Pharmacogenomics Flashcards
Human leukocyte antigen (HLA) is also known as:
Human major histocompatibility complex (MHC)
HLA encodes a number of proteins involved in immune function, such as:
Antigen presenting molecules, cell surface markers, etc. Class I HLA molecules present fragments of foreign antigens to CD8+ T-cells.
HLA B*5701
How does this gene predict efficacy or toxicity of drug therapy?
Which drug? How strong is the association?
Abacavir (Ziagen) hypersensitivity reaction is strongly associated with HLA B*5701 allele.
Background: Abacavir hypersensitivity reaction (HSR) occurs within the first 6 weeks of
initiating treatment. This reaction is associated with two or more of the following symptoms:
fever, rash, n/v/d, cough/SOB/sore throat, general malaise/fatigue/aches.
Patients with documented or suspected HSR should never take abacavir again as rechallenge can be fatal.
HLA B*5701 is more prevalent in:
Whites of European ancestry (~5-8%) and less prevalent in black patients (~2-3%).
How clinically relevant is testing for HLA B*5701?
Very. HLA B*5701 testing has 100% negative predictive value, meaning patients who test negative for the allele will not experience HSR when taking Abacavir
Will all patients that test positive for the HLA B*5701 have a HSR to Abacavir?
No, 50% will not develop the HSR reaction
Is testing for HLA B*5701 routine in all patients being started on Abacavir?
Yes
HLA B*5701 is also correlated with what?
Natural HIV control, meaning they can naturally control HIV replication
HLA B*1502
How does this gene predict efficacy or toxicity of drug therapy?
Patients with HLA B*1502 have an increased risk for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) secondary to carbamazepine (Tegretol).
What population possesses the HLA B*1502 allele?
HLA B*1502 is found almost exclusively in patients of Asian ancestry.
Who should be screened for HLA B*1502?
Patients that are genetically at risk.
Not a standard of care in the US
Patients of Asian descent being started on carbamazepine should be screen (not usually used d/t newer anticonvulsants)
CYP 2C19*2
How does this gene predict efficacy or toxicity of drug therapy? Which drug?
CYP 2C192 is a loss of function allele. Patients carrying this allele have limited to no functional CYP 2C19 enzymes, making it very difficult to metabolize drugs that rely predominantly on this pathway. Clopidogrel (Plavix) is a prodrug that is activated after it is metabolized by CYP 2C19. Patients with CYP 2C192 are unable to metabolize and activate clopidogrel, rendering clopidogrel highly ineffective. Although the association is strong, it is not the only explanation for why some patients are clopidogrel-resistant (meaning the drug is ineffective).
CYP 2C19*2 is most prevalent in:
Most prevalent in Asians followed by Caucasians and African-Americans.
Why is there mixed opinion on the relevance of CYP 2C19*2?
Studies have been mixed. Patients taking clopidogrel who had reduced-function CYP
2C192 allele have had a significantly increased risk of stent thrombosis and death from
MI or stroke (TRITON-TIMI 38, RECLOSE, and other trials). On the other hand, some
studies show no correlation between CYP 2C192 and decreased clinical benefit of
clopidogrel (EXCELSIOR and CLARITY-TIMI 28 trials).
Is screening for 2C19*2 a standard of care?
In some institutions
IL28B genotypes CC, CT, TT
How does this gene predict efficacy or toxicity of drug therapy? Which drug?
IL28B genotypes (CC, CT, TT) predict efficacy of hepatitis C treatment with interferon alpha and ribavirin with/without HCV protease inhibitors. The genotypes are strong and independent predictors of viral responsiveness to treatment. Patients with genotype CC have been shown to have higher sustained virologic response (SVR) rates than patients with genotypes CT and TT. Note: SVR means that HCV RNA (HCV viral load) is not detected 8-12 weeks after completing HCV treatment (aka cure). IL28B are human genotypes, not to be confused with HCV genotypes 1-4, which are viral genotypes.
Prevalence of IL28B genotypes CC, CT, TT,
Genotype CC (the one associated with higher cure rate) is more prevalent in Caucasians compared to Hispanics; African-Americans have the lowest rate of genotype CC and the highest rate of genotype TT. African Americans have always had a significantly lower rate of SVR (cure) compared to Caucasians, and the difference in prevalence of the favorable CC genotype may explain some of the reason. However, African Americans with the CC genotype still have lower cure rates than Caucasians with the CC genotype. Therefore, IL28B does not explain the whole story.
Clinical relevance of IL28B:
IL28B genotype is a strong and independent predictor of response to a toxic treatment
regimen that was more relevant when HCV was difficult to treat and regimens were more
toxic. The availability of highly effective HCV treatment regimens without the need for
interferon/ribavirin decrease the clinical relevance of this type of genetic testing.
A variation in a DNA sequence is a:
SNP (single nucleotide polymorphism)
How are pharmacogenetics and pharmacogenomics different?
Pharmacogenetics is the study of variability of drug response d/t genetic factors while pharmacogenomics is the development of drugs based on pharmacogenetics
2D6 expression is functionally absent in 7% of ______ and _________ and high among _______ .
Caucasians and African Americans
Ethiopians
Polymorphisms that affect drug metabolism can result in what three types of metabolizers?
Ultra-rapid metabolizers
Extensive- normal metabolizers
Poor- poor metabolizers
How do patients who are ultra metabolizers of 2D6 respond to codeine and nortryptiline?
Codeine will be effective (must be metabolized by 2D6) but they will have an increase in AE
Nortryptiline will no be effective (it is an administered in an active form and metabolized to an inactive form) and there will be a decrease in AE
Patients who have polymorphism of ALOX5 will not respond to treatment of asthma with what drug?
Zileuton
