Origins of Pharmacogenomics

Archibald Garrod In 1902 Garrod characterized the condition of alcaptonuria as one resulting from an absence of the enzyme homogentisate oxidase. Garrod recognized that the condition was transmitted as a single recessive Mendelian trait. In 1902 Garrod characterized the condition of alcaptonuria as one resulting from an absence of the enzyme homogentisate oxidase. Garrod recognized that the condition was transmitted as a single recessive Mendelian trait.

Archibald Garrod While studying alcaptonuria in humans, Garrod advanced the hypothesis that genetically determined differences in biochemical processes could be the cause of adverse reactions after the ingestion of drugs.

Enzyme defects?? Garrod went on to suggest that enzymes were implicated in the detoxification of foreign substances and that such a mechanism might fail in persons lacking a specific detoxifying enzyme.

Malaria African-American soldiers taking the drug primaquine for malaria showed primaquine-induced hemolysis at a rate that was significantly higher than in Caucasian soldiers. primaquine

Tuberculosis- 1940’s Peripheral neuropathy occurred in some patients taking isoniazid but not others. Patients that exhibited the adverse effect were labeled “slow metabolizers”….. Peripheral neuropathy occurred in some patients taking isoniazid but not others. Patients that exhibited the adverse effect were labeled “slow metabolizers”…..

1950’s - Succinylcholine A very small percent of the population experiences prolonged muscle paralysis following administration of the muscle relaxant succinylcholine. Kalow described differences in patients ability to metabolize the succinylcholine based on genetic variability in their plasma cholinesterase enzyme. A very small percent of the population experiences prolonged muscle paralysis following administration of the muscle relaxant succinylcholine. Kalow described differences in patients ability to metabolize the succinylcholine based on genetic variability in their plasma cholinesterase enzyme.

1956 – Primaquine Toxicity Researchers identify a “genetic-link” between primaquine and unwanted hemolytic reactions

Motulsky After reviewing data from the isoniazid and succinylcholine trials Motulsky proposed that the inheritance of acquired traits might explain the individual differences in efficacy and adverse reactions for these drugs.

Vogel First proposed the term “pharmacogenetics” to describe the genetic-based differences in drug response that were being documented.

Kalow Wrote the first monograph on “Pharmacogenetics” (W. Kalow, Pharmacogenetics, 1962, Saunders, Philadelphia) Wrote the first monograph on “Pharmacogenetics” (W. Kalow, Pharmacogenetics, 1962, Saunders, Philadelphia)

1970’s London Physicians at St. Mary’s hospital note that the severe hypotensive response of a volunteer to the effects of debrisoquine was due to impaired oxidative metabolism in that subject.

Identical Twins In the 1970’s Vesell showed that identical twins were more similar than fraternal twins with regards to the plasma half-life of numerous drugs.  Implication was that multiple genes may determine individual drug metabolism….. In the 1970’s Vesell showed that identical twins were more similar than fraternal twins with regards to the plasma half-life of numerous drugs.  Implication was that multiple genes may determine individual drug metabolism…..

Advent of Molecular Biology Like most of science and medicine, the young field of pharmacogenetics benefited greatly from the advent of molecular biology techniques in the 80’s & 90’s.

Molecular Biology In the 1990’s simple PCR-based DNA tests became available for debrisoquine and acetylation polymorphism.

Definition Polymorphism - are changes in the genetic code (like mutations) that occur commonly enough in the population such that they are considered a variation on normal. These may be harmful, helpful or neither to the persons who have a polymorphism.

The Human Genome Project The ongoing effort to characterize and decode the human genome has likewise contributed greatly to the progress made in pharmacogenetics.

The Human Genome Project New technologies that arose from the Human genome Project such as DNA microarrays and lab card or “lab-on-a-chip” devices may eventually make it possible to cheaply and quickly prescreen patients for certain polymorphisms before drug therapy is initiated

TPMT Deficiency Polymerase chain reaction used to detect thiopurine S-methyl transferase deficiency – a cause of dangerous complications arising from mercaptopurine & azathioprine therapy.

SNP Consortium A collaboration of various companied and institutions set up to discover the extent of single nucleotide polymorphisms (SNP’S) in the human genome. The original goal was to identify 300,000 but the final results identified 1.4 million! A collaboration of various companied and institutions set up to discover the extent of single nucleotide polymorphisms (SNP’S) in the human genome. The original goal was to identify 300,000 but the final results identified 1.4 million!

Draft Human Genome Human Genome Project leaders announce the completion of a draft sequence of the human genome

Complete Human Genome 2003 Human genome project is officially completed.

FDA and Pharmacogenomics FDA issue guidance to the pharmaceutical industry for pharmacogenomic data submission.

Warfarin the FDA announced that warfarin’s label will carry new information describing the role of genetics in dosing.

Table of Valid Genomic Biomarkers FDA releases a table listing genomic biomarkers that have established roles in determining drug response