Introduction of the AmpliChip CYP450 Test to a South African cohort: a platform comparative prospective cohort study.
BACKGROUND
Adverse drug reactions and lack of therapeutic efficacy associated with currently prescribed pharmacotherapeutics may be attributed, in part, to inter-individual variability in drug metabolism. Studies on the pharmacogenetics of Cytochrome P450 (CYP) enzymes offer insight into this variability. The objective of this study was to compare the AmpliChip CYP450 Test® (AmpliChip) to alternative genotyping platforms for phenotype prediction of CYP2C19 and CYP2D6 in a representative cohort of the South African population.


METHODS
AmpliChip was used to screen for thirty-three CYP2D6 and three CYP2C19 alleles in two different cohorts. As a comparison cohort 2 was then genotyped using a CYP2D6 specific long range PCR with sequencing (CYP2D6 XL-PCR + Sequencing) platform and a PCR-RFLP platform for seven CYP2C19 alleles.


RESULTS
Even though there was a low success rate for the AmpliChip, allele frequencies for both CYP2D6 and CYP2C19 were very similar between the two different cohorts. The CYP2D6 XL-PCR + Sequencing platform detected CYP2D6*5 more reliably and could correctly distinguish between CYP2D6*2 and *41 in the Black African individuals. Alleles not covered by the AmpliChip were identified and four novel CYP2D6 alleles were also detected. CYP2C19 PCR-RFLP identified CYP2C19*9,*15, *17 and *27 in the Black African individuals, with *2, *17 and *27 being relatively frequent in the cohort. Eliminating mismatches and identifying additional alleles will contribute to improving phenotype prediction for both enzymes. Phenotype prediction differed between platforms for both genes.


CONCLUSIONS
Comprehensive genotyping of CYP2D6 and CYP2C19 with the platforms used in this study, would be more appropriate than AmpliChip for phenotypic prediction in the South African population. Pharmacogenetically important novel alleles may remain undiscovered when using assays that are designed according to Caucasian specific variation, unless alternate strategies are utilised.
Department of Pharmacology, University of Pretoria, Pretoria, South Africa.
Tyren M
TM
Dodgen
Warren E
WE
Hochfeld
Heidi
H
Fickl
Sahle M
SM
Asfaha
Chrisna
C
Durandt
Paul
P
Rheeder
Britt I
BI
Drögemöller
Galen E B
GE
Wright
Louise
L
Warnich
Christiaan D J
CD
Labuschagne
Antoinette
A
van Schalkwyk
Andrea
A
Gaedigk
Michael S
MS
Pepper
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D015331:Cohort Studies; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005787:Gene Frequency; D060005:Genotyping Techniques / Q000379:methods*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies
D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6