Ultrarapid Metabolizer (CYP2C19)
-increased activity (5-30% of patients)
Genotype:
- two increased activity alleles (17)
- one functional allele (1) + one increased activity allele (*17)
Ex) 1/17 or 17/17
Result:
- normal or increased platelet inhibition
- normal or decreased platelet aggregation
Recommendation:
- label recommended dosage/administration
Extensive Metabolizer (CYP2C19)
- homozygous wild type (35-50% of patients)
Genotype:
- two functional alleles (*1)
Ex) 1/1
Result:
- normal or increased platelet inhibition
- normal or decreased platelet aggregation
Recommendation:
- label recommended dosage/administration
Intermediate Metabolizer (CYP2C19)
- heterozygote or intermediate activity (18-45% of patients
Genotype:
- one functional allele (1) + one loss of function allele (2-*8)
- one loss of function allele + one increased activity allele
Ex) 1/2 or 1/3 or 2/17
Result:
- reduced platelet inhibition
- increased platelet aggregation
- increased risk of MACE
Recommendation:
- alternative antiplatelet therapy
Poor Metabolizer (CYP2C19)
- homozygous variant/mutant/low activity (2-15% of patients)
Genotype:
- two loss of function alleles (2-8)
Ex) 2/2 or 2/3 or 3/3
Result:
- significantly reduced platelet inhibition
- significantly increased platelet aggregation
- significantly increased risk of MACE
Recommendation:
- alternative antiplatelet therapy
How can a genotype determine a phenotype?
Change PK (effect body has on a drug)
- alters enzymatic activity during ADME
- directly leads to inter-patient difference in drug concentrations, doses, durations, etc
- inter-patient difference in toxicities and efficacies
Change PD (effect drug has on the body)
- alters drug target activity
- creates new drug target
- alters structure of protein
- change drug receptor binding
MAF
minor allele frequency
- % are population based and can differ between populations that were analyzed or viewed
- always testing the genotype (2N) –> combination of alleles
Observed Genotype Data
- there is always only 3 genotypes
- T/T or T/C or C/C
Formulas for MAF
T allele% : 2(# of ppl with homozygous T) + # of heterozygous people –> divided by 2N
C allele% : 2(# of ppl with homozygous C) + # of heterozygous people –> divided by 2N
T allele%: T genotype% + 1/2 (T/C genotype %)
C allele%: C genotype% + 1/2 (T/C genotype %)
Common and Rare Alleles
- allele frequencies normally stay stable within a population
Common/Major/Reference Allele: frequency > 50%
Rare/Minor/Mutant Allele: frequency < 50%
A RARE ALLELE IN ONE POPULATION CAN BE A COMMON ALLELE IN ANOTHER POPULATION
Crossover and Recombination
- occurs between homologous chromosomes during meiosis to produce gametes
Recombinant Chromosome: chromosome that is a result of crossover
Non-Recombinant Chromosome: chromosome without crossover (original)
FURTHER INCREASES THE GENETIC DIVERSITY OF A POPULATION
Haplotype
- group of genes within an organism that were inherited together from a single parent
- also referred to as a inheritance of a CLUSTER of SNP’s
Linkage Disequilibrium (LD)
- non random association of alleles at different locus on the same chromosome
When there are infinite recombination?
no LD
When there is no recombination?
complete LD
When recombination occurs in a portion of chromosomes?
incomplete LD
Examples of LD in Pgx
- If the distance between two loci is short enough, there will be no recombination in a population
- leads to co segregation of both loci to the next generation
- complete LD
- called a haplotype block - If the distance between the two loci is long enough, there will be a large number of recombination between the two loci in a population
- independent segregation of the two loci into the next generation
- no LD
Measures of LD
R2: how strong is the correlation between two variables
- measures the extent of concordance in genotypic association between two loci
- varies from 0 to 1
R2 = 0
no LD
R2 = 1
complete LD
R2 ≥ 0.8
strong LD
