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ANSWER THREE OF THE QUESTIONS

ALL QUESTIONS SHOULD BE ANSWERED IN A SEPARATE BOOKLET

Answer all parts of the chosen questions. All questions are for 22 marks.

1. (a) Discuss the design of a pharmacogenomic study, including pharmacokinetic and pharmacodynamic aspects, to evaluate the variability in response to warfarin in populations with different ancestries. [ 11 marks ]

(b) Describe 2 different enzymes affecting pharmacokinetic factors and drug response. Include drug substrates, disease(s) implicated, their genetic variations and explain how the knowledge of genotype/phenotype relationship could be useful in clinical practice. [ 11 marks ]

2. (a) The MSc gene is expressed in the liver of the Wild-Type (WT) rat and its enzyme product metabolises a drug called Pharmaco. Sequencing of the MSc gene in a new rat strain called GLA has identified a single base change from the WT sequence. Depending on where this change occurs in the MSc gene, what effect – if any – would it have on the GLA rats’ ability to metabolise Pharmaco? [ 14 marks ]

(b) Further investigation shows the base change in the MSc gene of GLA rats occurs in the promoter region and is likely to prevent the gene’s transcription in the liver. Briefly describe the methods that could be used to show the absence of MSc mRNA in GLA rat livers. What information might you need? What controls would you use? [ 8 marks ]

3. Gene therapy has been proposed as an alternative treatment option for cardiovascular disease. Describe the development of a gene therapy, focussing on the choice of therapeutic gene, the construction of an expression cassette, selection of gene therapy delivery vector and target organ for treatment. Discuss with reference to at least one specific example. [ 22 marks ]

4. a) How will pharmacogenomics lead to the development of “personalised medicine”? Give two specific examples. [ 11 marks ]

Pharmacogenomics is the study of how the variability of the expression of genes between people leads to differences in susceptibility to disease and responses to medicines.

http://www.crc.gov.my/newsletter/newsletter-issue-3/national-committee/423

http://www.admin.cam.ac.uk/offices/research/documents/local/events/downloads/pm/Stephen_Little.pdf

b) What are the ethical issues surrounding the use of pharmacogenomic information in clinical medicine. Focus on the following stakeholders: (i) the patient (and their family) (ii) the medical practitioner (iii) the health board paying for the treatment (iv) the pharmaceutical/ biotechnology industry (v) health insurance companies [ 11 marks ]

http://www.genomichealthcarestrategies.com/pdfs/tips_july2000.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376080/

http://www.scu.edu/ethics/practicing/focusareas/medical/pharmacogenomics.html

http://archive.ispub.com/journal/the-internet-journal-of-law-healthcare-and-ethics/volume-6-number-1/applying-existing-ethical-principles-to-personal-medicine.html#sthash.UjeF7nMj.dpbs

5. (a) Describe how the polymorphisms in CYP450 genes can affect drug response, adverse effects and individual treatment. Give two examples. [ 11 marks ]

(b) Giving a specific example, describe the identification of genetic markers for a drug-induced hypersensitivity reaction (‘off-target’ adverse drug reaction) to identify patients that may be at risk and patients that can benefit from the treatment. [ 11 marks ]

6. (a) Compare and contrast Mendelian versus complex traits, giving an example of each. [ 6 marks ]

(b) Define the terms linkage analysis and association studies. Describe how you would design a linkage study and an association study, and discuss the underlying assumptions and the limitations of these studies with examples. [ 8 marks ]

Linkage analysis: Study aimed at establishing linkage between genes.

http://www.practical-haemostasis.com/Genetics/linkage_analysis1.html

http://cshprotocols.cshlp.org/content/2012/3/pdb.top068163.full

http://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=4&cad=rja&sqi=2&ved=0CE8QFjAD&url=http%3A%2F%2Fwww.springer.com%2Fcda%2Fcontent%2Fdocument%2Fcda_downloaddocument%2F9780387895536-c1.pdf%3FSGWID%3D0-0-45-771051-p173877421&ei=kPZvUYbfMorYPYevgIgN&usg=AFQjCNGCboqYLEO-gxjuleyeE1c-trVkQA&bvm=bv.45368065,d.ZWU

(c) Enumerate the factors that will increase the false positive rate in genetic association studies. Discuss one of these factors in detail with examples and describe what measures are used to minimise these errors. [ 8 marks ]

http://cshprotocols.cshlp.org/content/2012/3/pdb.top068163.full

http://www.ncbi.nlm.nih.gov/pubmed/15231016

http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002822

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