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A SNPpet of background on pharmacogenomics Examples of polymorphisms (PDF document, 650Kb) November 2004 The emerging field of pharmacogenetics deals with genetic determinants of a single gene in drug therapy. Pharmacogenomics, in contrast, focuses on candidate genes and includes both the genome and proteome that affect drug metabolism, pharmacokinetics, or pharmacotherapy, or all three. Pharmacogenetics revolves around clinical observations of inherited differences in a single gene in response to drugs whereas pharmacogenomics describes the design of drugs to match a patient’s genetic profile. In other words, pharmacogenomics is a science that examines the inherited variations in genes that dictate drug response and explores the ways these variations can be used to predict whether a patient will have a good response to a drug, a bad response to a drug, or no response at all. Pharmacogenomics also encompasses the genetic predisposition to diseases and how that may affect the selection of a specific therapy for patients with certain genotypes or how the information can be used to predict the outcome of a therapeutic intervention. Despite the difference that exists between the two terms of pharmacogenetics and pharmacogenomics, they are used interchangeably in the literature. To make it easier to recognize the difference, one should refer to the use of the genetic and proteomic information in clinical practice as pharmacogenomic. In the post genomic era, molecular techniques are now becoming increasingly important in the diagnostic clinical laboratory. Pharmacogenomics may be one of the most immediate clinical applications of the Human Genome Project.1 The application of molecular genetics will provide new opportunities for more targeted and, it is hoped, a more efficacious therapy. Therefore, pharmacogenomic approaches are widely expected to bring about a revolution in medicine. Genetic polymorphism A single nucleotide polymorphism, or SNP (pronounced "snip"), is a small genetic change, or variation, that can occur within a person’s DNA sequence. The genetic code is specified by the four nucleotide "letters" A (adenine), C (cytosine), T (thymine), and G (guanine). SNP variation occurs when a single nucleotide, such as an A, replaces one of the other three nucleotide letters—C, G, or T. An example of a SNP is the alteration of the DNA segment AAGGTTA to ATGGTTA, where the second "A" in the first snippet is replaced with a "T." On average, SNPs occur in the human population more than one percent of the time. Because only about three to five percent of a person’s DNA sequence codes for the production of proteins, most SNPs are found outside of "coding sequences." SNPs found within a coding sequence are of particular interest to researchers because they are more likely to alter the biological function of a protein. Sometimes a mutation in the promoter region or the interon section of the gene, or in both, may also affect transcriptions and stability of RNA and ultimately the expression of the corresponding protein. For instance, variant DPYD*2A (dihydropyrimidine dehydrogenase *2A allele) contains a mutation in the first nucleotide of splice donor site immediately upstream of the exon 14 which affects splicing. The resultant mutated protein product lacks the coding region exon 14 and lacks the function of a normal DPYD metabolizing enzyme. As a result, patients carrying this variant are super susceptible to 5-fluorouracil therapeutic intervention and develop severe toxicity. There has been a recent flurry of SNP discovery and detection. A Web site is dedicated to reporting the newly discovered SNP, which also serves as a database for all SNPs (http://snp.cshl.org/). I will provide a number of examples of genetic polymorphisms that are recognized to be important in drug efficacy and toxicity. Drug metabolizing enzymes Drug metabolizing enzymes are usually categorized into two groups: phase I and phase II metabolizing enzymes. In pharmacogenomics of phase I metabolism a number of polymorphisms are more important than others such as polymorphisms in CYP (Cytochrome P450) families, dihydropyrimidine dehydrogenase (DPYD), and pseudocholinesterase enzymes. Among phase II drug metabolizing enzymes, N-acetyltransferase (NAT), thiopurine methyl transferase (TPMT), and UDP glucuronosyl transferase are the most important phase II metabolizing enzymes with high influence on drug efficacy. CYP family carries a complex nomenclature (www.imm.ki.se/CYPalleles/). Other databases are available on the Internet explaining polymorphism and nomenclature of various phase I and phase II metabolizing enzymes. Listed in the accompanying table (PDF, 650 Kb)are examples of the most important polymorphisms of a number of these enzymes. Other important variants Glucose 6 phosphate dehydrogenase (G6PD) deficiency is a genetic determinant for susceptibility to certain drugs such as anti-malarial agents in the presence of stress. Almost 400 variants are identified for glucose 6 phosphate dehydrogenase worldwide. Some variants show a higher degree of susceptibility to certain medications. This deficiency is an X-linked recessive disorder found in 200 million people worldwide, most residing in the Mediterranean area, Southeast Asia, Africa, and India. Another important polymorphism example is seen in multiple drug resistance gene (MDR-1). This gene is responsible for expression of P-glycoprotein, which is an efflux pump found in intestine and brain. The pump influences the bioavailability of many drugs such as digoxin from the intestine and the drug concentrations in brain. For instance, a mutation in the MDR-1 gene that leads to a nonfunctional pump can increase the bioavailability of the drug and consequently increases the drug toxicities. A recent study identified a functionally active polymorphism (C3435T) at exon 26 of MDR-1 gene with T/T genotype with a lower activity versus the normal gene (C/C genotype). The person carrying the T/T variants will have an increase in bioavailability and toxicity of certain drugs, such as digoxin. Many other polymorphisms have been found to be important in clinical medicine. For instance, variants in receptor such as ß-receptor can affect the efficacy of anti-asthma agents. Other important polymorphism examples are α-1-acid glycoprotein and albumin (serum proteins that carry basic and acidic drugs), MRP2, OATP, and OCTP (efflux transporters), D3 receptor, and enzymes such as acetylcholinesterase and angiotensin converting enzymes. Many mutations in receptors or enzymes that are categorized in medical genetics may be qualified as pharmacogenetic polymorphisms. Examples of such mutations are congenital adrenal insufficiency and mutation in growth hormone receptor with severe consequences for sexual and growth development, respectively. Changes have to take place simultaneously at many levels to make the practice of individualized or genotypically directed medicine a reality for a large number of patients for a large number of indications. These changes should include legislation, the pharmaceutical and diagnostic industries, regulatory agencies, and the way we educate future health care professionals such as pharmacists, physicians, and laboratory medicine specialists. In addition, the Food and Drug Administration will probably demand that pharmacogenetic testing be implemented as a requirement for the filing of specific drugs in the near future. There is no doubt that the discipline of pharmacogenomics is growing quickly. There are now five journals with the words "pharmacogenetics" or "pharmacogenomics" in their titles, as well as an International Society of Pharmacogenomics, formed in 2001 and headquartered in the United Kingdom. And this year the American Society for Pharmacogenomics was incorporated in the United States. Its objective: to promote pharmacogenomics in the practice of clinical medicine and pharmaceutical care. References
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