Week 11 Pharmacogenetics

dinosaur1234's version from 2015-04-30 19:18


Question Answer
Pharmacogenomicsrole of inherited and acquired genetic variation in drug response; focused on how the entire genome impacts drug response
Pharmacogeneticsstudy of the genetic basis of inter-individual patient variability in the response to drug therapy; focused on how individual genes impact drug response
Chromosomepackaged and organized structure containing most of the DNA of a living organism
Genea series of codons that specifies a particular protein; contain several regions
Codonthree consecutive nucleotides that specify an amino acid; also tell you when to start/stop making protein
Polymorphismvariation in the genome that occur at a frequency of at least 1% in the human population; more than one genetic ariation (alleles) which are stable components in the population (>1%); must have 2 distinct populations separated by antimode; ex is poor and extensive metabolizers
Genotypethe identity of the alleles carried by an individual at a given gene locus; ex CYP2C9*1/*1
Homozygous genotypetwo identical alleles
Heterozygous genotypetwo different alleles
Phenotypethe outward expression of the genotype
SNPoccurs when one nucleotide base pair replaces anoter; single-base differences that exist between individuals
Nonsynonymous SNPSNPs that result in amino acid substitution; get different amino acids
Synonymous SNPSNPs that do NOT results in amino acid substitution; change to same amino acid, minimial impact
INDELsadding or removing nucleotide; may have dramatic impact; insertion or deletion of the bases in the DNA
Copy number variationsprotein will be produced more or less
Linkage disequilibrium SNPs that are passed down in more than a number that would happen by chance alone
Haplotypegroup of SNPs that vary together to influence a phenotype; common patterns of polymorphic variation; identified by examining gene expression patterns for commonality; make up a diplotype
Allelean alterantive form of a gene at a given locus; one of two or more variants of a gene; ex CYP2C9*1
Wild type allele“normal”, most common
Variant type allelealternative form of allele, not most common
Null variant allelecompletely lacks gene’s function won’t have particular gene
Tag SNPa SNP in a region of the genome with high linkage disequilibrium that represents a group of SNPs known as the haplotype; reduces time and expense of mapping genome areas associated with disease

CYP interactions and variations

Question Answer
CYP2C9 variants2C9*2 and 2C9*3; both have less activity (poor metabolizer)
Clinical applications of CYP2C9warfarin!, phenytoin!, NSAIDs, sulfonylureas
CPIC recommendations for warfarin and CYP2C9use available table or algorithms to initiats warfarin dosing based on VKORC1 and CYP2C9 genotypes
CPIC recommendations for phenytoin and CYP2C9 variationsputs patient at risk for developing phenytoin-induced toxicities; if intermediate metabolizer consider 25% dose reduction of recommended starting dose; if PM, consider 50% reduction of recommended starting maintenance dose
2C9 null variant2C9*6
CYP 2C19 most common variants2C19*2 (PM), *3 (PM), *17 (ultra rapid metabolizer)
2C19 null variants*4
Clinical applications of 2C19Clopidogrel!!, diazepam, TCAs, PPIs
CPIC recommendations for clopidogrel and 2C19 variationnormal dosing for ultrarapid metabolizer; alternative antiplatelet therapy for intermediate or poor metabolizers
TCA dosing recommendationsdosing for depression based on metabolizer status of 2C19
CYP2D6 normal functioning allelesCYP2D6 *1 and *2; *2xN leads to increased activity
CYP2D6 most common variant alleles with reduced functions2D6*10 and *17
CYP2D6 null variant allelesmany and common; 2D6*3, *4, *5
CYP2D6 exhibitscopy number variations
CYP2D6 clinical applicationsbrain and heart drugs; codeine!, TCA!, SSRI, AP, codeine/hydromorphone/oxycondone, dextromethorphan, tramadol, beta blockers, antiarrhythmics, tamoxifen
CPIC codeine recommendation with 2D6 variationalternate analgesics are recommended for ultrarapid and poor metabolizers; label recommended age or weight specific codeine dose for extensive and intermediate metabolizers
CPID TCA recommendation with 2D6 variationdosing recommendations for depression based on metabolizer status
Normal UGT1AUGT1A*1
UGT1A with reduced function*28
UGT1A clinical applicationsIrinotecan
N-acetyltransferase (NAT) normal alleleNAT2*4 is normal!!! Rest is reduced function (*5, 6, 7)
NAT2 slow acetylaytors have two NAT2*non-4 genes; are at increased risk of toxicity
Clinical applications of NATslow acetylators; isoniazid, hydralazine, sulfasalazine
Major superfamilies of drug transportersSLC (solute carrier) and ABC (ATP-binding cassette)
PGP (ABCB1) absorptionefflux pump that pumps drugs back into the GI lumen; absorption DI
SLOCO1B1 normal, wild type allelesSLOCO1B1*1A, *1B; these result in increased hepatocyte uptake
SLCO1B1 variant allelesSLCO1B1*5, *15, *17; result in decreased hepatocyte uptakes (decreased elimination, inc [ ] of statins)
SLOCO1B1 clinical applicationsStatins!!!
CPIC simvastatin recommendations with SLCO1B1start statins are lower dose or use alternative statin
VKOR alleles that DECREASE gene expressionVKORC1*2; decrease gene expression, so INR would increase since drug would be very effective
VKOR allele that INCREASES gene expressionVKORC1*3; need more warfarin for it to work properly
ADRB1 and ADRB2 clinical applicationsbeta agonists and beta blockers
ADRB with decreased sensitivity to beta agonists (natural beta blockade)ADRB1 389 and ADRB2 16
ADRB with increased sensitivity to beta agonists and resistant to desensitizationADRB1 49 and ADRB2 27
HMGCR SNPs and effectSNP12 and SNP 29 are both associated with a decreased statin effectiveness and have tight linkage disequilibrium (tend to be inherited together)
Clinical application fo HMGCRmore precise statin usage and dosing
Function of major histocompatibility complex (MHC)takes foreign proteins and pushes them to surface for t-cells which activates immune system; HLA is a subclass of MHC
Effect of HLA activationimmune system activated and ADR occurs
HLAb*5701 is found in which population more common in European populations
CPIC recommendation on screening for HLAB*5701prescreen for this allele in patient who are going to start abacavir; if HLA-B*5701 positive, then STOP abacavir because are at high risk for hypersensitivity reaction
HLA-B*5801 is found in which populationAsian americans
CPIC recommendations with HLA-B*5801if positive, take caution in use of allopurinol d/t possible severe cutaneous ADR; mutation is not very common at all which is why screening is not done to all patients who are going to start allopurinol
HLA-B*1502 found in which populationAsian populations (chiniese, Vietnam, Thailand, india, etc)
When to screen for HLA-B*1502patients with ancestry of populations with a high prevalence of HLA-B*1502 should be screened for mutation
Clinical application of HLA-B*1502 mutationCBZ and phenytoin; if positive, STOP CBZ (unless have already been on drug for 3 months without any cutaneous ADR); if positive, take caution in Phenytoin

Random notes

Question Answer
CYP2D6 deficiency and codeinedeficiency converts LESS of the codeine to morphine, which is responsible for most of the analgesic effect of codeine
Population with 2D6 PM5-10% of Caucasians; this is the highest percentage ; most commons is CYP2D6*4
How to dose warfarin if polymorphismslower initial doses for CYP2C9 PM and intermediate metabolizers and VKORC1*2 patients; higher initial doses with patients who have VKORC1*3
Trials done with warfarin dosing and testinghave seen mixed results; meta analysis showed no difference between genotypic and clinical dosing in terms of percent of time in a therapeutic INR
What is needed to convert clopidogrel to its active formCYP2C19; patients with poor metabolizer would demonstrate less efficacy
Population with 2C19 variant45-55% of asain americans express the PM phenotype
G6PD variant allelesclass 2 and class 3
DI if G6PD variant allelesrasburicase, primaquine, sulfonylureas, dapsone
Drugs with BBW due to pharmacogenomicsAbacavir, CBZ, Clopidogrel, Codeine, Rasburicase
Abacavir BBWrisk of hypersensitivity reactions, lactic acidosis, and severe hepatomegaly in patients with HLA-B*5701 allele
CBZ BBserious dermatologic reactions in HLA-B*1502 allele, including SJS and TEN, especially in Chinese and Asain ancestry
Clopidogrel BBWdiminished effectiveness in poor metabolizers of CYP2C19
Codeine BBWdeath related to ultra-rapid metabolism of codeine to morphine (CYP2D6)
Rasburicase BBWdo not administer to patients with G6PD deficiency due to risk of hemolysis; screen those at high risk (African or Meditteranea ancestry)


Question Answer
2C9 PM and IMCaucasian
2C19 PMAsians
2D6 PMCaucasian
UGT PMAfrican
NAT slow acetylatorAfrican and caucasian
SLCO1B1 increased heapti uptake (*1A, *1B)all 3 populations (African > Asian > Caucasian)
HLAB*5701 positiveCaucasian
HLAB*5801 positiveAsian
HLAB*1502 positiveAsian
G6PD class 2 and 3in parts of Africa, Asia, and Meditteranean; in US most prevalent in African