張淑秋教授課題組報道基于VKORC1基因多態(tài)性的
本土化華法林劑量預(yù)測模型
2021年8月7日c7c7.app藥學(xué)院臨床藥學(xué)教研室張淑秋教授課題組在Therapeutic Drug Monitoring雜志上發(fā)表題為“Performance Evaluation of Warfarin Dose Prediction Algorithms and Effects of Clinical Factors on Warfarin Dose in Chinese Patients”的論文，第一作者為2018級博士生高偉祺，通訊作者張淑秋。該研究對比分析了六種已發(fā)表的主要華法林劑量預(yù)測模型[1-6]對本地人群的預(yù)測性能及各臨床因素對華法林劑量的影響。
華法林(Warfarin)是最具代表性的香豆素類抗凝藥物之一，因其具有充足的循證醫(yī)學(xué)證據(jù)、確切的療效以及低廉的價格，被廣泛應(yīng)用于臨床抗凝治療中[7]。然而，華法林治療的藥理學(xué)難點在于其狹窄的安全劑量范圍以及顯著的個體間劑量差異[8]。隨著藥物基因組學(xué)、基因測序等新興學(xué)科的快速發(fā)展，國內(nèi)外研究者建立了很多以遺傳和非遺傳因素相結(jié)合采用多元線性回歸分析方法建立的華法林個體化劑量預(yù)測模型[9-11]。然而在臨床實踐中人們發(fā)現(xiàn)華法林劑量預(yù)測模型對預(yù)測人群有一定種族、地域特異性，在臨床普遍推廣使用這些模型之前，應(yīng)結(jié)合模型性質(zhì)及患者特征嘗試建立本土化的劑量預(yù)測模型。
圖1.華法林劑量預(yù)測模型預(yù)測性能評價研究過程示意圖
該研究通過觀察217名接受華法林抗凝治療的山西地區(qū)漢族人群患者，考察了各華法林劑量預(yù)測模型的預(yù)測準確性，結(jié)果表明基于日本人群建立的OHNO模型針對本地人群顯示出了最佳的劑量預(yù)測準確性。在此基礎(chǔ)上，團隊研究人員通過針對因變量進行多種形式的數(shù)據(jù)轉(zhuǎn)換，在尋找更佳的擬合效果后構(gòu)建了本土化華法林劑量預(yù)測模型并進行了準確性驗證。
圖2.華法林本土化劑量預(yù)測模型構(gòu)建研究過程示意圖
在對進入本土化劑量預(yù)測模型的因素進行影響權(quán)重分析后，課題組發(fā)現(xiàn)VKORC1基因型對華法林劑量影響權(quán)重占比最大。并進一步開展了VKORC1基因外顯子區(qū)SNP篩查及VKORC1與華法林相互作用模擬研究。
圖3.VKORC1基因外顯子區(qū)SNP篩查及VKORC1與華法林相互作用模擬研究示意圖
目前已成功篩選出一種可導(dǎo)致華法林藥物抵抗發(fā)生的VKORC1基因SNP突變位點，相關(guān)結(jié)果的論文正在撰寫中。該研究發(fā)現(xiàn)可為臨床篩選華法林藥物抵抗患者提供重要理論支持和技術(shù)方法。
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