319 Genetic Polymorphism

VIPs

Very important Pharmacogenes

Tier 1 VIPs

Genes with substantial evidence to support their importance in pharmacogenomics.

Genetic Polymorphism

Genetically controlled, hereditary. At the DNA level called genotype (*1, *2, *3). Effect lasts for a lifetime. Useful for individual treatment adjustment only when the individual patient is typed. May cause relative increase OR decrease in the metabolism by a particular enzyme, depending on the polymorphism. Relatively high, medium, or low. 

PM

Poor metabolizer 

IM

Intermediate metabolizer

EM

Extensive metabolizer

URM

Ultra-rapid metabolizer 

CYP2D6

Activity is extremely variable, more than 50 genetic variations. Has 4 main levels of activity. UM, EM, IM, PM

Ultra-rapid metabolizer

Only in certain population, has more than 3 copies of the active CYP2D6 gene, exhibits extremely high CYP2D6 Activity.

Extensive Metabolizer

Has 2-3 functional copies of the CYP2D6 Gene. Displays typical CYP2D6 activity. In presence of CYP2D6 inhibitor may show poor metabolizer phenotype. 70-90% of individuals

Intermediate Metabolizer

Decreased activity. In about 5-30% of individuals

Poor Metabolizer

Abolished activity in 0-8% of individuals. Has two nonfunctional CYP2D6 Alleles. Non CYP2D6 can be found in the liver. 

What is the genotype for phenotype PM Truncate protein

*3, *6

What is the genotype for phenotype PM non-functional

*4

What is the genotype for phenotype PM whole gene delete

*5

What is the genotype for phenotype IM Reduces Function

*10, *17, *29, *41

What is the genotype for phenotype IM/EM reduce function

*9

What is the genotype for phenotype EM similar to Wildtype 

*2 

What is the genotype for phenotype EM wildtype

*1

CYP2D6 URM Example Codeine

CYP2D6 URM individuals convert codeine into its active metabolite, morphing more rapidly and completely than other people. This rapid conversion results in higher-than-expected serum concentration of morphine levels. Even at labeled dosage regimens, individuals with URM might have life-threatening, fatal respiratory depression, or signs of OD. 

CYP2D6 Genotype alters Metoprolol effect on HR

If you have too little active CYP2D6 than the metoprolol is not being cleared so it stays in the body longer, lowering heart rate too much. If you have too many active CYP2D6 genes, the metoprolol is metabolized very quickly, so it does not stay in the body long and HR does not lower enough.

Inhibition of CYP2D6 metabolism

The use of a strong CYP2D6 inhibitor can render a patient that is a genotype CYP2D6 EM into a phenotypic 2D6 PM.

Extensive CYP2C19 Genotypes

Majority of population: CYP2C19*1/*1

Intermediate CYP2C19 Genotypes

CYP2C19*1 on one allele and CYP2C19*2 on the other
CYP2C19*1 on one allele and CYP2C19*3 on the other

Poor CYP2C19 Genotypes

two *2 or *3 variant alleles. Absence of CYP2C19 

Ultra-Rapid CYP2C19 Genotype

One or two *17 variant alleles, high 2C19 activity alleles

Clopidogrel and CYP2C19 variants

patients carrying at least one CYP2C19*2 allele (low
activity) are more prone to [clopidogrel resistance],
which is associated with poor clinical outcome

Prasrugrel

Does not need a cyp to convert into an active drug

Warfarin Metabolism

Wide individual variation in effective steady-state doses. Its elimination is almost entirely by metabolism to inactive metabolites. S-warfarin is oxidized by CYP2C9 to 7-hydroxy-warfarin. R-warfarin is oxidized by CYP3A4 and 1A2 to 10-hydroxy warfarin. Both the 7 and 10 metabolites can slow down the enzyme that made them (self limiting feedback)

Complete inhibition of CYP2C9

May be expected to result in lower maintenance dose requirement of warfarin

Warfarin Resistance

Should be suspected if large daily doses are required to maintain a patient’s TD within a normal range. It is caused by variant of VKORC1 that is not inhibited by warfarin