Recommendations of the NIGMS Working Group -- Understanding Individual Variations in Drug Responses: From Phenotype to Genotype

June 9-10, 1998, NIH Campus, Bethesda, MD

Rochelle M. Long, Ph.D., NIGMS
Richard M. Weinshilboum, M.D., Mayo Medical School


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 :

  • Identification of candidate proteins and their genes, including those that cause variations in human drug metabolism, transport, distribution, and excretion (for both small organic molecules and macromolecular drugs such as peptides and oligonucleotides), that may play a role in determining individual variations in drug responses
  • Identification of candidate proteins and their genes, including those that are direct targets for drug action (e.g., receptors, enzymes, signal transducing molecules, regulatory factors), that may play a role in determining individual variations in drug responses
  • Genetic studies, such as pedigree analysis, sib pair analysis, allelic association studies, and genome scanning approaches, to identify candidate genes responsible for variations in drug responses, including the study of individual variations in drug responses as a complex phenotype
  • Development and validation of in vivo, in vitro, and computer-based model systems to be used to identify functional genetic polymorphisms and to study their effects on the basic processes (and their interactions) that determine variations in individual drug responses.

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:

  • Establish a Pharmacogenetic Polymorphic Variants Resource database for genes encoding proteins that determine variations in drug responses. The purpose of the Polymorphic Variants Resource is to systematically, accurately, and comprehensively identify common genetic polymorphisms occurring at >1% frequency in a well-characterized, diverse, established sample set. Complete DNA sequences for common variants should be obtained, including exons, regulatory sequences, and introns (where feasible), from an appropriate set of human materials.

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:

  • Establish sample banks of materials (e.g., DNA, tissue and blood samples) in investigators' laboratories, from patients who have been well-characterized with respect to drug response phenotype, pathology, history, and with additional parental/family samples where feasible.

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:

  • Support basic research laboratories' access to the technology for rapid detection of DNA sequence variants, to aid in characterizing functionally significant genetic polymorphisms in normal human and patient populations.

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:

  • Training and cross-training in the field of computational biology/bioinformatics
  • Training and cross-training in the field of clinical pharmacology
  • Training and cross-training in the field of human genetics.

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 :

  • Understanding the mechanistic basis of the wide range of idiosyncratic adverse drug reactions of unknown origin.

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:

  • Inclusion of the principles of pharmacogenetics in the design of clinical trials and interpretation of their outcomes (refer to the FDA)
  • Discovery of genetic variants exclusively responsible for the pathophysiology of a specific disease (refer to the appropriate NIH categorical institute)
  • Support of analysis of the best medical, ethical, legal, and social approaches to the issues raised in the study of stratified populations (refer to the NHGRI)
  • Studies of the developmental and teratological aspects of the pharmacogenetics of variations in drug responses (refer to the NICHD)
  • Studies of specific gender- and aging-related issues involved in the pharmacogenetics of drug responses (refer to ORWH and NIA).

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