- 1. Geneting Profiling Shaza El NemrNashwa AlbaainiKhaled
Ibrahem
2. Preface Definitions Factors Affecting Genomic Analysis
Pharmacogenetics in clinical medicine The Complexities Credibility
of pharmacogenetics! Disadvantages Pharmacogenomics Testing! Issues
3. Definitions Pharmacogeneticsis the study of genetic variation
that affects responseto medicines. Pharmacogenomicsuse of genome
based techniques in drugdevelopment Personalized
Medicinestreatment, based upon the individual-specific
factorsunderlying disease and drug response (Vijverberg et al.,
2010) 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 drugfor its
pharmacokinetics, pharmacodynamics, doseresponse relationship and
drug interaction potential. (Vijverberg et al., 2010) 5. Clinical
significance of pharmacogenetic variability in pharmacokinetics
Metabolizing drugs needs more than a single enzyme. Expression of
drug metabolizing enzymes with alteredspecificity/functional
activity. Even the serious ADRs are not related to a
specificgenotype (Clark et al., 2004). P-glycoprotein and
associated organic ion transportersalso affect the disposition of
many drugs. PK is not an essential basis of all toxic effects.
(Shah RR., 2005) 6. Factors Affecting Genomic Analysis(Ding et al.,
2010)CopyNumbervariationPathway MutationAnalysisSpectrumMethylation
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 agiven locus No investigation of safety and
efficacy in the genotypesexcluded Design overlooks the importance
of PD polymorphisms(Shah RR., 2005) 8. Pharmacogenetics in
clinicalmedicine Inconsistence and contradiction ofpharmacogenetic
studies of specific drug-induced toxic effects. Discrepancy in
Thiorizadine and CYP2D6 status. Contradiction in the studies of
neuroleptics andantidepressants with CYP2D6. No evidence of
impaired metabolism of oraldiclofenac in heterozygous and
homozygouscarriers of the CYP2C9 alleles (Kirchheiner et al.2003c).
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
beSNPs (Idle et al. 2000). Interaction between Genotype and
Extrinsic factors. Drug-Drug Interactionfor example terfenadine,
mibefradil, cerivastatin, cisapride andlevacetylmethadol.(Shah RR.,
2005) 10. Figure1: Analysis of 164 Expression
Intersectiongenes/proteins in breast tumors (Pujana et al., 2007).
11. Figure2: The Map of global network containing 234 liver
cancer-associatedgenes, 1056 nodes and 3425 edges of liver
cancer(Wang Z. & Wang YY., 2013). 12. Pharmacogenomics Testing
Lack of genotypic data. Additional costs for genetic testing Lack
of large-scale prospective clinicalevaluations for impact of
genetic variability indrug disposition and response. Relative
Resistance to use genetic testing toindividualize drug
therapies.(Xie & Frueh, 2005) 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 75variant alleles detected. All to be tested before
speculation. Genetic and epigenetic background of a patient is
changing via environmentalchanges in a decade. Patients genome,
diet, intestinal flora, changes inlifestyle and exposure to drug
and chemicals should be analysedsimultaneously. (Nebert and Vesell,
2006) 14. Consent Clear description of the participants role.
Description of all members and firms involved in theresearch.
Protection of confidentiality. How the participants DNA will be
defined andshared with other investigators. Will the participant
share benefits if the researchcontributed to development of a
product? What if the participants DNA study revealedsensitive
information which might have unpleasantconsequences. (Nebert &
Bingham, 2001) 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 Canavans gene dispute.(Marshall, 2000)
16. Health Insurance Insurers might classify clients according to
theirgenotypes. If genotype indicates poor response to a drug
(orgroup of drugs), the client might be denied the cover,even if
he/she is completely healthy. Health insurers could set high
premium relying ononly drug history of clients, as that might
indicatetheir genotype 17. (Nebert & Bingham, 2001) 18. Social
Issues Pharmacogenomics may be used to promoteethnic/racial
stereotypes. Pharmacogenomics may broaden thehealthcare gap between
the rich and poor Insurance discrimination Employment
discrimination 19. Ethnicity/Race (Huang and Temple, 2008) 20.
Privacy Issues Confidentiality and Privacy Use of pharmacogenomic
information Pharmacogenomic information can be inferredfrom
relatives. A case when a father blocked his son from
participatingin a genetic research via OHRP after learning
that,family history was invaded without consent. Authority abuse
21. Religious IssuesGenetic screening will change the way humans
reproduce.1. People will use it to select for a Better child.
Messing with gods creation and nature.2. Abortion becomes an issue.
some religions consider any interference with the natural actof
reproduction to be immoral.Like: In the Roman Catholic view, any
act of reproduction that is notperformed by the natural way is
immoral (Smith, 1989).3. Individuals who were carriers for genetic
abnormalities.. Would they be encouraged not to reproduce? 22.
Educational IssuesPharmacists Pharmacists are responsible to
provide medication counselingand drug information to patients.
Assessment of the knowledge, attitudes and education ofover 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. Psychological Problems In case of
depression pharmacogenomic infocan be damaging. May lead to feeling
of helplessness. Some patients may become sad, angry oranxious if
they learn that they have amutation in a cancer susceptibility
gene. If these feelings are very intense,psychological counseling
will be a necessity. 24. Financial/Economic IssuesCommercial 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., BiDils
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.
Ethical IssuesEthical Principles in Human Genetics andGenomics
according to Chadwick and Knoppers : Reciprocity Mutuality (Family)
Solidarity Citizenry Universality(Vijverberg et al., 2010) 26.
Bonnie Green (PhD Sociology/Genomics)ESRC Centre for Genomics in
Society/University of Exeter(Posted 2 years ago). 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 workcompanies relying on their Genetic Profiling? Do
you Accept promotion of Race Marketing? Would you like to hear
Future Bizzard about you whichmay never happen? 28. References
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