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Pharmacogenomics
Pharmacogenomics--impact of race, ethnicity, and environment
| Question | Answer |
|---|---|
| A single nucleotide difference must be present in what percentage of the population in order for it to be considered an SNP? | >1% of population |
| What are the three types of SNPs? | Coding non-synonomous, coding synonomous, noncoding |
| Coding non-synonymous SNP | change in the coding sequence |
| Coding synonymous SNP | No change in the coding sequence, although it could change the translational efficiency |
| Noncoding SNP: what is it, where could it occur? | SNP results in noncoding of the gene (could be a change in the promoter, intron, or the regulatory region) |
| If an insertion or deletion is very large, what could it be classified as? | A copy number variation (CNV) |
| CNV | variation in the number of a specific segment of DNA found in one or more populations; averages from 10^3-10^6 bp; present in 10% of human genome |
| What phenotype is a CNV (duplication) of CYP2D6 associated with? | Ultra rapid metabolizers |
| Which type of SNP account for the most genetic variations associated with complex human traits (including drug response phenotypes)? | Non-coding SNPs |
| Which type of SNPs change the function of a protein function the most? | Coding non-synonymous |
| Most genetic variants (including SNPs) that are likely to alter drug response (are/are not) contained within gene coding regions | Are NOT |
| Mutations in what three types of genes are most likely to affect drug action? | Common cytochrome P450s (CYPS), transporters, and receptors |
| Genetic polymorphisms in major therapeutically relevant CYPs affect the _____ of drugs. | Pharmacokinetics |
| CYP genetic polymorphisms are responsible for different ___ ___ ___. | Drug metabolizing phenotypes |
| How can genetic polyumorphisms of transporter proteins affect the pharmacokinetics and pharmacodynamics of drugs? | PK: drug absorptions and elimination; PD: drug concentrations @ site of action |
| What is the most well studied transporter with known polymorphisms? What is it associated with? | P-glycoprotein, which is a product of the ABCB1 gene (aka multidrug resistance [MDR1] gene); associated with drug resistance |
| What does p-glycoprotein do? What happens to drug PK + PD if it is defective? | It transports molecules from the outside of the cell into the cell; malfunctioning protein results in accumulation in blood (can't go into tissue)-->drug resistance + drug toxicity |
| A defect in the ABCB1 would result in what modbidity when treating with calcineurin inhibitors? | In renal patients, results in nephrotoxicity (usually due to cyclosporin A and tacrolimus) |
| What is the gene associated with B2-adrenergic receptor? What is the most common mutation? What types of drugs might be affected? | ADBR2; coding non-synonymous SNPs resulting in change of Arg16 to Gly and Gln27 to Glu-->change patient response to Beta blockers (Beta-2 adrenergic antagonists) and agonists (albuterol [asthma medication]) |
| What receptors do beta-blockers act on? | B2 adrenergic receptor (antagonists) |
| What receptors does albuterol affect? What's it used for? | B2 adrenergic receptor (agonist); asthma |
| What is trastuzumab used to treat? How does it work? | Monoclonal antibody against Her-2 receptor; used to treat cancers with CNVs (gene amplification) of Her-2 |
| How can genetic polymorphisms affect the drug pharmacodynamics without altering drug levels in blood? | By changing the transporters at the site of action, drug response may differ (???) |
| ____ (___) polymorphisms are present in all ethnic groups with different frequencies among those groups | Cosmopolitan (racial) polymorphisms |
| What is the difference between cosmopolitan and population specific polymorphisms? | cosmopolitan polymorphisms are present in all groups (before great migratory events) while ethnic polymorphisms are typically newer when groups have become genetically isolated |
| Which population in America has the greatest amount of population-specific polymorphisms? Why? | African Americans; have both population specific polymorphisms and relatively large number of older (cosmopolitan) polymorphisms |
| What drug trial lead to the only "race-specific" drug approval by the FDA? What was the drug? What did it treat? | The African American Heart Failure Trial (A-HeFT); isosorbide (vasodilator) and hydralazine (anti-hypertensive); congestive heart failure |
| How could one more accurately predict drug treatment outcomes? | May be more reliable to look at genetic rather than ethnic or racial differences. |
| What gene is most strongly associated with ADR to statins? What other gene was associated to a lesser degree? | Organic anion transport gene (SLCO1B1)--associated with risk of simvastatin induced myopathy; older data suggested CYP3A4 |
| What is an epigenetic trait? | Stably heritable phenotype resulting from changes in a chromosome without alterations in DNA sequence |
| What is pharmacoepigenetics? | Study of the consequence of epigenetic changes on drug action |
| What two structures/places are the sites of epigenetic differences? | DNA itself or chromatin associated proteins |
| Epigenetic changes relevant to drug action mainly alter the ____ levels of proteins involved in drug action. | Expression |
| What environmental factors can trigger epigenetic alterations in drug metabolism? Are they reversible? | Prenatal nutrition, prenatal stress, smoking; irreversible |
| CYP1A1: what does it do to tobacco smoke, where is it induced, how is it changed? | Activates specific procarcinogens in tobacco smoke; induced in the lung by tobacco smoke mainly due to alterations in methylation within promoter sequence |
| Technological barriers to obtaining wide information of relevance to drug action have largely been overcome with the advent of ___ ___ ___ for SNP, CNV, and epigenetic analysis. | Genome wide chips |
| What are some of the limitations of genome wide chips? | Based upon sequence information from Americans of European descent; some procedures will not reveal duplications, CNVs, expanded triplet repeats; ethical issues with knowledge of genetic predispositions |
Created by:
karkis77
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