Flashcards in Pharmacogenetics Deck (28):
What is pharmacogenomics?
A subdiscipline of pharmacogenetics that uses tools to survey the entire genome to assess the genetic determinants of drug response
What is a polymorphism?
A variation in DNA sequence that present at a frequency of at least 1% in a population
What is the difference between a genotyping and phenotyping test for metabolic enzymes?
Genotyping - test DNA for presence of specific polymorphism
Phenotyping - administer a probe substrate known to be metabolized by the substrate of question, and monitor blood levels to assay metabolism
What are some of the positive clinical applications of pharmacogenetics?
1. Better screening for potential drug candidates
2. Better identification of therapeutic dose
3. Improved ability to select potential protein targets for drug development
4. Better ability to ID patients who might e at increased risk for therapeutic failure / adverse drug reaction
What is a "phenotype-to-genotype" approach?
A method of identifying pharmacogenetic traits by looking at drug response outliers and comparing them to normal to determine the genetic basis for the response
What is the debrisoquine polymorphism example?
Dr. Robert Smith was developing an anti-hypertensive drug. Took a dose of it, and had orthostatic hypertension for several days. Was found to have a CYP2D6 mutation which made him metabolically deficient in drug processing -> drug product found in his urine even days later.
What can cause an extensive metabolizer of debrisoquine vs poor vs ultrarapid?
Poor = mutant CYP2D6 alleles
Extensive = normal
Ultrarapid = multiple copies of CYP2D6
What is the newest approach for discovering pharmacogenetic traits?
Reverse genetic, genotype-to-phenotype approach
Use GWAS (Genome wide association studies) to identify genetic polymorphisms, and then determine if these associate with a phenotypic variability.
What have twin studies shown regarding drug metabolism?
Drug metabolism is highly heritable -> monozygotic twins are much more similar than dizygotic
What is a multigenerational kindred study?
One that studies interfamily vs intrafamily variability in drug metabolism
What is meant by autosomal dominant, recessive, and co-dominant genetic inheritance of drug metabolism and which is most common?
Dominant - need just one copy of the mutant allele to have impaired metabolism
Recessive - need both copies of mutant allele to have impaired metabolism
Co-dominant - **most common** - drug metabolism is based on copy number. Those heterozygous for the mutant allele will have a slightly slower metabolism than those with two functional alleles
When is it easy vs hard to make accurate predictions about drug metabolism based on genetics?
Monogenic traits - easy, based on one gene
Multigenic - based on multiple genes, can be near impossible to predict phenotype because of all the different combinations
What type of system governs warfarin metabolism?
Digenic trait -> two genes. One is fully dominant, the other is co-dominant.
What are the three major types of genetic polymorphisms and which is most common?
1. SNPs - single nucleotide repeats, most common, every 100 to 1000 bp
2. Insertions and deletions
3. Copy number variants
What is a non-synonymous vs synonymous SNP?
Two types of SNPs occuring in the coding region (cSNPs)
Non-synonymous = missense - change in amino acid
Synonymous = sense - silent - can still lead to a meaningful change in protein due to changes in processing of protein speed -> change in folding / conformation
What is a nonsense SNP?
Base pair change introduces a stop codon
How can polymorphisms in non-coding regions be relevant?
In 5' or 3' UTRs can alter cis-elements which determine mRNA translation or stability.
Can alter promoter or ehancer
Can lead to alternate splice sites if near exon-intron boundaries (introducing frameshift or premature stop)
can affect intergenic regions
How can a SNP in an intergenic region be impactful?
May affect DNA tertiary structure and interaction with chromatin, topoisomerases, or DNA replication
What two sites for SNPs show the largest association with human variants in disease?
1. Intronic - due to splice site changes
2. Intergenic - due to reasons described previously
What is a haplotype? How does this relate to SNP function?
A specific set of SNPs on a single chromosome or gene
(if two bases are known to vary in the gene, the haplotype you have would just be the two bases associated with those numbers)
Some SNPs are only relevant when in combination with other SNPs, others are only relevant when alone
What is linkage disequilibrium?
When the genotypes at two loci are not independent of one another -> one gene tends to be inherited with another
What is complete linkage disequilibrium?
Genotypes at two loci always occur together
i.e. when one SNP is present, a second SNP is always present.
What factors of a drug can make a pharmacogenetic polymorphism more important?
1. Narrowness of therapeutic index / sharpness of dose response curve
2. Limited availability of alternative clearance pathways / enzymes
3. Absence of alternative drugs
Why might a drug polymorphism be maintained in a population?
Without selective pressure such as metabolism of a drug to cure a disease, there may be no issue with a variation in drug response.
What is the acetylation polymorphism and what is the major gene affected?
NAT2 is primarily affected
"Fast" acetylation is dominant, individual must have two "slow" alleles to see an affect. Large ethnic variability, with altered response to many chemicals including caffein and 4-aminobiphenyl (bladder carcinogen)
Why is acetylation polymorphism clinically important?
Slow acetylators are more prone to hemolytic anemia during treatment with sulfra drugs, and have a higher incidence of bladder cancer
Why do white people tend to get way less flushed than Asians when drinking alcohol?
Asians often have an ADH2*2 polymorphism, while whites have ADH2*1. ADH2*2 has a much higher Vmax, causing toxic buildup of acetaldehyde very quickly.
Additionally, half of asians have an Aldehyde dehydrogenase which makes a slower conversion to acetic acid, making them even less able to detoxify the acetaldehyde which is being quickly produced.