Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

• Published in: PloS one Vol. 12; no. 1; p. e0169233
• Main Authors: Goh, Liuh Ling, Lim, Chia Wei, Sim, Wey Cheng, Toh, Li Xian, Leong, Khai Pang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.01.2017; Public Library of Science (PLoS)
• Subjects: Alleles; Annotations; Asian Continental Ancestry Group - genetics; Automation; Biology and Life Sciences; China; Clinical medicine; Consortia; Copy number; CYP2D6 protein; Cytochrome; Cytochrome P-450; Cytochrome P-450 Enzyme System - genetics; Cytochrome P450; Deoxyribonucleic acid; DNA; Drug metabolism; Drug therapy; Enzyme Assays; Enzymes; Ethnic Groups - genetics; Gene Frequency; Genes; Genetic aspects; Genetic diversity; Genetic Loci; Genetic Variation; Genomics; Genotype & phenotype; Genotypes; Genotyping; Haplotypes - genetics; Humans; Identification and classification; India; Knowledge bases (artificial intelligence); Laboratories; Malaysia; Medicine and Health Sciences; Metabolism; Minority & ethnic groups; People and places; Pharmacogenomics; Pharmacological research; Pharmacology; Phenotype; Precision medicine; Properties; Reproducibility of Results; Research and Analysis Methods; Singapore; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Test procedures; Therapy; Toxicity; Workflow
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0169233

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. 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. 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. 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.