Chung Jee-Eun, Chang Byung Chul, Lee Kyung Eun, Kim Joo Hee, Gwak Hye Sun
College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayedae-gil, Seodaemun-gu, Seoul, 120-750, South Korea.
Department of Thoracic & Cardiovascular Surgery, Yonsei University Medical Center, Seoul, 120-752, South Korea.
Eur J Clin Pharmacol. 2015 Oct;71(10):1229-36. doi: 10.1007/s00228-015-1915-y. Epub 2015 Aug 11.
NAD(P)H dehydrogenase, encoded by NAD(P)H quinone oxidoreductase 1 (NQO1), is an enzyme that catalyzes the reduction of quinones, including vitamin K. Given its potential role in vitamin K metabolism, this study aimed to investigate the effects of NQO1 polymorphisms on stable warfarin doses.
We tested a possible effect of gene polymorphisms on variability in warfarin response using 206 Korean patients with mechanical cardiac valves. Single nucleotide polymorphisms (SNPs) of NQO1 with a minor allele frequency of at least 15% were included. Also, genotypes of vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 (CYP) 2C9, CYP4F2, gamma-glutamyl carboxylase (GGCX), and GATA4 were determined.
NQO1 rs1800566 (C>T) and rs10517 (C>T) were significantly associated with stable warfarin doses. Variant homozygote carriers required lower stable warfarin doses than those with wild-type C allele in rs1800566 (4.85 ± 1.61 vs. 5.61 ± 1.94 mg; p = 0.033), whereas patients with wild homozygote required lower doses than those with T allele in rs10517 (5.11 ± 1.73 vs. 5.75 ± 1.98 mg; p = 0.017). Similar results were obtained from stratified analysis using VKORC1 variant homozygote carriers in both SNPs. Multivariate analysis showed that rs10517 (C>T) increased contribution of gene variations to the overall warfarin dose variability from 42.5 to 43.8%.
Our results demonstrate that NQO1 gene polymorphisms influence stable warfarin doses in Korean patients.
由NAD(P)H醌氧化还原酶1（NQO1）编码的NAD(P)H脱氢酶是一种催化醌类还原的酶，包括维生素K。鉴于其在维生素K代谢中的潜在作用，本研究旨在探讨NQO1基因多态性对稳定华法林剂量的影响。
我们使用206例韩国机械心脏瓣膜患者测试了基因多态性对华法林反应变异性的可能影响。纳入次要等位基因频率至少为15%的NQO1单核苷酸多态性（SNP）。此外，还测定了维生素K环氧化物还原酶复合体亚基1（VKORC1）、细胞色素P450（CYP）2C9、CYP4F2、γ-谷氨酰羧化酶（GGCX）和GATA4的基因型。
NQO1 rs1800566（C>T）和rs10517（C>T）与稳定华法林剂量显著相关。在rs1800566中，变异纯合子携带者所需的稳定华法林剂量低于野生型C等位基因携带者（4.85±1.61 vs. 5.61±1.94 mg；p = 0.033），而在rs10517中，野生纯合子患者所需剂量低于T等位基因携带者（5.11±1.73 vs. 5.75±1.98 mg；p = 0.017）。在两个SNP中使用VKORC1变异纯合子携带者进行分层分析也得到了类似结果。多变量分析显示，rs10517（C>T）使基因变异对总体华法林剂量变异性的贡献从42.5%增加到43.8%。
我们的结果表明，NQO1基因多态性影响韩国患者的稳定华法林剂量。
