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Genetic Profiling Debate


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Genetic Profiling Debate

  1. 1. Geneting Profiling Shaza El Nemr Nashwa Albaaini Khaled Ibrahem
  2. 2. Preface• Definitions• Factors Affecting Genomic Analysis• ‘Pharmacogenetics in clinical medicine’• The Complexities• “Credibility” of pharmacogenetics!• Disadvantages• Pharmacogenomics Testing!• Issues
  3. 3. Definitions• Pharmacogenetics is the study of genetic variation that affects response to medicines.• Pharmacogenomics use of genome based techniques in drug development• Personalized Medicines treatment, based upon the individual-specific factors underlying disease and drug response (Vijverberg et al., 2010)
  4. 4. Factors of Pharmacogenesis• Pharmacogenetic factors operate at pharmacokinetic (PK) levels pharmacodynamic(PD) levels (Shah RR., 2005)• The role of genetic factors when investigating a drug for its pharmacokinetics, pharmacodynamics, dose– response relationship and drug interaction potential. (Vijverberg et al., 2010)
  5. 5. Clinical significance of pharmacogenetic variability in pharmacokinetics• Metabolizing drugs needs more than a single enzyme.• Expression of drug metabolizing enzymes with altered specificity/functional activity.• Even the serious ADRs are not related to a specific genotype (Clark et al., 2004).• P-glycoprotein and associated organic ion transporters also affect the disposition of many drugs.• PK is not an essential basis of all toxic effects. (Shah RR., 2005)
  6. 6. Factors Affecting Genomic Analysis (Ding et al., 2010) Copy Number variationPathway MutationAnalysis Spectrum Methylation
  7. 7. Disadvantages of Pharmacogenetic Studies Design• Insufficient knowledge about potential variability• Overestimation of the results and efficacy of drug• More erosion of short-term and long-term safety data• Distorted comparisons in active controlled trials• Arbitrary exclusion conditions• Neglect of the presence of multiple variant alleles at a given locus• No investigation of safety and efficacy in the genotypes excluded• Design overlooks the importance of PD polymorphisms (Shah RR., 2005)
  8. 8. Pharmacogenetics in clinical medicine• Inconsistence and contradiction of pharmacogenetic studies of specific drug- induced toxic effects. – Discrepancy in Thiorizadine and CYP2D6 status. – Contradiction in the studies of neuroleptics and antidepressants with CYP2D6. – No evidence of impaired metabolism of oral diclofenac in heterozygous and homozygous carriers of the CYP2C9 alleles (Kirchheiner et al. 2003c).
  9. 9. Complexity in Pharmacogenetics– Pharmacokinetic levels– pharmacodynamic levels– Phenotype– Heterozygous & Homozygous States– Multiple alleles at a single locus– nucleotide polymorphism(s)– Not all relevant pharmacogenetic variations will be SNPs (Idle et al. 2000).– Interaction between Genotype and Extrinsic factors.– Drug-Drug Interaction for example terfenadine, mibefradil, cerivastatin, cisapride and levacetylmethadol. (Shah RR., 2005)
  10. 10. Figure1: Analysis of 164 “Expression Intersection”genes/proteins in breast tumors (Pujana et al., 2007).
  11. 11. Figure2: The Map of global network containing 234 liver cancer-associated genes, 1056 nodes and 3425 edges of liver cancer (Wang Z. & Wang YY., 2013).
  12. 12. Pharmacogenomics Testing• Lack of genotypic data.• Additional costs for genetic testing• Lack of large-scale prospective clinical evaluations for impact of genetic variability in drug disposition and response.• Relative Resistance to use genetic testing to individualize drug therapies. (Xie & Frueh, 2005)
  13. 13. Credibility of pharmacogenetics! Impossibility to achieve distinct genotype in phenotype-genotype associationstudies of human populations.Examples:• Reviewing 12 hospital that linked thiopurine-related drug toxicity to thiopurine methyltransferase TPMT genotype, found more than 78% of adverse drug reactions were associated with different factors other than TPMT-gene polymorphism.• CYP2D6 monooxygenase metabolises 25-30% of drugs. CYP2D6 gene 75 variant alleles detected. All to be tested before speculation.• Genetic and epigenetic background of a patient is changing via environmental changes in a decade. Patient’s genome, diet, intestinal flora, changes in lifestyle and exposure to drug and chemicals should be analysed simultaneously. (Nebert and Vesell, 2006)
  14. 14. Consent• Clear description of the participant’s role.• Description of all members and firms involved in the research.• Protection of confidentiality.• How the participant’s DNA will be defined and shared with other investigators.• Will the participant share benefits if the research contributed to development of a product?• What if the participant’s DNA study revealed sensitive information which might have unpleasant consequences. (Nebert & Bingham, 2001)
  15. 15. Consent The following is a section from consent form in genetic research:“Discoveries made with your DNA samples may be patented by us and theUniversity. These patents may be sold or licensed, which could give a companythe sole right to make and sell products or offer testing based on the discovery.Royalties may be paid to us, the University, and the Sponsor. It is not our intent toshare any of these possible royalties with you.” Commercialization of patient gene. • Example on Canavan’s gene dispute. (Marshall, 2000)
  16. 16. Health Insurance• Insurers might classify clients according to their genotypes.• If genotype indicates poor response to a drug (or group of drugs), the client might be denied the cover, even if he/she is completely healthy.• Health insurers could set high premium relying on only drug history of clients, as that might indicate their genotype
  17. 17. (Nebert & Bingham, 2001)
  18. 18. Social Issues• Pharmacogenomics may be used to promote ethnic/racial stereotypes.• Pharmacogenomics may broaden the healthcare gap between the rich and poor• Insurance discrimination• Employment discrimination
  19. 19. Ethnicity/Race (Huang and Temple, 2008)
  20. 20. Privacy Issues Confidentiality and Privacy Use of pharmacogenomic information Pharmacogenomic information can be inferred from relatives. • A case when a father blocked his son from participating in a genetic research via OHRP after learning that, family history was invaded without consent. Authority abuse
  21. 21. Religious IssuesGenetic screening will change the way humans reproduce.1. People will use it to select for a “Better child”. Messing with god’s creation and nature.2. Abortion becomes an issue. – some religions consider any interference with the natural act of reproduction to be immoral. Like: In the Roman Catholic view, any act of reproduction that is not performed by the natural way is immoral (Smith, 1989).3. Individuals who were carriers for genetic abnormalities.. Would they be encouraged not to reproduce?
  22. 22. Educational Issues “Pharmacists”• Pharmacists are responsible to provide medication counseling and drug information to patients.• Assessment of the knowledge, attitudes and education of over 700 pharmacists.  Total doctors registered on LRMP 252,469  63.2% from the UK (GMC, 2012)  More than 50,000 registered pharmacists (GPhC, 2010) (Roederer et al., 2012)
  23. 23. Psychological Problems• In case of depression pharmacogenomic info can be damaging.• May lead to feeling of helplessness.• Some patients may become sad, angry or anxious if they learn that they have a mutation in a cancer susceptibility gene.• If these feelings are very intense, psychological counseling will be a necessity.
  24. 24. Financial/Economic Issues Commercial Goal Dominates the Scientific Goal.• OpGen Closes $17M to Market Microbial Whole-Genome Analysis Platform ( Gene Engineering and Biotechnology News, 2010)• Economic :Royal claimed, which are not being widely discussed, namely that NitroMed Inc., BiDil’s manufacturer, has a monopoly on this patent, which was due to expire in 2007 but has now been extended to 2020 as a result of the drugmaker re-marketing BiDil for use among African Americans.• Cost: BiDil sells for $1.80 per pill, far more than generic drugs at 30 cents a pill So or $10.80 per day, based on the target dose of six pills per day.• Very expensive . What about Failures Cost?
  25. 25. Ethical IssuesEthical Principles in Human Genetics andGenomics according to Chadwick and Knoppers :• Reciprocity• Mutuality (Family)• Solidarity• Citizenry• Universality (Vijverberg et al., 2010)
  26. 26. Bonnie Green (PhD Sociology/Genomics)ESRC Centre for Genomics in Society/University of Exeter(Posted 2 years ago).
  27. 27. Rising Questions• Would you undergo the ‘Genetic Test’? Why?• Are statistics of genetic studies sufficiently credible?• Does gene analysis stand solely in treatment sector?• Is it ethical to discriminate people in Insurance and work companies relying on their Genetic Profiling?• Do you Accept promotion of “Race Marketing”?• Would you like to hear ‘Future Bizzard’ about you which may never happen?
  28. 28. References• Clark, D. W., Donnelly, E., Coulter, D. M., Roberts, R. L. & Kennedy, M. A. (2004). Linking pharmacovigilance with pharmacogenetics. Drug Safety; 27: 1171–1184.• CLeod H. (2012). DisclosuresPersonalized Medicine; 9(1):19-27.• Ding L., Wendl C.M., Koboldt C.D., Mardis R.E. . (2010). Analysis of next- generation genomic data in cancer: accomplishments and challenges. Human Molecular Genetics . 19 (R2)• Huang M-S., Temple R.. (2008). Is This the Drug or Dose for You?: Impact and Consideration of Ethnic Factors in Global Drug Development, Regulatory Review, and Clinical Practice. CliniCal pharmaCology & TherapeuTiCs, nature publishing group; 84 (3):287-294.• Idle, J. R., Corchero, J. & Gonzalez, F. J. (2000). Medical implications of HGP’s sequence of chromosome 22.Lancet ; 355, 319.• Kirchheiner, J., Meineke, I., Steinbach, N., Meisel, C., Roots, I. & Brockmoller, J. (2003c). Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2. No relationship to the CYP2C9 genetic polymorphism in humans. Br. J. Clin. Pharmacol. 55:51–61.• Littlejohns P. (2006). Trastuzumab for early breast cancer: evolution or revolution? The lancet; 7:22-23.
  29. 29. References• Meissner D. (2007). Report of an International Group of Experts. Ethical, Legal and Social Implications of Pharmacogenomics in Developing Countries. Switzerland: World Health Organization. p2-67.• Merz JF., Magnus D., Cho MK. and Caplan AL. (2002). Protecting Subjects’ Interests in Genetics Research. Am. J. Hum. Genet. 70:965–97.• Mordini E. (2004). Ethical considerations on pharmacogenomics. Pharmacological Research; 49:375-379.• Nebert D. W. and Bingham E. (2001). Pharmacogenomics: out of the lab and into the Community. TRENDS in Biotechnology; 19:519-523.• Nebert D. W. and Vesell E. S. (2006). Can personalized drug therapy be achieved? A closer look at pharmaco-metabonomics. TRENDS in Biotechnology; 27:580-586.• Nebert DW., Jorge-Nebert L., Vesell ES. (2003). Pharmacogenomics and "individualized drug therapy": high expectations and disappointing achievements, J. Pharmacogenomics; 3(6):361-70.• Özdemir V.,Fisher E., Dove E. S., Burton H., Wright G. E. B., Masellis M., and Warnich L. (2012). End of the Beginning and Public Health Pharmacogenomics: Knowledge in ‘Mode 2’ and P5 Medicine, Current Pharmacogenomics Person Medicine; 10:1-6.
  30. 30. References• Pujana MA., Han JD., Starita LM., Stevens KN., ..., Livingston DM., Gruber SB., Parvin JD., Vidal M. (2007). Nature Genetics; 39(11):1338-49.• Roederer WM., Riper VM., Valgus J., Knafl G., McLeod H. (2012). DisclosuresPersonalized Medicine; 9(1):19-27.• Shah RR.. (2005). Pharmacogenetics in drug regulation: promise, potential and pitfalls. Philosophical Transactions; Royal Society ;Biological Science; 360 :1617-1638.• Vijverberg S.J.H., Pieters T., Cornel M.C. . (2010). Ethical and Social Issues in Pharmacogenomics Testing. Current Pharmaceutical Design; 16 :245-252.• Wallace H. (2008). Paper For The Council For Responsible Genetics. Prejudice, Sigma and DNA Database; by Genewatch UK.• Wang Z. & Wang YY. (2013). Modular pharmacology: deciphering the interacting structural organization of the targeted networks. Drug Discovery Today; (13):26-30.• Xie GH. & Fruef WF. (2005). Pharmacogenomics steps toward personalized medicine. Future Medicine; 2(4):325-337.