BCH 4101 Lecture 7: Precision Medicine and Pharmacogenomics
28 Apr 2018
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October 18, 2017
Precision Medicine and Pharmacogenomics
Consequences of Genetic Variation on Human Health
Impact depends on what they are and where they are
The majority of genetic variation is in non-coding regions, so the vast majority of genetic variation has no effect
-Genetic variants in a coding sequence might still be a silent mutation, and have no effect
Can have positive effects on health (ex. Heterozygote advantage, sickle cell anemia, and malaria)
Can have very adverse effects on health (ex. Huntington’s, CF)
-Almost every single human disease has a genetic component (not necessarily a large component)
-Odds are every disease will have a genetic component (ex. GxE interactions)
Need for Precision Medicine
Medicine is an inexact science
-Based on clinical manifestation and biochemical/functional measures
Diagnostic and prescription of a treatment
-Works most of the time, but is it the best?
Precision medicine is the best way to ensure that everyone receives the treatment they need - make medicine more
exact
Adverse Drug Reactions
Canada: 200 000 cases of adverse drug reactions (ADR) per year, ~20 000 of which are fatal
-Cost of $15 billion/year
USA: 2 million cases of ADRs per year, ~100 000 of which are fatal
What is the major underlying cause of these ADRs?
-Distinct genetic variants cause conditions that respond to different treatments yet share a similar set of symptoms
Need a mechanism in place to determine the underlying genetic cause in order to determine beforehand which
treatment will be most effective —> Pharmocogenomics
-Using genomic information to understand how individuals react differently to the same prescribed drug treatment
Ex. Warfarin (aka Coumadin): most popular anticoagulant drug on the market
-Originally marketed as a pesticide
-Inhibits vitamin-K dependent synthesis of active forms of clotting factors - prevents blood clots from forming
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October 18, 2017
•Prevents vitamin-K synthesis
-Narrow therapeutic margin: have to get the dose just right
•Too much: they bleed out
•Too little: clots will still form
-Interacts with drugs, foods, and natural health products (NHPs)
•Many things prevent Warfarin from working properly
-Patients must be monitored very closely to determine proper dosage
•Ex. Patient requires >20 visits to the hospital in order to establish the correct dose over 5 years
-Measure clotting time to determine proper dosage
-DNA genotyping ahead of time would save the 20 visits to the hospital
•Sequence of CYP2C9 gene can indicate how well the patient will establish the drug
-Warfarin metabolism:
•CYP2C9: cytochrome P450
-27 alleles (haplotypes)
->300 variations in DNA sequence
-Variation in CYP2C9 can account for almost all of the variation seen in Warfarin
-Main alleles:
•CYP2C9*1 = wild type
•CYP2C9*2 = R144C variant
•CYP2C9*3 = I359L variant
-Both SNPs lead to a decrease in the ability to convert Warfarin into its active metabolites
-Possible genotypes:
•1*/1*: normal, WT —> extensive rapid, ultra-metabolizer
-Need a smaller dose
•1*/2* or 3*: heterozygote —> poor, slow metabolizer
•2*/3*: compound heterozygote —> poor, slow metabolizer
•2*/2* or 3*/3*: homozygote —> will have extreme difficulty metabolizing the drug
-Require a larger dose to maintain a sustained effect
•VKORC1: vitamin K epoxide reductase (Warfarin target)
-Main SNP: 1639G>A
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