Qatar University, Doha, Qatar.
Hamad Medical Corporation, Doha, Qatar.
Pharmacogenomics J. 2020 Apr;20(2):277-284. doi: 10.1038/s41397-019-0116-y. Epub 2019 Oct 25.
The objective of this study is to estimate the prevalence of VKORC1, CYP2C9, and CYP4F2 genetic variants and their contribution to warfarin dose variability in Qataris. One hundred and fifty warfarin-treated Qatari patients on a stable dose and with a therapeutic INR for at least three consecutive clinic visits were recruited. Saliva samples were collected using Oragene DNA self-collection kit, followed by DNA purification and genotyping via TaqMan Real-Time-PCR assay. The population was stratified into derivation and validation cohorts for the dosing model. The minor allele frequency (MAF) of VKORC1 (-1639G>A) was A (0.47), while the MAF's for the CYP2C9*2 and 3 and CYP4F23 were T (0.12), C (0.04) and T (0.43), respectively. Carriers of at least one CYP2C9 decreased function allele (*2 or 3) required lower median (IQR) warfarin doses compared to noncarriers [24.5 (14.5) mg/week vs. 35 (21) mg/week, p < 0.001]. Similarly, carriers of each additional copy of (A) variant in VKORC1 (-1639G>A) led to reduction in warfarin dose requirement compared to noncarriers [21(7.5) vs. 31.5(18.7) vs. 43.7(15), p < 0.0001]. CYP4F2*3 polymorphism on the other hand was not associated with warfarin dose. Multivariate analysis on the derivation cohort (n = 104) showed that a dosing model consisting of hypertension (HTN), heart failure (HF), VKORC1 (-1639G>A), CYP2C92 & 3, and smoking could explain 39.2% of warfarin dose variability in Qataris (P < 0.001). In the validation cohort (n = 45), correlation between predicted and actual warfarin doses was moderate (Spearman's rho correlation coefficient = 0.711, p < 0.001). This study concluded that VKORC1 (-1639G>A), CYP2C92 & *3 are the most significant predictors of warfarin dose along with HTN, HF and smoking.
本研究旨在评估 VKORC1、CYP2C9 和 CYP4F2 遗传变异在卡塔尔人群中的流行率及其对华法林剂量变异性的影响。我们招募了 150 名在稳定剂量下接受华法林治疗且连续三次就诊时 INR 值均在治疗范围内的卡塔尔患者。使用 Oragene DNA 自采集试剂盒采集唾液样本，然后通过 TaqMan Real-Time-PCR 检测进行 DNA 纯化和基因分型。该人群被分为推导和验证队列，以建立剂量模型。VKORC1(-1639G>A)的次要等位基因频率(MAF)为 A(0.47)，而 CYP2C92 和3 以及 CYP4F23 的 MAF 分别为 T(0.12)、C(0.04)和 T(0.43)。与非携带者相比，至少携带一个 CYP2C9 降低功能等位基因(2 或3)的患者需要更低的中位(四分位间距)华法林剂量[24.5(14.5)mg/周比 35(21)mg/周，p<0.001]。同样，与非携带者相比，VKORC1(-1639G>A)中的每一个(A)变体等位基因的额外拷贝都导致华法林剂量需求降低[21(7.5)比 31.5(18.7)比 43.7(15)，p<0.0001]。另一方面，CYP4F2*3 多态性与华法林剂量无关。在推导队列(n=104)中的多变量分析显示，由高血压(HTN)、心力衰竭(HF)、VKORC1(-1639G>A)、CYP2C92 和3 以及吸烟组成的剂量模型可以解释卡塔尔人群中 39.2%的华法林剂量变异性(P<0.001)。在验证队列(n=45)中，预测的华法林剂量与实际剂量之间的相关性为中度(Spearman 的 rho 相关系数=0.711，p<0.001)。本研究得出结论，VKORC1(-1639G>A)、CYP2C92 和*3 是华法林剂量的最重要预测因子，此外还与 HTN、HF 和吸烟有关。
