms (SNPs), both in humans and in experimental animals. Developments in the science of genomics potentially present unique opportunities to a wide range of researchers, working at levels ranging from the most basic to the most clinical, in the fields of pharmacology, physiology, genetics, genomics, medicine, statistics, and computer science, to apply this knowledge and these techniques to rapidly accelerate the pace of discovery in pharmacogenetics today.
Recommendations
NIGMS has supported research activities and resource development in the fields of pharmacology and genetics throughout its history. Based upon recent advances in the understanding of the pharmacology of drug responses, and in the fields of genetics and genomics, the working group strongly recommended that NIGMS support investigator-initiated research in the following areas :
The working group also strongly recommended that NIGMS support development of the following resource , to serve as a firm foundation for future use in devising hypothesis-driven research projects to identify functionally significant pharmacogenetic variants:
The main beneficiaries of the information held in a central Pharmacogenetic Polymorphic Variants Resource will be the communities of scientists and clinician-researchers who observe significant phenotypes in study populations of human subjects, and would like to test for polymorphic variant sequences. This Resource will enable these laboratories to test, and then evaluate and correlate variant genotypes with observed drug response phenotypes in patient populations. It will greatly facilitate translational research in this field, especially for laboratories that are not heavily invested in sequence discovery technologies, thus broadening the pool of researchers who have the potential to make an impact in a cost-efficient manner.
The working group recommended that NIGMS encourage individual investigators in creating, maintaining, and sharing patient sample repositories, in order to conduct hypothesis-driven research projects to identify genetic polymorphisms that are functionally important for determining individual variations in drug responses:
The working group recommended that NIGMS encourage individual investigators in obtaining access to the technologies for polymorphic variant detection, in order to identify genetic polymorphisms that are essential for determining individual variations in drug responses:
The working group strongly recommended that NIGMS promote the following fields of training , by supporting the development of new programs where appropriate, and/or by expanding existing programs to include research training opportunities in pharmacogenetics, and by incorporating didactic training on recent developments in pharmacogenetics into the curricula:
The working group also recommended that NIGMS may wish to consider support of the following area related to pharmacogenetics, but the concept would need to be further developed :
Finally, the working group recommended that the following areas are extremely important to the field of pharmacogenetics, but would be best-served by referral elsewhere for further development:
Roster
Mark S. Boguski, M.D., Ph.D. National Center for Biotechnology Information National Library of Medicine Building 38A, Room 5S514 Bethesda, MD 20892 Tel: (301) 496-2475 Fax: (301) 480-9241 boguski@ncbi.nlm.nih.gov
C. Thomas Caskey, M.D., F.A.C.P. Senior Vice President, Research Merck and Co., Inc. Basic Research Summeytown Pike, P.O. Box 4 West Point, PA 19486 Tel: (215) 652-7399 Fax: (215) 652-4538 c_thomas_caskey@merck.com Assistant: Connie Johnson Assistant Tel: (215) 652-7454
Maureen T. Cronin, Ph.D. Protogene Laboratories, Inc. 1454 Page Mill Road Palo Alto, CA 94304 Tel: (650) 842-7117 Fax: (650) 842-7110 maureen@protogene.com
F. Peter Guengerich, Ph.D. Professor of Biochemistry and Director Center in Molecular Toxicology Vanderbilt University School of Medicine Department of Biochemistry 23rd Avenue at Pierce Avenue Nashville, TN 37232-0146 Tel : (615) 322-2261 Fax: (615) 322-3141 guengerich@toxicology.mc.vanderbilt.edu Assistant: Dorothy P. McCombs Assistant Tel: (615) 322-2261
Stephen B. Liggett, M.D.* Professor of Medicine, Molecular Genetics, and Pharmacology Director of Pulmonary and Critical Care Medicine University of Cincinnati Division of Pulmonary and Critical Care Medicine 231 Bethesda Avenue Cincinnati, Ohio 45267-0564 Tel: (513) 558-4831 Fax: (513) 558-0835 stephen.liggett@uc.edu Assistant: Mary Anne Rosensweet Assistant Tel: (513) 558-0484
* Dr. Liggett was unable to attend the Working Group meeting due to an injury, but submitted his comments for incorporation into the final report.
Arno G. Motulsky, M.D. Professor (emeritus - active) of Medicine and Genetics University of Washington Division of Medical Genetics Department of Medicine 1959 NE Pacific Street, BB567 Box 356423 Seattle, WA 98195-6423 Tel: (206) 543-3594 Fax: (206) 616-4196 agmot@u.washington.edu Assistant: Susanne L. Seales Assistant Tel: (206) 543-3593
Steven M. Paul, M.D. Vice President, Therapeutic Area Discovery Research & Clinical Investigation Eli Lilly and Company Lilly Research Laboratories Lilly Corporate Center Indianapolis, IN 46285-0530 Tel: (317) 276-8799 Fax: (317) 277-1125 paul_steven_m@lilly.com Assistant: Pamela J. Edmonds Assistant Tel: (317) 276-1277
Stephen Peroutka, M.D., Ph.D. President and Medical Director Spectra Biomedical, Inc. 111 Anza Boulevard, Suite 104 Burlingame, CA 94010 Tel: (650) 685-8585 Fax: (650) 685-8588 drperoutka@aol.com Assistant: Heather R. Arnold Assistant Tel: (650) 685-8585
Erin G. Schuetz, Ph.D. Associate Member Jude Children's Research Hospital Department of Pharmaceutical Sciences 332 N. Lauderdale Memphis, TN 38105 Tel: (901) 495-2205 Fax: (901) 525-6869 erin.schuetz@stjude.org
Michael W. Smith, Ph.D. Genetic Epidemiology Laboratory, SAIC Frederick Laboratory of Genomic Diversity Division of Basic Sciences National Cancer Institute P. O. Box B Frederick, Maryland 21702-1201 Tel: 301 846-1913 Fax: 301 846-1909 smithm@ncifcrf.gov
Stephen P. Spielberg, M.D., Ph.D. Global Head, Pediatric Drug Development R.W. Johnson Pharmaceutical Research Institute Global Clinical Research and Development 920 Route 202 Raritan, NJ 08869 Tel: (908) 704-4875 Fax: (908) 526-1590 sspielbe@prius.jnj.com Assistant: Janet Rudyk Assistant Tel: (908) 704-4618
Richard S. Spielman, Ph.D. University of Pennsylvania School of Medicine Department of Genetics Clinical Research Building 415 Curie Boulevard Philadelphia, PA 19104-6145 Tel: (215) 898-5763 Fax: (215) 573-5892 spielman@pobox.upenn.edu Assistant: Dr. Kathryn Ewens Assistant Tel: (215) 898-3696
Richard Weinshilboum, M.D. Professor of Pharmacology and Medicine Mayo Medical School, Mayo Clinic, Mayo Foundation Pharmacology 200 First Street, S.W. Rochester, MN 55905 Tel: (507) 284-2246 Fax: (507) 284-9111 weinshilboum.richard@mayo.edu Assistant: Luanne Wussow Assistant Tel: (507) 284-2790
Attendees
NCI Joe Covey Kumi Iwamoto Mary Wolpert
NCRR Dorothy Sogn Richard Knazek
NHGRI Elke Jordan Jerry Roberts
NHLBI Susan Banks-Schlegel Stephen Mockrin Susan Old
NIAAA Enoch Gordis
NICHD George Giacoia
NIEHS Jose Velaquez
NIGMS Marvin Cassman Alison Cole Alison Davis Irene Eckstrand Warren Jones Judith Greenberg Cathy Lewis Rochelle Long Alisa Machalek Pam Marino Michael Martin Peter Preusch Michael Rogers Michael Sesma John Schwab W. Sue Shafer Scott Somers
Office of the Director, NIH Greg Downing
