Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand.
Clin Transl Sci. 2024 Oct;17(10):e70019. doi: 10.1111/cts.70019.
Next-generation sequencing (NGS) has transformed pharmacogenomics (PGx), enabling thorough profiling of pharmacogenes using computational methods and advancing personalized medicine. The Thai Pharmacogenomic Database-2 (TPGxD-2) analyzed 948 whole genome sequences, primarily from the Electricity Generating Authority of Thailand (EGAT) cohort. This study is an extension of the previous Thai Pharmacogenomic Database (TPGxD-1) and specifically focused on 26 non-very important pharmacogenes (VIPGx) genes. Variant calling was conducted using Sentieon (version 201808.08) following GATK's best workflow practices. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0. Star allele analysis was performed with Stargazer v2.0.2, which called star alleles for 22 of 26 non-VIPGx genes. The variant analysis revealed a total of 14,529 variants in 26 non-VIPGx genes, with TBXAS1 had the highest number of variants (27%). Among the 14,529 variants, 2328 were novel (without rsID), with 87 identified as clinically relevant. We also found 56 known PGx variants among the known variants (n = 12,201), with UGT2B7 (19.64%), CYP1B1 (8.9%), SLCO2B1 (8.9%), and POR (8.9%) being the most common. We reported a high frequency of intermediate metabolizers (IMs) in CYP2F1 (34.6%) and CYP4A11 (8.6%), and a high frequency of decreased functional alleles in POR (53.9%) and SLCO1B3 (34.9%) genes. This study enhances our understanding of pharmacogenomic profiling of 26 non-VIPGx genes of notable clinical importance in the Thai population. However, further validation with additional computational and reference genotyping methods is necessary, and novel alleles identified in this study should undergo further orthogonal validation.
下一代测序（NGS）改变了药物基因组学（PGx），使其能够使用计算方法全面分析药物基因，并推进个体化医疗。泰国药物基因组数据库-2（TPGxD-2）分析了 948 个全基因组序列，主要来自泰国发电局（EGAT）队列。这项研究是前泰国药物基因组数据库（TPGxD-1）的扩展，专门针对 26 个非重要药物基因（VIPGx）基因。使用 Sentieon（版本 201808.08）根据 GATK 的最佳工作流程实践进行变体调用。然后使用 Golden Helix VarSeq 2.5.0 注释变体调用格式（VCF）文件。使用 Stargazer v2.0.2 进行星等位基因分析，该分析对 26 个非 VIPGx 基因中的 22 个基因调用了星等位基因。变体分析在 26 个非 VIPGx 基因中共发现了 14529 个变体，其中 TBXAS1 的变体数量最多（27%）。在 14529 个变体中，有 2328 个是新的（没有 rsID），其中 87 个被确定为具有临床相关性。我们还在已知变体（n=12201）中发现了 56 个已知的 PGx 变体，其中 UGT2B7（19.64%）、CYP1B1（8.9%）、SLCO2B1（8.9%）和 POR（8.9%）最为常见。我们报告了 CYP2F1（34.6%）和 CYP4A11（8.6%）中中间代谢物（IM）的高频率，以及 POR（53.9%）和 SLCO1B3（34.9%）基因中功能降低等位基因的高频率。这项研究增强了我们对泰国人群中 26 个具有重要临床意义的非 VIPGx 基因的药物基因组分析的理解。然而，还需要使用其他计算和参考基因分型方法进行进一步验证，并且本研究中鉴定的新等位基因应进行进一步的正交验证。
