title: Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation.
abstract: BACKGROUND
  Genetic determinants of drug response remain stable throughout life and offer great promise to patient-tailored drug therapy. The adoption of pharmacogenetic (PGx) testing in patient care requires accurate, cost effective and rapid genotyping with clear guidance on the use of the results. Hence, we evaluated a 32 SNPs panel for implementing PGx testing in clinical laboratories.
  
  
  METHODS
  We designed a 32-SNP panel for PGx testing in clinical laboratories. The variants were selected using the clinical annotations of the Pharmacogenomics Knowledgebase (PharmGKB) and include polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A5 and VKORC1 genes. The CYP2D6 gene allele quantification was determined simultaneously with TaqMan copy number assays targeting intron 2 and exon 9 regions. The genotyping results showed high call rate accuracy according to concordance with genotypes identified by independent analyses on Sequenome massarray and droplet digital PCR. Furthermore, 506 genomic samples across three major ethnic groups of Singapore (Malay, Indian and Chinese) were analysed on our workflow.
  
  
  RESULTS
  We found that 98% of our study subjects carry one or more CPIC actionable variants. The major alleles detected include CYP2C9*3, CYP2C19*2, CYP2D6*10, CYP2D6*36, CYP2D6*41, CYP3A5*3 and VKORC1*2. These translate into a high percentage of intermediate (IM) and poor metabolizer (PM) phenotypes for these genes in our population.
  
  
  CONCLUSIONS
  Genotyping may be useful to identify patients who are prone to drug toxicity with standard doses of drug therapy in our population. The simplicity and robustness of this PGx panel is highly suitable for use in a clinical laboratory.
authors.affiliation: TTSH Research Laboratory, Clinical Research & Innovation Office, Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Liuh Ling
authors.initials: LL
authors.lastname: Goh
authors.affiliation: TTSH Research Laboratory, Clinical Research & Innovation Office, Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Chia Wei
authors.initials: CW
authors.lastname: Lim
authors.affiliation: TTSH Research Laboratory, Clinical Research & Innovation Office, Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Wey Cheng
authors.initials: WC
authors.lastname: Sim
authors.affiliation: TTSH Research Laboratory, Clinical Research & Innovation Office, Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Li Xian
authors.initials: LX
authors.lastname: Toh
authors.affiliation: TTSH Research Laboratory, Clinical Research & Innovation Office, Tan Tock Seng Hospital, Singapore, Singapore.|Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Khai Pang
authors.initials: KP
authors.lastname: Leong
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D002681:China; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D057075:Enzyme Assays; D005006:Ethnicity / Q000235:genetics; D005787:Gene Frequency; D056426:Genetic Loci; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007194:India; D008296:Malaysia; D010641:Phenotype; D015203:Reproducibility of Results; D012846:Singapore
chemical_list: D003577:Cytochrome P-450 Enzyme System