Goh Liuh Ling, Lim Chia Wei, Sim Wey Cheng, Toh Li Xian, Leong Khai Pang
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.
PLoS One. 2017 Jan 3;12(1):e0169233. doi: 10.1371/journal.pone.0169233. eCollection 2017.
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 CYP2C93, CYP2C192, CYP2D610, CYP2D636, CYP2D641, CYP3A53 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.
药物反应的遗传决定因素在整个生命过程中保持稳定，为患者量身定制的药物治疗带来了巨大希望。在患者护理中采用药物遗传学（PGx）检测需要准确、经济高效且快速的基因分型，并对结果的使用提供明确指导。因此，我们评估了一个包含32个单核苷酸多态性（SNP）的面板，用于在临床实验室中实施PGx检测。
我们设计了一个用于临床实验室PGx检测的32-SNP面板。这些变体是根据药物基因组学知识库（PharmGKB）的临床注释选择的，包括CYP2C9、CYP2C19、CYP2D6、CYP3A5和VKORC1基因的多态性。通过针对内含子2和外显子9区域的TaqMan拷贝数测定法同时确定CYP2D6基因等位基因定量。根据与Sequenome质谱阵列和液滴数字PCR独立分析确定的基因型的一致性，基因分型结果显示出高检出率准确性。此外，我们对新加坡三个主要种族（马来族、印度族和华裔）的506个基因组样本进行了分析。
我们发现98%的研究对象携带一种或多种临床药物基因组学实施联盟（CPIC）可操作变体。检测到的主要等位基因包括CYP2C93、CYP2C192、CYP2D610、CYP2D636、CYP2D641、CYP3A53和VKORC1*2。在我们的人群中，这些等位基因导致这些基因的中间代谢型（IM）和慢代谢型（PM）表型的比例很高。
基因分型可能有助于识别我们人群中在标准剂量药物治疗下易发生药物毒性的患者。这个PGx面板的简单性和稳健性非常适合在临床实验室中使用。
