Pharmacogenomics, by kk sahu

INTRODUCTION
What is pharmacogenomics
History
Principle
So what’s new about pharmacogenomics?
single nucleotide polymorphism (SNP)?
Genes commonly involved in pharmacogenomic drug metabolism and response
The anticipated benefits of pharmacogenomics
Pharmacogenetics Research/Database Program
Some of the barriers to using pharmacogenomics
Conclusion
References

1. “ PHARMACOGENOMICS ” By KAUSHAL KUMAR SAHU Assistant Professor (Ad Hoc) Department of Biotechnology Govt. Digvijay Autonomous P. G. College Raj-Nandgaon ( C. G. )

2. SYNOPSIS :- INTRODUCTION What is pharmacogenomics History Principle So what’s new about pharmacogenomics? single nucleotide polymorphism (SNP)? Genes commonly involved in pharmacogenomic drug metabolism and response The anticipated benefits of pharmacogenomics Pharmacogenetics Research/Database Program Some of the barriers to using pharmacogenomics Conclusion References

3. INTRODUCTION Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. It aims to develop rational means to optimize drug therapy, with respect to the patients genotype, to ensure maximum efficacy with minimal adverse effects. Pharmacogenomics is the whole genome application of pharmacogenetics , which examines the single gene interactions with drugs.

4. What is pharmacogenomics? Pharmacogenomics means “ Pharma ” = drug or medicine “ Genomics” = the study of genes . Pharmacogenomics is the study of how genes affect a person’s response to drugs. The emerging field of pharmacogenomics arises from the convergence of advances in pharmacology, genetics , and more recently genomics . Pharmacogenomics combines traditional pharmaceutical sciences such as biochemistry with annotated knowledge of genes, proteins, and single nucleotide polymorphisms.

5. History Genomics was established by Fred Sanger when he first sequenced the complete genomes of a virus and a mitochondrion. His group established techniques of sequencing, genome mapping, data storage, and bioinformatic analyses in the 1970-1980s. The first free-living organism to be sequenced was that of Haemophilus influenzae in 1995, and since then genomes are being sequenced at a rapid pace. As of September 2007, the complete sequence was known of about 1879 viruses, 577 bacterial species and roughly 23 eukaryote organisms.

6. principle “Pharmacogenomics” is the study of how individual genetic differences affect drug response. This definition encompasses inter individual genetic differences such as variation in DNA sequence, gene expression, and copy number related to an individual’s metabolism of drugs (pharmacokinetics) or physiological response to drugs ( pharmacodynamics ). Researchers in this field study genes that produce drug metabolizing-enzyme in the body . In some cases, an active drug is made inactive or less active through metabolism.

7. So what’s new about pharmacogenomics? The field of pharmacogenomics really developed only in the last 15 years because of new technology for the large-scale and high-speed collection of data, for measuring DNA sequence variations , especially single nucleotide polymorphisms (SNPs), and drug responses , especially mRNA expression analysis using microarrays.

8. single nucleotide polymorphism (SNP)? It is variability in a single nucleotide (A, C, G, or T) within an otherwise fixed DNA sequence, where a certain fraction of the population have one nucleotide (say C) and another fraction of the population have another nucleotide (say T).

9. What is a single nucleotide polymorphism (SNP)? It is variability in a single nucleotide (A, C, G, or T) within DNA sequence. ……. G G T A A C T G …… ……. G G C A A C T G …... SNPs are very common in the human population. Between any two people, there is an average of one SNP every ~1250 bases. Most of these have no phenotypic effect

10. How do I know this? By searching the NIH databases, as follows:

11. Single Nucleotide Polymorphisms (SNPs) A key to human variability Functional but altered protein Functional protein DNA sequence variation at a single nucleotide that may alter the function of the encoded protein Polymorphisms are common and contribute to common diseases and influence our response to medications

12. Genes commonly involved in pharmacogenomic drug metabolism and response There are several genes responsible for differences in drug metabolism and response. Among the most common are the Cytochrome P450 (CYP) genes, encoding enzymes that control the metabolism of more than 70 percent of prescription drugs. People who carry variations in certain CYP genes often do not metabolize drugs at the same rate or extent as in most people, and this can influence response in many ways.

13. The anticipated benefits of pharmacogenomics More Powerful Medicines Pharmaceutical companies will be able to create drugs based on the proteins, enzymes, and RNA molecules associated with genes and diseases. Advanced Screening for Disease Knowing one's genetic code will allow a person to make adequate lifestyle and environmental changes at an early age so as to avoid or lessen the severity of a genetic disease. More Accurate Methods of Determining Appropriate Drug Dosages Current methods of basing dosages on weight and age will be replaced with dosages based on a person's genetics --how well the body processes the medicine and the time it takes to metabolize it.

14. Better Vaccines Vaccines made of genetic material, either DNA or RNA, promise all the benefits of existing vaccines without all the risks. They will activate the immune system but will be unable to cause infections. Decrease in the Overall Cost of Health Care Decreases in the number of adverse drug reactions, the number of failed drug trials, the time it takes to get a drug approved, and an increase in the range of possible drug targets will promote a net decrease in the cost of health care.

15. Is pharmacogenomics in use today? Today, clinical trials researchers use genetic tests for variations in cytochrome P450 genes to screen and monitor patients. Today, doctors can use a genetic test to screen patients for this deficiency, and the TMPT ( thiopurine methyltransferase ) activity is monitored to determine appropriate thiopurine dosage levels.

16. Overview of the NIH’s Pharmacogenetics Research/Database Program In 1999, the General Medical Sciences unit of the NIH (NIGMS) announced its intention to create a pharmacogenetics research network and database program. Stanford Medical Informatics was one of the organizations that received funding to create the database portion of the system, dubbed the PharmGKB (http://www.nih.gov/grants/guide/rfa-files/RFA-GM-99-004.html   ; Pharmacogenetics Knowledge Base).

17. The NIGMS is providing funding for studies of several gene systems that are known to be important in determining drug response. Its targets include the following: The cytochrome P450 system The transferases of the so-called phase 2 metabolism, sulfylation and methylation systems Transporters of molecules, which are critical for (1) moving drugs out of the gastrointestinal system and through the kidneys and (2) transporting compounds into cells so as to provide pharmacologic activity Steroid receptors Intercellular signal transduction elements Cell surface receptors, such as beta receptors that respond to beta agonists

18. In addition to Stanford Medical Informatics ’ work on the PharmGKB , participants in the NIH ’ s pharmacogenetics program include the following institutions, which are handling differing aspects of this effort: University of California – San Francisco ( Giacomini ): transporter molecules University of Chicago ( Ratain ): anticancer agents Georgetown University ( Flockhardt ): tamoxifen as a model system for other steroids and steroid family agonists Brigham and Women's Hospital ( Drazen ): three pathways of asthma — beta agonists, steroids, and leukotrienes University of California – Los Angeles ( Licinio ): depression Houston (Rothstein): a lawyer analyzing the legal implications of pharmacogenetics research Yale University ( Nadkarni ): informatics, looking at the infrastructure behind the pharmacogenetics knowledge base

19. Pharmacogenomics in future New developments in this field will impact on drug design at three main levels: the interaction of the drug with its receptor binding site; (2) the absorption and distribution of the drug; (3) the elimination of the drug from the body.

20. Some of the barriers to using pharmacogenomics Pharmacogenomics is a developing research field that is still in its infancy. Several of the following barriers will have to be overcome before many pharmacogenomics benefits can be realized. Complexity of finding gene variations that affect drug response Single nucleotide polymorphisms (SNPs) are DNA sequence variations that occur when a single nucleotide ( A,T,C,or G) in the genome sequence is altered. Limited drug alternatives - Only one or two approved drugs may be available for treatment of a particular condition. Disincentives for drug companies to make multiple pharmacogenomic products - Most pharmaceutical companies have been successful with their "one size fits all" approach to drug development.

21. Conclusion Pharmacogenomics in pharmaceutical industry is a potential tool. The main aims of it are; personalized therapy, improvement in efficacy and reduction in adverse drug reactions, correlation of genotype with clinical genotype, identification of novel targets for new drugs, and pharmacogenetic profiling of patients to predict disease susceptibility and drug response.

22. References David W.Mount (2004) Bioinformatics :sequence and genome analysis. Second edition. Internet: http://www.genetics.edu.au