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Pharmacogenetics and Pharmacogenomics

Pharmacogenetics and Pharmacogenomics

The complete sequencing of the human genome in 2000, along with new technologies, such as DNA microarrays, for analyzing human genes on a genome-wide scale, provides scientists with the tools to study the molecular basis of diseases on a level and scale that previously had not been possible. Pharmacogenomics is a biomedical science that aims to use this knowledge to tailor drug therapies based on patients' individual genetic makeup. Doctors hope to use pharmacogenomics to develop safer and more effective medical treatments. For some diseases, this promise has already been realized.

Molecular Interactions and Drug Effectiveness

Pharmacogenomics is a branch of pharmacogenetics, a science that deals with the heritable traits responsible for the individual differences in the ways people respond to drugs. It is remarkable, considering the myriad of medications we have today, how little we understand about how most of them actually work. There are many factors that influence the effectiveness of a particular drug, including how the drug enters the body's cells, how rapidly it is degraded by metabolic enzymes , and how it interacts with target molecules in the body, such as drug receptors.

Consider, for example, a common general anesthetic drug, called succinylcholine. In the 1950s doctors noticed that some patients suffered prolonged respiratory apnea (difficulty breathing) after being treated with succinylcholine. This syndrome was found to be caused by mutations in a gene for the enzyme butyrylcholinesterase. Normally butyrylcholinesterase in the blood degrades succinylcholine, and the anesthetic effects of the drug wear off with time. But in patients with mutations that inactivate or weaken butyrylcholinesterase, the anesthetic persists in the body, causing the dangerous side effect.

Cytochrome P450 is a member of a large family of enzymes that inactivate more than half of all drugs. There are many different alleles of cytochrome P450. Some alleles are very inefficient at inactivating drugs. In individuals with these alleles, termed "poor metabolizers," drugs can accumulate in the body to levels that produce toxic effects. In contrast, some people have extra copies of cytochrome P450 genes and produce excessive levels of the enzyme. In these individuals ("ultrarapid metabolizers"), drugs become inactivated so rapidly that they may not accumulate to the concentrations needed to be effective.

Adverse drug reactions such as the examples just discussed account for over one hundred thousand deaths each year in the United States. If a physician can determine the genotype of patients with respect to the genes that encode these proteins, then he or she may be able to prescribe the most appropriate dosage for a particular drug, or a better-suited drug.

A major obstacle, however, is that so many different proteins affect each drug. Some are well characterized, but most are completely unknown. This is where pharmacogenomics promises to revolutionize medicine. With the sequence of the entire human genome having been determined, and with the development of modern gene analysis technologies, scientists may now be able to pinpoint every gene that influences the effectiveness of any drug. Physicians would then be able to genotype their patients. For example, they could determine whether a patient has P450 alleles that make him a poor metabolizer or an ultrarapid metabolizer.

Not only can pharmacogenomics provide information about the best drug therapy for patients, but it can also be used to predict whether a person is predisposed to contracting a heritable disease. Mutant alleles of many genes have been shown to predispose people to diseases such as breast cancer, Alzheimer's disease, and Huntington's disease. If doctors can identify such mutant alleles in patients long before any sign of disease becomes apparent, they may be able to treat the disease better when it first appears or even prevent it before it strikes.

Of course, this powerful technology carries with it many ethical questions: If you carried a gene that gave you a moderate probability of eventually contracting a fatal disease, should you be told? What if there were no treatments for the disease? Who should have access to a patient's genetic information? If a health insurance company finds out that a person has a set of genes that predispose her to a disease that is costly to treat, should it be allowed to deny her insurance coverage?

Genetic Diagnoses That Can Improve Treatments

In addition to the complex interactions that drug compounds can have with molecules in the body, there are other reasons why some patients experience different responses to drugs. Two people that appear to have the same disease may actually have different diseases that may not respond to the same drug treatment. Modern genomic analysis methods, such as microarray gene expression profiling, can distinguish two diseases that, by all other clinical and diagnostic methods, appear to be identical.

An example is diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin's lymphoma, a cancer of the white blood cells. About 40 percent of patients can be cured by the standard chemotherapy for DLBCL, but 60 percent respond poorly and eventually die. Using microarray technology to gather and compare the gene expression patterns of cancer cells from many different DLBCL patients, molecular biologists have discovered that DLBCL actually comprises two distinct disease forms. Patients with one form are treatable with the standard chemotherapy, while those with the other form are not. Using this kind of genomic information, doctors can now diagnose patients more accurately and put them on the most appropriate drug-therapy regime. Similar genomic diagnoses based on gene expression profiles are being developed for important diseases such as breast cancer and Alzheimer's disease.

Using SNPs to Identify Disease Genes

Of the approximately 3 billion nucleotides in each of the two sets of chromosomes in human cells, the vast majority are identical from person to person. On average, though, the genomes of individuals differ from one another by about 1 million nucleotides. This is largely what accounts for the enormous diversity of humans. A nucleotide in a gene from one person that is different from the nucleotide found at the same position of the gene in most other people is called a single nucleotide polymorphism , or SNP (pronounced "snip").

Almost 1.5 million human SNPs have been identified and catalogued as part of the human genome sequencing project. Many of these polymorphisms are within the protein-coding or control regions of genes and may contribute to particular diseases, to a predisposition to a disease, or to adverse drug reactions. By comparing the SNP patterns of many different people, geneticists can infer whether a particular SNP (and therefore the gene it is in) is correlated with a disease or adverse drug reaction. Once a correlation is found, doctors can determine if their patients have the SNP in their genomes, to test for the likelihood of contracting the disease or experiencing the adverse reaction.

see also DNA Microarrays; Genomic Medicine; Polymorphisms.

Paul J. Muhlrad


Alberts, Bruce, et al. Molecular Biology of the Cell, 4th ed. New York: Garland Science,2002.

Lodish, Harvey, et al. Molecular Cell Biology, 4th ed. New York: W. H. Freeman, 2000.

Internet Resource

The SNP Consortium. <>.

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