Understanding Pharmacogenetics

Understanding Pharmacogenetics

How feasible is the notion that a clinician prescribing psychotropic medication may take genetic information into account? The idea is not new.

In 1902, British physician Sir Archibald Garrod, D.M., suggested that genetic factors direct chemical transformations in humans and underlie individual variability. In 1957, Arno Motulsky, M.D., demonstrated the relationship between adverse drug reactions and genetically determined variation. Friedrich Vogel coined the term pharmacogenetics in 1959. Werner Kalow, M.D., (1962) showed that an abnormal form of serum cholinesterase leads to catastrophic adverse reactions to succinylcholine (Anectine, Quelicin), and he wrote the first systematic account of pharmacogenetics. Polymorphism of the enzyme now called cytochrome P450 (CYP) 2D6 was first observed in the 1970s in healthy volunteers who developed adverse effects to the antihypertensive agent debrisoquine (Mahgoub et al., 1977). The completion of the human genome sequence and the rapid cataloging of human genetic variation that has followed have given enormous impetus to pharmacogenetics and pharmacogenomics. These developments have ushered in an era of great optimism for the prospect of individualized medicine based on the patient's genetic profile (Roses, 2000). Their potential impact on the pharmaceutical industry and on new drug development is considerable.

Pharmacogenetics is the study of genetically based, inter-individual variability in response to drugs and susceptibility to drug-induced adverse effects (Lerer, 2002). Pharmacogenomics applies genomic technologies to drug development. Genetically based differences between individuals in their response to drugs can be attributed to two classes of factors. Pharmacokinetic factors encompass the processes that influence the bioavailability of a drug (i.e., the concentration that is available at its site of action). Pharmacodynamic factors are differences in the protein targets upon which drugs act. Both sets of factors influence the response of an individual to a given drug and may interact within the same individual and with the environment.

The focus of pharmacogenetics is on genetic polymorphisms that influence the structure or function of the protein for which the gene codes. The most common variation, the single nucleotide polymorphism (SNP), is a single base change in the sequence of the gene, which occurs at a frequency of about one in every 1,000 bases. Less than 10% of SNPs have functional significance. Nonfunctional SNPs are an invaluable resource in genetic mapping, however.

Classical genetics of human disease deals with monogenic disorders in which a single mutation in a single gene is causatively related to the phenotype. This paradigm holds true in pharmacogenetics for pharmacokinetic polymorphisms that have a major effect on drug bioavailability (such as the effect of CYP 2D6 polymorphism on the metabolism of a variety of psychotropic and other drugs, which is inherited as an autosomal recessive trait). For the most part, however, pharmacogenetic traits are polygenic and multifactorial. A polygenic trait is influenced by a number of different genes, each of which contributes a portion of the effect and may do so additively as well as interactively (epistasis). The term multifactorial indicates that both genetic and environmental factors contribute substantially and variably to the phenotype.

Pharmacogenetics has the potential to fill a very important clinical need. For as long as medicine has been practiced, physicians have known that patients respond differently to the same therapeutic agent, even though there are no obvious differences in the nature or severity of their illnesses. Susceptibility to adverse effects is also highly variable. When several drugs from the same or different pharmacological classes are available to treat the same condition, the clinician has virtually no rational basis upon which to make a choice.

Therefore, individual or illness characteristics that might aid in choosing an appropriate treatment have long been sought. The principal objective of pharmacogenetics is to identify and categorize the genetic factors that underlie differences among individuals in their response to drugs and to apply these observations in the clinic. The hoped-for end point is a simple DNA test that can be easily and cheaply performed and will yield results that enable the clinician to make reasonable predictions regarding the outcome of treatment with a particular drug and the likelihood of adverse effects.


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