Pharmacogenetics

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Pharmacogenetics refers to genetic differences in metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects.

In oncology, pharmacogenetics historically refers to germline mutations (e.g., single-nucleotide polymorphisms affecting genes coding for liver enzymes responsible for drug deposition and pharmacokinetics), whereas pharmacogenomics refers to somatic mutations in tumoral DNA leading to alteration in drug response (e.g., KRAS mutations in patients treated with anti-Her1 biologics).

The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably, and a precise, consensus definition of either remains elusive. Pharmacogenetics is generally regarded as the study or clinical testing of genetic variation that gives rise to differing responses to drugs, while pharmacogenomics is the broader application of genomic technologies to new drug discovery and further characterization of older drugs.

Predicting drug-drug interactions

Much of current clinical interest is at the level of pharmacogenetics, involving variation in genes involved in, drug metabolism with a particular emphasis on improving drug safety. The wider use of pharmacogenetic testing is viewed by many as an outstanding opportunity to improve prescribing safety and efficacy. Driving this trend are the 106,000 deaths and 2.2 Million serious events caused by adverse drug reactions in the US each year. As such ADRs are responsible for 5-7% of hospital admissions in the US and Europe, lead to the withdrawal of 4% of new medicines and cost society an amount equal to the costs of drug treatment.

Comparisons of the list of drugs most commonly implicated in adverse drug reactions with the list of metabolizing enzymes with known polymorphisms found that drugs commonly involved in adverse drug reactions were also those that were metabolized by enzymes with known polymorphisms (see Phillips, 2001).

Scientists and doctors are using this new technology for a variety of things, one being improving the efficacy of drugs. In psychology, we can predict quite accurately which anti-depressant a patient will best respond to by simply looking into their genetic code^{[citation needed]}. This is a huge step from our previous way of adjusting and experimenting with different medications to get the best response. Antidepressants also have a large percentage of unresponsive patients and poor prediction rate of ADRs (adverse drug reactions). In depressed patients, 30% are not helped by antidepressants. In psychopharmacological therapy, a patient must be on a drug for 2 weeks before the effects can be fully examined and evaluated. For a patient in that 30%, this could mean months of trying medications to find an antidote to their pain. Any assistance in predicting a patient’s drug reaction to psychopharmacological therapy should be taken advantage of. Pharmacogenetics is a very useful and important tool in predicting which drugs will be effective in various patients. The drug Plavix blocks platelet reception and is the second best selling prescription drug in the world, however, it is known to warrant different responses among patients. GWAS studies have linked the gene CYP2C19 to those who cannot normally metabolize Plavix. Plavix is given to patients after receiving a stent in the coronary artery to prevent clotting.

Stent clots almost always result in heart attack or sudden death, fortunately it only occurs in 1 or 2% of the population. That 1 or 2% are those with the CYP2C19 SNP. This finding has been applied in at least two hospitals, Scripps and Vanderbilt University, where patients who are candidates for heart stents are screened for the CYP2C19 variants.

Another newfound use of Pharmacogenetics involves the use of Vitamin E. The Technion Israel Institute of Technology observed that vitamin E can be used to in certain genotypes to lower the risk of cardiovascular disease in patients with diabetes, but in the same patients with another genotype, vitamin E can raise the risk of cardiovascular disease. A study was carried out, showing vitamin E is able to increase the function of HDL in those with the genotype haptoglobin 2-2 who suffer from diabetes. HDL is a lipoprotein that removes cholesterol from the blood and is associated with a reduced risk of atherosclerosis and heart disease. However, if you have the misfortune to possess the genotype haptoglobin 2-1, the study shows that this same treatment can drastically decrease your HDL function and cause cardiovascular disease.

Pharmacogenetics is a rising concern in clinical oncology, because the therapeutic window of most anticancer drugs is narrow and patients with impaired ability to detoxify drugs will undergo life-threatenting toxicities. In particular, genetic deregulations affecting genes coding for DPD, UGT1A1, TPMT, CDA and Cyp2D6 are now considered as critical issues for patients treated with 5-FU/capecitabine, irinotecan, mercaptopurine/azathioprine, gemcitabine/capecitabine/AraC and tamoxifen, respectively. The decision to use pharmacogenetic techniques is influenced by the relative costs of genotyping technologies and the cost of providing a treatment to a patient with an incompatible genotype. When available, phenotype-based approaches proved their usefulness while being cost-effective.

In the search for informative correlates of psychotropic drug response, pharmacogenetics has several advantages:

• The genotype of an individual is essentially invariable and remains unaffected by the treatment itself.
• Molecular biology techniques provide an accurate assessment of the genotype of an individual.
• There has been a dramatic increase in the amount of genomic information that is available. This information provides the necessary data for comprehensive studies of individual genes and broad investigation of genome-wide variation.
• The ease of accessibility to genotype information through peripheral blood or saliva sampling and advances in molecular techniques has increased the feasibility of DNA collection and genotyping in large-scale clinical trials.

History

The first observations of genetic variation in drug response date from the 1950s, involving the muscle relaxant suxamethonium chloride, and drugs metabolized by N-acetyltransferase. One in 3500 Caucasians has less efficient variant of the enzyme (butyrylcholinesterase) that metabolizes suxamethonium chloride. As a consequence, the drug’s effect is prolonged, with slower recovery from surgical paralysis. Variation in the N-acetyltransferase gene divides people into "slow acetylators" and "fast acetylators", with very different half-lives and blood concentrations of such important drugs as isoniazid (antituberculosis) and procainamide (antiarrhythmic). As part of the inborn system for clearing the body of xenobiotics, the cytochrome P450 oxidases (CYPs) are heavily involved in drug metabolism, and genetic variations in CYPs affect large populations. One member of the CYP superfamily, CYP2D6, now has over 75 known allelic variations, some of which lead to no activity, and some to enhanced activity. An estimated 29% of people in parts of East Africa may have multiple copies of the gene, and will therefore not be adequately treated with standard doses of drugs such as the painkiller codeine (which is activated by the enzyme). The first study using Genome-wide association studies (GWAS) linked age-related macular degeneration (AMD) with a SNP located on chromosome 1 that increased one’s risk of AMD. AMD is the most common cause of blindness, affecting more than seven million Americans. Until this study in 2005, we only knew about the inflammation of the retinal tissue causing AMD, not the genes responsible.

Thiopurines and TPMT (thiopurine methyl transferase)

One of the earliest tests for a genetic variation resulting in a clinically important consequence was on the enzyme thiopurine methyltransferase (TPMT). TPMT metabolizes 6-mercaptopurine and azathioprine, two thiopurine drugs used in a range of indications, from childhood leukemia to autoimmune diseases. In people with a deficiency in TPMT activity, thiopurine metabolism must proceed by other pathways, one of which leads to the active thiopurine metabolite that is toxic to the bone marrow at high concentrations. Deficiency of TPMT affects a small proportion of people, though seriously. One in 300 people have two variant alleles and lack TPMT activity; these people need only 6-10% of the standard dose of the drug, and, if treated with the full dose, are at risk of severe bone marrow suppression. For them, genotype predicts clinical outcome, a prerequisite for an effective pharmacogenetic test. In 85-90% of affected people, this deficiency results from one of three common variant alleles. Around 10% of people are heterozygous - they carry one variant allele - and produce a reduced quantity of functional enzyme. Overall, they are at greater risk of adverse effects, although as individuals their genotype is not necessarily predictive of their clinical outcome, which makes the interpretation of a clinical test difficult. Recent research suggests that patients who are heterozygous may have a better response to treatment, which raises whether people who have two wild-type alleles could tolerate a higher therapeutic dose. The US Food and Drug Administration (FDA) have recently deliberated the inclusion of a recommendation for testing for TPMT deficiency to the prescribing information for 6-mercaptopurine and azathioprine. Hitherto the information has carried the warning that inherited deficiency of the enzyme could increase the risk of severe bone marrow suppression. Now it will carry the recommendation that people who develop bone marrow suppression while receiving 6-mercaptopurine or azathioprine be tested for TPMT deficiency.

Hepatitis C

A recent breakthrough in pharmacogenetics identified a polymorphism near a human interferon gene that is predictive of the effectiveness of an artificial interferon treatment for Hepatitis C. For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature, showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained virological response after the treatment than others. Later report from Nature demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.

Integrating pharmacogenetics into the health care system

Despite the many successes, most drugs are not tested using GWAS. However, it is estimated that over 25% of common medication have some type of genetic information that could be used in the medical field. If the use of personalized medicine is widely adopted and used, it will make medical trials more efficient. This will lower the costs that come about due to adverse drug side effects and prescription of drugs that have been proven ineffective in certain genotypes. It is very costly when a clinical trial is put to a stop by licensing authorities because of the small population who experiences adverse drug reactions. With the new push for pharmacogenetics, it is possible to develop and license a drug specifically intended for those who are not the small population genetically at risk for adverse side effects.

Technological advances

As the cost per genetic test decreases, the development of personalized drug therapies will increase. However, as of now, we only have access to single-gene test and which is currently quite expensive. In the future, more advanced sequencing will be able to test for multiple genes in a short amount of time. A disposable DNA sequencing device, which will retail for under $900 has recently been announced. The device was made to be the size of a USB memory drive to make it portable and easy to use Likewise, companies like DeCode Genetics, Navigenetics and 23andMe offer genome scans. The companies use the same genotyping chips that are used in GWAS studies and provide customers with a write-up of individual risk for various traits and diseases and testing for 500,000 known SNPs. Costs range from $995 to $2500 and include updates with new data from studies as they become available. The more expensive packages even included a telephone session with a genetics counselor to discuss the results.

See also

• Pharmacogenomics
• Pharmacovigilance
• Chemogenomics
• Structural genomics
• Toxicogenomics
• Therapygenetics

Further reading

• Abbott A (October 2003). With your genes? Take one of these, three times a day. Nature 425 (6960): 760–2.
• Evans WE, McLeod HL (February 2003). Pharmacogenomics – drug disposition, drug targets, and side effects. N. Engl. J. Med. 348 (6): 538–49.
• Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (November 2001). Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 286 (18): 2270–9.
• Weinshilboum R (February 2003). Inheritance and drug response. N. Engl. J. Med. 348 (6): 529–37.

External links

• Pharmacogenomics: Medicine and the new genetics from the Human Genome Project
• Pharmacogenomics in Drug Discovery and Development, a book on pharmacogenomics, diseases, personalized medicine, and therapeutics
• The Pharmacogenomics Journal
• PharmGKB The Pharmacogenetics and Pharmacogenomics Knowledge Base, a free online tool for Pharmacogenetics research