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Pharmacogenetics
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You’re at MD at urgent care...
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Both need painkillers. You decide on codeine
Codeine is a very common painkiller and is on the list of the World Health
Organization’s Essential Medicines.
How much do you prescribe each of them?
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Based on your codeine dose...
Lebron is asleep, constipated, and wakes up only to vomit.
Italian grandma is still in pain
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What do you do now?
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Decreased dose for Lebron
Now, he’s getting way less than what you prescribed for a 5year old yesterday, but:
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Increased the dose for grandma...
Still in pain?
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Give grandma a very small dose of morphine
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Codeine is a prodrug
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Bioactivation by CYP2D6
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Bioactivation by CYP2D6
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Bioactivation by CYP2D6
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Variation in CYP2D6 activity
1/Efficiency of metabolizing codeine
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Variation in CYP2D6 activity
1/Efficiency of metabolizing codeine
Why don’t we have 3 distinct
buckets?
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dbSNP showing CYP2D6 region
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CYP2D6 and codeine
Kirchheiner 2007
Death of 3
children in 2012
Ultrametabolizers who take codeine may end up with
50% more morphine in their bodies than the average
person taking the same dose
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Pharmacogenetic dream
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You just performed a cesarean section...
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24 hours later...
What may have happened?
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24 hours later...
codeine morphine
codeine morphine
At least one baby has died from this in real life.
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Clinical Pharmacogenetics Implementation Consortium
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Pharmacogenetic testing is safer
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170905
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CPIC
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CPICHOW not WHETHER
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Cytochrome P450 familyCommon theme: Detoxification of endogenous and environmental compounds. (hormones, drugs, carcinogenic compounds in food, plant chemicals).
One original cytochrome P450 from 2 billion years ago that has duplicated and divided into 14 families.
The recent 'burst' in new P450 genes appears to be the result of animal-plant warfare.
Induction of expression by environmental exposures.
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Cytochrome P450s and genetic variation
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Cytochrome P450s and genetic variation
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Grapefruit and CYP3A4 inhibition
What type of pharmacogenetic metabolizer group does this mimic?
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Types of pharmacogenetic variation
Metabolizer enzymes (like the Cytochrome P450s)
Transporter proteins (control flow of molecules through membranes)
Allergic reactions (like abacavir and HLA-B*15:02 hypersensitivty)
Pharmacodynamic effects (the mechanism of action like ivacaftor in cystic fibrosis)
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Warfarin (Coumadin) - anticoagulant
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Warfarin (Coumadin) - anticoagulant
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Narrow therapeutic window
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Narrow therapeutic window
Lower CYP2C9 activity
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Table vs Algorithm. Genetics and warfarin dose
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Genetic variation and warfarin dose in Caucasians
The CYP2C9*2 and CYP2C9*3 alleles explain 12% of dose variability.
Two SNPs in VKORC1 explain 30% of dose variability.
How we can get these values of proportions explained?
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Warfarin daily dose algorithm (Caucasian only)Coefficients Estimate Standard error P
Intercept 9.468 0.118 < 2 × 10−16
VKORC1 rs9923231 A/G −0.901 0.049 < 2 × 10−16
rs9923231 A/A −2.018 0.067 < 2 × 10−16
CYP2C9 *1/*1 (no *2 or *3 variant) 0
*1/*2 −0.508 0.058 < 2 × 10−16
*1/*3 −0.975 0.070 < 2 × 10−16
*2/*2 −1.102 0.197 3.0 × 10−8
*2/*3 −1.747 0.203 < 2 × 10−16
*3/*3 −3.400 0.330 < 2 × 10−16
Age, y −0.036 0.001 < 2 × 10−16
sexF −0.276 0.046 4.2 × 10−9
Interaction × number of drugs that increase INR† −0.069 0.018 .001
http://www.bloodjournal.org/content/113/4/784?sso-checked=true
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Warfarin daily dose algorithm (Caucasian only)
Variants don’t all do the same
thing!
Coefficients Estimate Standard error P
Intercept 9.468 0.118 < 2 × 10−16
VKORC1 rs9923231 A/G −0.901 0.049 < 2 × 10−16
rs9923231 A/A −2.018 0.067 < 2 × 10−16
CYP2C9 *1/*1 (no *2 or *3 variant) 0
*1/*2 −0.508 0.058 < 2 × 10−16
*1/*3 −0.975 0.070 < 2 × 10−16
*2/*2 −1.102 0.197 3.0 × 10−8
*2/*3 −1.747 0.203 < 2 × 10−16
*3/*3 −3.400 0.330 < 2 × 10−16
Age, y −0.036 0.001 < 2 × 10−16
sexF −0.276 0.046 4.2 × 10−9
Interaction × number of drugs that increase INR† −0.069 0.018 .001
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CYP2C9 variation globally
pharmGKB allele frequency tables
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Knowledge of variant function
pharmvar.org
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Knowledge of variant function
CYP2C9*3
pharmvar.org
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Knowledge of variant function
CYP2C9*4
CYP2C9*5
CYP2C9*6
pharmvar.org
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VKORC1 More SNPs, more precision?
rs2359612 explained 33.3% (P = 5.78 × 10−73) of dose variability
rs9923231 explained 32.8% (P = 3.97 × 10−72)
Included together, they explain 34% of variability.
Why?
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Let’s look up our SNPs on LDpop
https://ldlink.nci.nih.gov/?tab=ldpop
rs9923231 and rs2359612(use r2)Look at CEU, YRI, CHB and JPT.
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Let’s look up our SNPs on LDpop
https://ldlink.nci.nih.gov/?tab=ldpop
rs9923231 and rs2359612CEU: 1.0YRI: 0.13CHB: 1.0JPT: 1.0
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Let’s look up our SNPs on LDpop
https://ldlink.nci.nih.gov/?tab=ldpop
rs9923231 and rs2359612CEU: 1.0YRI: 0.13CHB: 1.0JPT: 1.0
In African Americans, VKORC1 genotype still matters, but results in ½ the effect size as in
these other populations
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African American as a variable
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513254/
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Summary
• Genetics can change drug response by altering drug target, drug metabolism, and drug transport, and by triggering allergies. Using genetic information can improve toxicity and efficacy of drugs.
• These variants only matter when faced with an external substance.
• Frequencies of variants vary greatly across the world.
• Genetic tests can inform treatment but are based incomplete information (complex biological systems and limited understanding of functional effects of variants).