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.
Department of Pathology and Laboratory, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
Sci Rep. 2020 Jul 15;10(1):11613. doi: 10.1038/s41598-020-68519-9.
Warfarin is a frequently prescribed oral anticoagulant with a narrow therapeutic index, requiring careful dosing and monitoring. However, patients respond with significant inter-individual variability in terms of the dose and responsiveness of warfarin, attributed to genetic polymorphisms within the genes responsible for the pharmacokinetics and pharmacodynamics of warfarin. Extensive warfarin pharmacogenetic studies have been conducted, including studies resulting in genotype-guided dosing guidelines, but few large scale studies have been conducted with the Saudi population. In this study, we report the study design and baseline characteristics of the Saudi WArfarin Pharmacogenomics (SWAP) cohort, as well as the association of the VKORC1 promoter variants with the warfarin dose and the time to a stable INR. In the 936 Saudi patients recruited in the SWAP study, the minor allele C of rs9923231 was significantly associated with a 8.45 mg higher weekly warfarin dose (p value = 4.0 × 10), as well as with a significant delay in achieving a stable INR level. The addition of the rs9923231 status to the model, containing all the significant clinical variables, doubled the warfarin dose explained variance to 31%. The SWAP cohort represents a valuable resource for future research with the objective of identifying rare and prevalent genetic variants, which can be incorporated in personalized anticoagulation therapy for the Saudi population.
华法林是一种常用的口服抗凝药物，治疗指数较窄，需要谨慎给药和监测。然而，患者对华法林的剂量和反应存在显著的个体间差异，这归因于负责华法林药代动力学和药效学的基因中的遗传多态性。已经进行了广泛的华法林药物遗传学研究，包括导致基于基因型的给药指南的研究，但针对沙特人群的大型研究很少。在这项研究中，我们报告了沙特华法林药物基因组学（SWAP）队列的研究设计和基线特征，以及 VKORC1 启动子变异与华法林剂量和达到稳定 INR 时间的关联。在 SWAP 研究中招募的 936 名沙特患者中，rs9923231 的次要等位基因 C 与每周华法林剂量增加 8.45mg 显著相关（p 值=4.0×10），并且达到稳定 INR 水平的时间显著延迟。将 rs9923231 状态添加到包含所有显著临床变量的模型中，将华法林剂量解释的方差增加了一倍，达到 31%。SWAP 队列代表了未来研究的宝贵资源，旨在确定罕见和常见的遗传变异，这些变异可以纳入沙特人群的个体化抗凝治疗。
