Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
Institute of Clinical Pharmacology, Central South University Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China.
J Cardiovasc Pharmacol. 2020 Jul;76(1):71-76. doi: 10.1097/FJC.0000000000000834.
Warfarin international normalized ratio (INR)-related phenotypes such as the percentage of INR time in the therapeutic range (PTTR) and INR variability are associated with warfarin adverse reactions. However, INR-related phenotypes greatly vary among patients, and the underlying mechanism remains unclear. As a key cofactor for coagulation proteins, vitamin K can affect warfarin INR values. The aim of this study was to address the influence of vitamin K-related single-nucleotide polymorphisms (SNPs) on warfarin INR-related phenotypes. A total of 262 patients who were new recipients of warfarin therapy and followed up for 3 months were enrolled. Twenty-nine SNPs were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass array. Sixteen warfarin INR-related phenotypes were observed. After association analysis, 11 SNPs were significantly associated with at least one INR-related phenotype, and 6 SNPs were associated with at least 2 INR-related phenotypes (P < 0.05). In these SNPs, rs1800139, rs1800154, rs1800141, and rs486020 were the most representative. rs1800139, rs1800154, and rs1800141 locate in LRP1 and were found to be correlated with 1-month and 2-month INR variability (P < 0.05). Besides, the APOA1 rs486020 was significantly associated with the first month PTTR (P = 0.009), and patients with C-allele had higher PTTR than those with G-alleles almost during the entire monitoring period. In conclusion, the study revealed that the polymorphisms of LRP1 and APOA1 gene may play important roles in the variation of warfarin INR-related phenotypes. Our results provide new information for improving warfarin anticoagulation management.
华法林国际标准化比值（INR）相关表型，如 INR 治疗范围内的时间百分比（PTTR）和 INR 变异性，与华法林不良反应相关。然而，INR 相关表型在患者之间差异很大，其潜在机制尚不清楚。维生素 K 作为凝血蛋白的关键辅助因子，可影响华法林 INR 值。本研究旨在探讨维生素 K 相关单核苷酸多态性（SNP）对华法林 INR 相关表型的影响。共纳入 262 例新接受华法林治疗并随访 3 个月的患者。采用基质辅助激光解吸电离飞行时间质谱阵列技术对 29 个 SNP 进行基因分型。观察了 16 个华法林 INR 相关表型。关联分析后，有 11 个 SNP 与至少一种 INR 相关表型显著相关，6 个 SNP 与至少 2 种 INR 相关表型相关（P<0.05）。在这些 SNP 中，rs1800139、rs1800154、rs1800141 和 rs486020 最具代表性。rs1800139、rs1800154 和 rs1800141 位于 LRP1 基因中，与 1 个月和 2 个月 INR 变异性相关（P<0.05）。此外，APOA1 rs486020 与第一个月 PTTR 显著相关（P=0.009），C 等位基因患者的 PTTR 高于 G 等位基因患者，几乎在整个监测期间都是如此。综上所述，本研究表明 LRP1 和 APOA1 基因的多态性可能在华法林 INR 相关表型的变化中发挥重要作用。研究结果为改善华法林抗凝管理提供了新的信息。
