June 9-10, 1998, NIH Campus, Bethesda, MD
Rochelle M. Long, Ph.D., NIGMSRichard M. Weinshilboum, M.D., Mayo Medical School
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.
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.
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:
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Stephen B. Liggett, M.D.*Professor of Medicine, Molecular Genetics, and PharmacologyDirector of Pulmonary and Critical Care MedicineUniversity of CincinnatiDivision of Pulmonary and Critical Care Medicine231 Bethesda AvenueCincinnati, Ohio 45267-0564Tel: (513) 558-4831Fax: (513) email@example.comAssistant: Mary Anne RosensweetAssistant 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.
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