Pharmaceutical Care Services, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
Medical Genomics Research Department, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
Pharmacogenomics J. 2023 Jul;23(4):82-88. doi: 10.1038/s41397-023-00300-3. Epub 2023 Feb 4.
Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins's narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients' therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness.
A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation.
The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.
华法林是一种常用的口服抗凝剂，用于治疗和预防血栓栓塞事件。华法林的治疗指数窗口狭窄是临床实践中的主要挑战之一；因此，需要频繁监测和剂量调整以维持患者的治疗范围。华法林剂量变化和反应归因于几个个体间和个体内因素，包括参与华法林药代动力学（PK）和药效动力学（PD）途径的酶的遗传变异。因此，我们旨在利用下一代测序（NGS）方法来鉴定可能与华法林反应性相关的罕见和常见遗传变异。
使用预先设计的包括 16 个参与华法林 PK/PD 途径的基因的 NGS 面板，对来自沙特华法林药物基因组学队列（SWAP）的 786 名患者进行测序。使用几种注释工具对鉴定的变体进行注释，以确定这些变体的致病性和等位基因频率。我们对华法林剂量进行了变体水平的关联测试。我们在测序基因中发现了 710 个变体；19%是新变体，其中绝大多数是稀有变体。遗传关联测试表明，VKORC1（rs9923231 和 rs61742245）、CYP2C9（rs98332238、rs9332172、rs1057910、rs9332230、rs1799853、rs1057911 和 rs9332119）、CYP2C19（rs28399511 和 rs3758581）和 CYP2C8（rs11572080 和 rs10509681）与华法林每周剂量显著相关。我们的模型包括遗传和非遗传因素，解释了华法林剂量变化的 40.1%。
该研究确定了与沙特人群华法林剂量相关的新变体。这些变体更可能是特定于人群的变体，这表明在采用通用华法林基因型指导的剂量算法之前，应该进行特定于人群的研究。
