張淑秋教授課題組報(bào)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日山西醫(yī)科大學(xué)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(jí)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(jià)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(diǎn)在于其狹窄的安全劑量范圍以及顯著的個(gè)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(gè)體化劑量預(yù)測模型[9-11]。然而在臨床實(shí)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(píng)價(jià)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(zhǔn)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(zhǔn)確性。在此基礎(chǔ)上，團(tuán)隊(duì)研究人員通過針對因變量進(jìn)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(jìn)行了準(zhǔn)確性驗(yàn)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(jìn)入本土化劑量預(yù)測模型的因素進(jìn)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(jìn)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(diǎn)，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。
參考文獻(xiàn)：
[1]Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data [J]. The New England journal of medicine, 2009, 360(8): 753-764.
[2]Huang SW, Chen HS, Wang XQ, Huang L, Xu DL, Hu XJ, Huang ZH, He Y, Chen KM, Xiang DK, Zou XM, Li Q, Ma LQ, Wang HF, Chen BL, Li L, Jia YK, Xu XM. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients [J]. Pharmacogenetics and genomics, 2009, 19(3): 226-234.
[3]Miao L, Yang J, Huang C, Shen Z. Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients [J]. European journal of clinical pharmacology, 2007, 63(12): 1135-1141.
[4]Ohno M, Yamamoto A, Ono A, Miura G, Funamoto M, Takemoto Y, Otsu K, Kouno Y, Tanabe T, Masunaga Y, Nonen S, Fujio Y, Azuma J. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients [J]. European journal of clinical pharmacology, 2009, 65(11): 1097-1103.
[5]Kim HS, Lee SS, Oh M, Jang YJ, Kim EY, Han IY, Cho KH, Shin JG. Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement [J]. Pharmacogenetics and genomics, 2009, 19(2): 103-112.
[6] Bress A, Patel SR, Perera MA, Campbell RT, Kittles RA, Cavallari LH. Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans [J]. Pharmacogenomics, 2012, 13(16): 1925-1935.
[7]Kimachi M, Furukawa TA, Kimachi K, Goto Y, Fukuma S, Fukuhara S. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease [J]. The Cochrane database of systematic reviews, 2017, 11(11): Cd011373.
[8] Xu Q, Zhang S, Wu C, Xiong Y, Niu J, Li F, Zhu J, Shen L, Zhu B, Xing Q, He L, Chen L, Li M, Li H, Ge J, Qin S. Genetic Associations With Stable Warfarin Dose Requirements in Han Chinese Patients [J]. Journal of cardiovascular pharmacology, 2021, 78(1): e105-e111.
[9]Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data [J]. The New England journal of medicine, 2009, 360(8): 753-764.
[10] Hyun G, Li J, Bass AR, Mohapatra A, Woller SC, Lin H, Eby C, McMillin GA, Gage BF. Use of signals and systems engineering to improve the safety of warfarin initiation [J]. Journal of thrombosis and thrombolysis, 2016, 42(4): 529-533.
[11] Saffian SM, Wright DF, Roberts RL, Duffull SB. Methods for Predicting Warfarin Dose Requirements [J]. Therapeutic drug monitoring, 2015, 37(4): 531-538.
