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Pharmacogenomics: advent of personalized medicineMini Review
Pharmacogenomics: Advent of personalized medicine
Lipika Sahoo* and Richa Nath*
Lifeintelect Consultancy Pvt. Ltd., Marathahalli, Bangalore 560037, India.
Received: 20 November 2013 Accepted: 15 December 2013 Published online: 31 December 2013 Abstract
Pharmacogenomics is the technology that analyses how genetic makeup affects an individual’s response to drugs.
Pharmacogenomics helps to predict response to a medication and negative side effects. It aims to develop effective, safe
drug and optimize drug therapy with respect to the patients’ genotype which leads to maximum efficacy and minimal
adverse effect. Pharmacogenomics combines knowledge of genes, proteins and single nucleotide polymorphisms (SNPs)
to speed the discovery of drug response markers. It has implications in diseases like heart diseases, cancer, asthma, HIV,
depression and many other common diseases.
Key words: Pharmacogenomics, personalized medicine, drug response, single nucleotide polymorphisms, drug
response markers, Pharmacokinetic, Pharmacodynamic.
Pharmacogenomics combines pharmacology and genomics.
Pharmacogenomics combines knowledge of genes, It is the technology that analyses how genetic makeup affects proteins and single nucleotide polymorphisms (SNPs) to an individual’s response to drugs (1). It deals with the speed the discovery of drug response markers. It helps in influence of genetic variation on drug response in patients identifying drug target, drug metabolism or disease by analysing the gene expression or single-nucleotide pathways. Pharmacogenetic studies have established the polymorphisms. Many drugs that are currently available in importance of polymorphic drug metabolizing enzymes such market are “one size fits all,” and they work differently for as CYP2D6, a member of cytochrome P450 family; in the different people. Pharmacogenomics helps to predict who differential response to drugs (3). Recently, the genetic factors will respond to a medication, who will not respond at all, and at the level of drug target or the disease pathway have been who will have negative side effects. Pharmacogenomics aims identified. For example, ApoE4, an allele at the apolipoprotien to develop effective, safe drug and optimize drug therapy E locus, not only correlates with risk of developing customized with respect to the patients’ genotype leading Alzheimer ’s disease but also predicts poor response to to maximum efficacy and minimal adverse effects (2). Such cholinesterase treatment (4, 5). Polymorphism within a approaches promise the beginning of “personalized disease related gene is predictive of drug response. Each different disease like cancer, atherosclerosis Alzheimerdisease, HIV/AIDS, asthma and neurodegenerative disorders *Corresponding author: [email protected] and have distinct etiologies and therefore, distinct responses to therapy. That is the basic principle of pharmacogenomics.
2013 Sahoo and Nath ; licensee Green Earth Research Foundation. This article distributed under terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/) GERF Bulletin of Biosciences 2013, 4(2):11-13 12 Determinants of drug response
The efficacy of drug response depends on genetic DNA genotyping studies evolved from linkage and differ en ces (polymor ph ism) in dr ug metabolism, association of complex disease. Linkage studies involve pharmacokinetic variations and genetic differences in genotyping families with micro satellite-markers and the goal mechanism of drugs on its target, pharmacodynamic is to correlate inheritance of a particular chromosomal region with inheritance of disease. Association studies correlatethe presence of chromosomal region and a trait (disease or Pharmacokinetic variations
drug response) in unrelated individuals of a population. Now,the rapid pace of DNA marker discovery together with novel Isolation and sequencing of DNA clones of drug metabolizing genotyping techniques permit genome-wide association enzymes allow the study of catalytic specificity and activity of many individual drug-metabolizing enzymes. Some of thewidely studied enzymes are cytochrome P450 isoenzymes These technical considerations favour the use of SNP’s (CYP 450), N-acetyl transferase (NAT) isoenzymes, the UDP that are simple base substitutions, occuring within and glucuronoyl transferase and the methyl transferases. CYP450 outside genes. SNP’s are used as a diagnostic tool to predict genes is the best studied one, which encode enzymes that drug response (11, 12, 13). DNA micro arrays (or DNA chips) influence the metabolism of more than 80 percent of current are an evolving technology make it easy for doctors to prescription drugs like, Codeine, clopidogrel, tamoxifen and examine their patients for the presence of specific SNP’s warfarin (6,7). For most of the drugs, activity of CYP 450 quickly and affordably. A single micro array can now be determines how much and how long a drug remains in the used to screen 1,00,000 SNP’s found in patient’s genome in body. In humans, six forms of CYP 450 viz; CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 are largelyresponsible for eliminating drugs (8). Individuals who arepoor or slow metabolisers have enzyme deficiency related Application and uses
polymorphisms and are at an increased risk of concentrationrelated toxicity. While others have polymorphism (e.g., gene Doctors are starting to use pharmacogenomic information amplification) that enhance enzyme activity/ levels; they are to prescribe drugs, but such tests are routine for only a few characterized as extensive or ultra rapid metabolisers and diseases like heart disease, cancer, asthma, HIV, depression can be r esistan t to th er apy. Poor metabolism of and many other common diseases. In HIV disease, before prescribing the antiviral drug abacavir (Ziagen), doctors an tiarr hythmics, an d oth er s that leads to systemic routinely check the genetic variant of the patient that makes accumulation and toxicity are linked with polymorphisms in them more likely to have a bad reaction to the drug. Another CYP2C19 and glucuronosyl transferase locus UGT2B7; poor example is the breast cancer drug trastuzumab (Herceptin).
metabolisers of psychotropic drugs such as S-mephenytoin Her ceptin th er apy wor ks on ly for women h avin g suffer from drowsiness or more serious side effects which overproduction of a protein called HER2. US FDA also are associated with CYP2D6 and CYP3A4 polymorphisms.
recommends genetic testing before giving the chemotherapy In patients polymorphic for poor metabolisers forms of drug mercaptopurine (Purinethol) and irinotecan (Camptosar) CYP2D6, terfenadine competes with erythromycin for to reduce side effects and increase risk of infection.
CYP3A4, wh ich slows th e br eakdown , leadin g to Apart from improving use and efficacy of existing drugs, pharmacogenomics research also leads to the development Pharmacodynamic variations
of better drugs. Scientists are using genomic information to Genetic variations in receptor function have been relatively identify and design drugs aimed at subgroups of patients rare in healthy individuals. Metabolizing enzymes are low with specific genetic profiles. Pharmacogenomic tools also affinity systems and receptors are high affinity systems with aid in search for drugs that target specific molecular and specific structural requirements. Mutations in receptors cellular pathways involved in a disease. Pharmacogenomics result in individual differences in behaviour and drug research can be used to develop more personalized and cost- responses. For example, large variations in efficacy of the effective strategies for using drugs to improve human health.
psychotropic drug Sumitriptan have been attributed to singleamino acid substitutions in 5-hydroxy tryptamine (5HT) Pharmacogenomics may help in reviving abandoned drugs.
r eceptor s (4, 10). Th us gen etic var iation in both For example, development of the beta-blocker drugwon FDA pharmacokinetic and pharmacodynamic factors attributes to approval to treat heart failure. But interest in Gencaro revived after tests showed that the drug worked well in patients with 13 GERF Bulletin of Biosciences 2013, 4(2):11-13 two genetic variants that regulate heart function (14).
an d Zh on g XB. Gen etic polymorphisms in Incancer, chemotherapy drugs, gefitinib (Iressa) and erlotinib cytochr ome P450 oxidor eductase in fluence (Tarceva), work much better in lung cancer patients whose tumors have a certain genetic change. On the other hand, metabolism. Pharmacogenet Genomics. 2008; research has shown that the chemotherapy drugs cetuximab (Erbitux) and panitumumab (Vecitibix) do not work very well Gomes AM, Winter S, Klein K, Turpeinen M, in the 40 percent of colon cancer patients whose tumors Schaeffeler E, Schwab M and Zanger UM.
have a particular genetic change (4).
Pharmacogenomics of human liver cytochrome P450oxidoreductase: multifactorial analysis and impact Conclusion
on microsomal drug oxidation. Pharmacogenomics.
Some gene alleles vary in frequency between specificpopulations. These alleles have differential responses to Evans DA, Manley KA and McKusick VA. Genetic specific drugs. For example, The beta blocker Atenolol is an control of isoniazide metabolism in man. Br Med J.
anti-hypertensive medication that is shown to be more Marshall A. Laying the foundation for personalized American patients in US. Similarly, antiretroviral drug abcavir medicines. Nat Biotech. 1997; 15:954-957.
hypersensitivity is strongly associated with SNPs that varies 10. Lichter J and McNamara D. What is in a gene: Using in frequency between populations. The FDA approval of genetic information for the design of clinical specific drugs affecting particular population has produced trials. Curr Opin Biotechnol. 1995; 6:715-717. a storm of controversy over race-based medicine and genetic 11. Zhao LP, Aragaki C, Hsu L and Quiaoit F. Mapping stereotyping. It is certain that pharmacogenomics has of complex tr aits by sin gle-n ucleotide profound effect on drug usage and development process. It polymorphism. Am J Hum Genet 1998; 63:225-240.
is now very important to have a clear focus on technologies 12. Brookes AJ. The essence of SNP’s. Gene 1999; and a synchronized multidisciplinary effort. At the same time, it is also necessary to frame detailed regulatory policies at 13. Hacia JG, Fan JB, Ryder O, Jin L, Edgemon K, an international level and national level. In developing Ghandour G, et al . Determination of ancestral alleles countries, pharmacogenomics is still at nascent stage.
for human single nucleotide polymorphism using Though the benefits are tremendous, the cost factor to high-density oligonucleotide arrays. Nat Genet.
develop pharmacogenomics based therapy is the major deterrent. Concerted efforts are necessary from international bodies, governments, and pharma majors to ensure that highefficacy drugs reach the common man at a feasible price.
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Editor’s Overview THIS TWELFTH ISSUE OF THE International Productivity Monitor , published by the Centre for theStudy of Living Standards, differs from past issues. Five of the six articles address one topic, namelythe impact of the Boskin Commission after one decade on price measurement. A final article dis-cusses the role of information technology in the US growth resurgence. summarizes t