Individual responses to drugs vary widely. Lack of drug efficacy can lead to ABCB1ABCB4ABCB11ABCC1ABCC2ABCC3ABCC4ABCG2CES1CES2CYP1A1CYP2D6CYP4B1CYP1A2CYP2E1CYP4F2DPYDFMO1NAT1NAT2SLC19A1SLC22A12SLC47A2SLC22A1CYP1B1CYP2J2CYP4F3FMO2NUDT1SLC22A2CYP2A6CYP2S1CYP4F8CYP2A13CYP2W1CYP4F12FMO3FMO4NUDT15SLC22A3PORSLC22A4CYP2B6CYP3A4CYP4Z1FMO5SLC10A1SLC22A5CYP2C8CYP3A5CYP11A1GSTA1SLC10A2SLC22A6CYP2C9CYP3A7CYP17A1GSTM1SLC15A1SLC22A8CYP2C18CYP3A43CYP19A1GSTP1SLC15A2SLC22A9CYP2C19CYP4A11CYP26A1GSTT1SLC16A7SLC22A11SLC47A1UGT1A3SLC28A1SLCO1B1UGT1A4SLC28A2SLCO1B3UGT1A5SLC28A3SLCO2B1UGT1A6SLC29A1SLUT1A1UGT1A7SLC29A2SLUT1A2UGT1A8SLC29A3SLUT1E1UGT1A9SLC31A1SLUT2B1UGT1A10SLC46A1TPMTUGT2B7UGT1A1VKORC1V68GP34S123456789W128XR296CR296CS486TS486TC191LL231PN285SS486TR296CG340RS486TR334QR296CR414CS486TR296CP430LS486TR497H23Genomic DNA samples collected for the international 100 important pharmacokinetics-related genes, including60drug-metabolizing enzymes and 37 drug transporterscollaborative project with SEAPharmGreece304Vietnam100Laos100UAE100MyanmarPhilippines100Thailand100Indonesia562Novel CYP2D6 haplotypes identified in 990 Japanese subjects*1*128*129*130*131*132*133*134*135*136*137Comparisons of novel nonsynonymous variants of 19 genes between Japanese and populations in the SEAPharmproject100Malaysia105JapaneseSEAPharmNovelKnowninadequate disease control and is furthermore a waste of resources; con-versely, adverse drug reactions (ADRs) are frequent and often unpredictable. Many germline polymorphisms, which are called pharmacogenomics (PGx) biomarkers, have been identified in genes that affect efficacy or ADR risk for various drugs. In Japan, the National Health Insurance System currently cov-ers only three germline genetic tests, UGT1A1, NUDT15 and BRCA1/2 tests, to predict drug responses prior to drug administration. We conduct genomic analyses for the identification of PGx biomarkers useful for predicting drug re-sponses.A newly-developed next-generation sequencing (NGS) panel, PKseq, can comprehensively and accurately analyze common and rare variants of 100 pharmacokinetics (PK)-related genes with higher sensitivity and specificity compared to whole-genome and whole-exome sequencing. Indeed, when we applied the PKseq technology to determination of haplotypes of CYP2D6, a very important drug-metabolizing enzyme for clinical therapeutics, in 990 Jap-anese subjects, 14 novel variants and 10 novel haplotypes were identified that affected the in vitro metabolic activities of CYP2D6. In addition, we clarified genetic diversity in the 100 genes by sequencing 1,571 genomic DNA samples of individuals from nine countries in Southeast Asia, Sothern Asia, Middle East, and Southern Europe, in collaboration with the South East Asian Pharma-cogenomics Research Network (SEAPharm). These results indicate that PKseq will be useful not only for the identification of all the variants of PK-related genes associated with drug responses, but also for clinical sequencing to achieve genotype-guided drug therapies.Figure: Targeted next generation sequencing panel, PKseq, for resequencing of 100 genes related to pharmacokineticsPharmacokinetic (PK) variabilities in intestinal absorption, hepatic drug metabolism, biliary and renal excretions are often responsible for inter-individual differences in drug efficacy and risk of adverse drug reactions. PKseq is a highly efficient and accurate next generation sequencing (NGS) platform for the resequencing of PK-related genes. It targets the coding regions of 37 drug transporters, 30 cytochrome P450 isoforms, 10 UDP-glucuronosyltransfer-ases, 5 flavin-containing monooxygenases, 4 glutathione S-transferases, 4 sulfotransferases, and 10 other genes.Recent Major PublicationsFukunaga K, Hishinuma E, Hiratsuka M, Kato K, Okusaka T, Saito T, Ikeda M, Yoshida T, Zembutsu H, Iwata N, Mushiroda T. Determination of novel CYP2D6 haplotype using the targeted sequencing followed by the long-read sequencing and the functional characterization in the Japanese population. J Hum Genet 66, 139-149 (2021)Nakamura R, Ozeki T, Hirayama N, Sekine A, Yamashita T, Mashimo Y, Mizukawa Y, Shiohara T, Watanabe H, Sueki H, Ogawa K, Asada H, Kaniwa N, Tsukagoshi E, Matsunaga K, Niihara H, Yamaguchi Y, Aihara M, Mushiroda T, Saito Y, Morita E. Association of HLA-A*11:01 with Sulfonamide-Related Severe Cutaneous Adverse Reactions in Japanese Patients. J Invest Dermatol 140, 1659-1662 (2020)Tamura K, Imamura CK, Takano T, Saji S, Yamanaka T, Yonemori K, Takahashi M, Tsurutani J, Nishimura R, Sato K, Kitani A, Ueno NT, Mushiroda T, Kubo M, Fujiwara Y, Tan-igawara Y. CYP2D6 Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study. J Clin Oncol 38, 558-566 (2020)Invited presentationsMushiroda T. “A recent update of pharmacogenomics” The 41st Annual Scientific Meeting of the Japanese Society of Clinical Pharmacology and Therapeutics (Fukuoka, Japan) December 2020Hikino K. “PGx informed precision medicine in pediatrics” The 41st Annual Scientific Meeting of the Japanese Soci-ety of Clinical Pharmacology and Therapeutics (Fukuoka, Japan) December 2020Mushiroda T. “Targeted NGS panel for developing infra-structure to support pharmacogenomics research” Bio Asia Pacific 2020 (Bangkok, Thailand) October 2020Fukunaga K. “Bioinformatics analysis tools using in SEAPharm research 100 pharmacogenes PKSeq panel” Bio Asia Pacific 2020 (Bangkok, Thailand) October 2020Hikino K. “HLA-B*51:01 and CYP2C9*3 are risk factors for phenytoin-induced eruption in the Japanese population: analysis of data from the Biobank Japan Project” The 5th International Stevens-Johnson Syndrome Symposium (Kyoto, Japan) February 2020Laboratory for PharmacogenomicsTeam Leader: Taisei Mushiroda
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