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Pharmacogenomics

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Presentation about significance of pharmacogenomics

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Pharmacogenomics

  1. 1. 2
  2. 2. 3 One-size fits all …??
  3. 3. 4 Adverse Drug Reactions
  4. 4. 5 Pharmacogenomics and its significance Devi Lekshmi S 2013-11-192 Department of Plant Biotechnology Major Advisor, Dr. P A Nazeem
  5. 5. 6 Outline Pharmacogenomics Genes and enzymes involved in drug metabolism Variants and SNPs Role of bioinformatics in pharmacogenomics Clinical significance of pharmacogenomics Personalized medicine Benefits and challenges Significance in plants Conclusion
  6. 6. Pharmacogenomics : pharmacology + genomics How genetic variation influences drug action 7 Pharmacogenomics
  7. 7. 8 …pharmacogenomics Different platforms Human Genome Project (2001-2003) International HapMap Project (2003) 1000 Genomes Project (2010 onwards)) (Carr et al., 2014)
  8. 8. Pharmacogenetics and pharmacogenomics Pharmacogenetics (Friedrich Vogel) often used 9 interchangeably with pharmacogenomics Pharmacogenetics focus on single drug-gene interaction Pharmacogenomics- a more genome-wide association approach incorporating genomics and epigenetics
  9. 9. 10 Genes involved in drug metabolism PK genes and PD genes Pharmacokinetics (PK) - “what the body does to the drug” Pharmacodynamics (PD) - “what the drug does to the body” PK genes encode proteins involved in ADME of drug (Altman et al., 2012)
  10. 10. 11 Fate of drug in a human body
  11. 11. Enzymes involved in drug metabolism • Cytochrome P450 enzymes (<20) Clinical drugs metabolized by one or more cytochrome P450 enzymes 12 (Ma and Lu, 2011)
  12. 12. 13 Cytochrome P450 enzymes a) CYP2D6 Metabolism of 20-25%of marketed drugs Polymorphism best studied Drugs: antidepressants, antipsychotics b) CYP2C19 More than 20 polymorphism reported Eg: CYP2C19*2, *3 Drugs: antiulcerative, anticonvulsant
  13. 13. 14 …cytochrome P450 enzymes c) CYP3A4/5 Most abundant Seen in human liver Metabolism of more than 50% of drugs 20 variants identified Eg: CYP3A4*16, CYP3A4*2CYP3A4*7
  14. 14. 15 Polymorphism of drug transporters 1. ABCB1 genes Encode P-glycoprotein : transporter protein SNP C3435T occurs most frequently Effects metabolism of drug statin
  15. 15. 16 …polymorphism of drug transporters 2. ABCG2 genes Breast Cancer Resistance Protein (BCRP) Polymorphism adversely affect disposition of anticancerous drugs Eg: Rosuvastatin (Hesselink et al., 2003)
  16. 16. 17 How variants formed ? SNP and addition, deletion, duplication of nucleotide bases Single nucleotide polymorphism - most common variation 14 million SNP identified in human genome 60,000 SNPs are located in the coding region Certain SNPs associated with drug efficacy (Alwi, 2005)
  17. 17. 18 SNP and drug efficacy
  18. 18. 19 …SNP and drug efficacy Statin- highly effective in reducing risk of cardiovascular and cerebrovascular events MDR1 gene helps in metabolism of drug 50 SNP were reported 3 main SNPs C3435T, G2677T/A, C1236T Reduced bioavailability of statins (Babu et al., 2012)
  19. 19. 20 Role of bioinformatics in pharmacogenomics
  20. 20. 21 Role of bioinformatics Interdisciplinary field – develop methods and tools for understanding biological data Reduces time to interpret the data Many bioinformatic tools and databases to help pharmacogenomics (Satendra et al., 2010)
  21. 21. 22 Bioinformatic tools and databases Retrieval of data from databases (Uniprot Knowledge Database ) Multiple sequence alignment using clustalW2 server - To identify the identical, similar and different regions in the sequences - To generate phylogenetic tree
  22. 22. 23 ClustalW2
  23. 23. 24 …bioinformatic tools and databases Basic Local Alignment Search Tool (BLAST) •Widely used for searching regions of similarity between biological sequence To compute the potential effects of SNP on RNA structure use SNPfold PolyPhen tool used for assessment of variants- • Predict the functional effects of aminoacid changes using 3D statistical models
  24. 24. 25 …bioinformatic tools and databases Pharmacogenomics Knowledge Base (PharmGKB) Information about variants Interpret evidence behind each variant Genes in which variants found Variants influencing the drug <http://www.pharmgkb.org>
  25. 25. 26 PharmGKB data base
  26. 26. Clinical significance of pharmacogenomics 27
  27. 27. David Belk, July 2, 2008 28 Warfarin: significant problems for humans Company director died- brain hemorrhage Warfarin effect: cause of the death (Brutlag, 2014)
  28. 28. 29 Significance in cardiology Anti thrombotic drugs : warfarin and clopidogrel Oral coumarin anticoagulants (OCAS) Enzymes influence OCAS dose response 1. CYP2C9- metabolizes OCAS 2. VKORC1- target for two drugs (Ventola, 2011)
  29. 29. 30 …significance in cardiology CYP2C9*2 and *3 variants inhibit the metabolism of OCAS VKORC1 – 1639G >A influences pharmacodynamic response to coumarins Improper metabolism- ADR FDA – optimized drug dose for patients identified with above variants either one or both
  30. 30. 31 Oncology Human epidermal growth factor receptor 2 HER+3 variant - high level of HER2 Over expression – breast cancer HER2 expression variability- Trastuzamb treatment
  31. 31. 32 Diagnostics in pharmacogenomics Highly accurate diagnostic tests are available First diagnostic- BRAC1: Myriad genetics (1997) Use high throughput technologies (Daniel et al., 2014)
  32. 32. 33 Invitro diagnostic tests by FDA Biomarker Disease Drug Assay Kit Technology HER2 gene amplification Breast cancer Trastuzumab SPOT-Light HER2 CISH CYP2C19 variants+ Depressi on Atomoxetine Roche Amplichip CYP450 test FISH
  33. 33. Biomarker Indication Drug Assay Kit Technology 34 EGFR protein expression Colorectal cancer Cetuximab ` EGFR pharmDx IHC KRAS mutation Colorectal cancer Cetuximb Therascreen Real-time PCR …invitro diagnostic tests by FDA
  34. 34. Personalized 35 medicine
  35. 35. 36 Personalized medicine Prescription of drugs based on patients genetic profile Reduce speculation in drug prescription Increases the confidence of both physicians and patients Every patient is different, we need to individualize every patients therapy (Verma, 2012)
  36. 36. Lung cancer Victor- lung cancer (2010) Too advanced stage for radiation Genetic mutation- ALK gene ALK- Anaplastic Lymphoma Kinase 37 (www.uchospitals.edu/specialties/cancer/patient-stories /victor-lung)
  37. 37. 38 … lung cancer Discovered EML4-Alk gene in 2007 Pfizer, the company developed drug to block gene Drug: Gizotinib Prescribed dosage CAT result: shrunken tumour and not producing any new growth spots
  38. 38. Angelina Jolie Effect On February 16, 2013 Jolie underwent double mastectomy Family tree warranted genetic testing for BRCA mutation Found out 87% of risk in developing cancer Mastectomy lowered this risk to under 5% 39 (www.breast-cancer-research.com/content/16/5/442)
  39. 39. 40 …Angelina Jolie Effect Mutation in BRCA1 and BRCA2 shows 45 to 90%chance to develop breast cancer Jolie’s announcement in media, increased number of women preferred for testing A positive celebrity effect- Angelina Jolie Effect
  40. 40. Benefits of pharmacogenomics 41
  41. 41. 42 Benefits Identification of diseases related to genes and specific drugs- more drug specific cure Categorizing of human diseases at genome level Can adopt primary and secondary preventive measures Maximal patient care and minimum ADR
  42. 42. Challenges in clinical practice 4343434343
  43. 43. 44 1. Ethical issues Privacy of the study subjects - Individuals - Family May not be affordable for a common man - Developing countries - Subsidized by government
  44. 44. 45 2. Legal issues What is the legal liability if the genetic data is lost ? How much the doctor is obliged to inform the person? What is the legal issue for job discrimination? (Bansal et al., 2005)
  45. 45. Pharmacogenomics in plants 46
  46. 46. 47 Significance in plants Pharmacogenomic enzymes: significant role in plants Plants are exposed to toxic compounds Eg: Herbicides, insecticides and pollutants Detoxification: P450 enzymes and ABC transporters
  47. 47. 48 Detoxification by plants Plant CYP enzyme Herbicide (Substrate) H. tuberosus CYP76B1 Phenylureas Soybean CYP71A10 Phenylureas Tobacco CYP81B2, CYP71A11 Chlortoluron (Kumar et al., 2012)
  48. 48. 49 Phytoremediation Using transgenic plants for herbicide metabolism Uses cytochrome P450 genes from plants and human Transgenic rice encoding human genes - CYP1A1, CYP2B6, CYP2C19 Showed more tolerance to atrazine and diuron A promising field in near future (Kawahigashi, 2009)
  49. 49. 50 Conclusion A boon for medical fraternity Unravels the genetic basis of individual variability in drug response Not well studied and exploited in plants Right drug, in right dose for the right patient at right time
  50. 50. 50

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