VKORC1、CYP2C9、CYP1A2、UGT1A1 和 GGCX 多态性对华法林维持剂量的影响：在接受机械心脏瓣膜置换术的华南患者中探索新的算法。

Impact of VKORC1, CYP2C9, CYP1A2, UGT1A1, and GGCX polymorphisms on warfarin maintenance dose: Exploring a new algorithm in South Chinese patients accept mechanical heart valve replacement.

机构信息

Emergency Department of the Second Affiliated Hospital of Nanchang University, Nanchang, China.

School of Science, Nanchang University, Nanchang, China.

出版信息

Medicine (Baltimore). 2022 Jul 22;101(29):e29626. doi: 10.1097/MD.0000000000029626.

DOI:10.1097/MD.0000000000029626

PMID:35866816

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9302374/

Abstract

BACKGROUND

Warfarin is the most recommended oral anticoagulant after artificial mechanical valve replacement therapy. However, the narrow therapeutic window and varying safety and efficacy in individuals make dose determination difficult. It may cause adverse events such as hemorrhage or thromboembolism. Therefore, advanced algorithms are urgently required for the use of warfarin.

OBJECTIVE

To establish a warfarin dose model for patients after prosthetic mechanical valve replacement in southern China in combination with clinical and genetic variables, and to improve the accuracy and ideal prediction percentage of the model.

METHODS

Clinical data of 476 patients were tracked and recorded in detail. The gene polymorphisms of VKORC1 (rs9923231, rs9934438, rs7196161, and rs7294), CYP2C9 (rs1057910), CYP1A2 (rs2069514), GGCX (rs699664), and UGT1A1 (rs887829) were determined using Sanger sequencing. Multiple linear regressions were used to analyze the gene polymorphisms and the contribution of clinical data variables; the variables that caused multicollinearity were screened stepwise and excluded to establish an algorithm model for predicting the daily maintenance dose of warfarin. The ideal predicted percentage was used to test clinical effectiveness.

RESULTS

A total of 395 patients were included. Univariate linear regression analysis suggested that CYP1A2 (rs2069514) and UGT1A1 (rs887829) were not associated with the daily maintenance dose of warfarin. The new algorithm model established based on multiple linear regression was as follows: Y = 1.081 - 0.011 (age) + 1.532 (body surface area)-0.807 (rs9923231 AA) + 1.788 (rs9923231 GG) + 0.530 (rs1057910 AA)-1.061 (rs1057910 AG)-0.321 (rs699664 AA). The model accounted for 61.7% of individualized medication differences, with an ideal prediction percentage of 69%.

CONCLUSION

GGCX (rs699664) may be a potential predictor of warfarin dose, and our newly established model is expected to guide the individualized use of warfarin in clinical practice in southern China.

摘要

背景

华法林是人工机械瓣膜置换术后最推荐的口服抗凝剂。然而，个体之间的治疗窗较窄以及安全性和有效性的差异使得剂量确定变得困难。可能会导致出血或血栓栓塞等不良事件。因此，迫切需要先进的算法来使用华法林。

目的

结合临床和遗传变量，为中国南方接受人工机械瓣膜置换术的患者建立华法林剂量模型，并提高模型的准确性和理想预测百分比。

方法

详细跟踪和记录了 476 名患者的临床数据。使用 Sanger 测序确定 VKORC1（rs9923231、rs9934438、rs7196161 和 rs7294）、CYP2C9（rs1057910）、CYP1A2（rs2069514）、GGCX（rs699664）和 UGT1A1（rs887829）的基因多态性。使用多元线性回归分析基因多态性和临床数据变量的贡献；逐步筛选出引起多重共线性的变量并将其排除在外，以建立预测华法林维持剂量的算法模型。使用理想预测百分比来测试临床效果。

结果

共纳入 395 例患者。单因素线性回归分析提示 CYP1A2（rs2069514）和 UGT1A1（rs887829）与华法林的维持剂量无关。基于多元线性回归建立的新算法模型如下：Y=1.081-0.011（年龄）+1.532（体表面积）-0.807（rs9923231AA）+1.788（rs9923231GG）+0.530（rs1057910AA）-1.061（rs1057910AG）-0.321（rs699664AA）。该模型解释了 61.7%的个体化药物差异，理想预测百分比为 69%。