VKORC1基因多态性对汉族静脉血栓栓塞患者服用华法林剂量的影响

目的探讨VKORC11173C>T和3730G>A基因多态性与静脉血栓栓塞患者服用华法林剂量的关系。方法应用扩增受阻突变体系聚合酶链式反应技术(ARMS-PCR)对205例华法林治疗达标患者(INR2-3)的VKORC1的1173C>T和3730G>A位点进行基因分型。结果205例患者中,在VKORC11173位点,CC型患者2例(1.0%),CT型25例(12.2%),TT型178例(86.8%);C等位基因频率7.1%,T等位基因频率92.9%。在VKORC13730位点,AA型2例(1.0%),GA型26例(12.7%),GG型177例(86.3%);G和A的基因频率分别为7.3%和92.7%。VKORC11173位点和3730位点存在着强烈连锁不平衡关系(D’=0.77,r2=0.58)。VKORC1的基因型差异与华法林维持剂量相关,VKORC11173的CC、CT和TT型患者的华法林维持剂量分别为(8.13±0.88)mg.d-1、(5.33±2.03)mg.d-1和(3.86±1.52)mg.d-1。VKORC13070的AA、GA和GG型患者的华法林维持剂量分别为(8.13±0.88)mg.d-1、(5.48±2.05)mg.d-1和(3.83±1.49)mg.d-1。单因素方差分析的结果显示,VKORC1两位点基因型对华法林维持剂量具有显著相关性(P均小于0.0001)。结论VKORC11173和3730位点对VTE患者服用华法林剂量有明显的影响。     

EPHX1基因多态性与华法林稳定剂量关系的研究

目的:探讨环氧化物水解酶基因(EPHX1)rs4653436(G>A)基因多态性位点与个体间华法林稳定剂量差异的关系。方法:采用聚合酶链反应/变性高效液相色谱技术,检测217例已获得华法林稳定剂量患者的rs4653436(G>A)位点基因型;比较不同基因型患者华法林稳定剂量的差异。结果:217例患者中,基因型GG、GA和AA分别有141、72和4例,各占65.0%、33.2%和1.8%,G和A等位基因的频率分别为81.6%和18.4%。GG、GA和AA基因型患者的华法林稳定剂量分别为(2.84±1.19)、(2.91±1.09)和(2.66±1.29)mg/d,3组之间差异无统计学意义(F=0.155,P=0.856)。结论:EPHX1 rs4653436(G>A)基因多态性可能不是影响华法林个体间用量差异的遗传因素。     

CYP2C9和VKORC1 基因多态性与华法林抗凝剂量的相关性研究

目的:探讨细胞色素P450 酶2C9基因 (CYP2C9) 和维生素K环氧化物还原酶复合体亚单位1基因(VKORC1)多态性对华法林临床应用剂量的影响.方法:收集南通地区临床口服华法林患者70例,对照组70例,应用限制性片段长度多态性分析(RFLP)方法检测CYP2C9-1061A/C 和VKORC1-1639 G/A 基因多态性,并比较不同基因型间平均华法林剂量.结果:华法林组检出CYP2C9-1061A/C AA、AC、CC 型分别有59例(80.8%)、12例(16.4%)及2例(2.8%),患者华法林剂量分别为(26.25±11.36)mg/周、(17.38±7.20)mg/周及(13.57±7.10)mg/周,变异型(AC型和CC型)较野生纯合型AA型华法林需求剂量减少,差异有统计学意义(P<0.05).VKORC1-1639G/A AA、GA、GG型分别有56例(76.7%)、14例(19.2%)及3例(4.1%),需求剂量分别为(12.46±7.42)mg/周、(16.67±7.46)mg/周及(24.75±11.68)mg/周,变异型(GA型和AA型)较野生纯合型GG型华法林需求剂量减少,差异有统计学意义(P<0.05).结论:在南通地区汉族人群中,存在CYP2C9-1061A/C和VKORC1-1639G/A的基因多态性,且不同基因型患者间华法林用量存在差异.     

CYP2C9和VKORC1基因多态性对老年房颤患者华法林稳定剂量影响及分析

摘要：目的:探讨CYP2C9和VKORC1基因多态性对老年房颤患者华法林稳定剂量的影响,建立适合汉族人群老年房颤患者的华法林给药模型,指导华法林个体化抗凝治疗。方法:对195例口服华法林抗凝的老年患者进行CYP2C9和VKORC1基因分型,比较不同基因型房颤老年患者华法林日均稳定剂量差异。采用多重线性回归分析法依据CYP2C9和VKORC1基因型、年龄、体表面积（BSA）、胺碘酮建立华法林稳定剂量计算公式。结果:国际标准化比值（INR）稳定在2.0～3.0之间时,CYP2C9*1/*1基因型患者日均华法林剂量（3.10±0.91） mg,显著高于CYP2C9*1/*3与CYP2C9*3/*3基因型患者的（2.10±0.89） mg和（1.25±0.00） mg; VKORC1-1639AA基因型患者日均华法林剂量（2.86±0.88） mg,显著低于VKORC1-1639GA/GG基因型患者的（3.68±0.88） mg和（6.38±0.91） mg（P<0.05）。通过多元线性回归分析得出华法林稳定剂量公式,建立的回归模型中包含年龄、BSA、胺碘酮、CYP2C9和VKORC1-1639基因型,该模型能解释约60.4%个体间华法林剂量差异。结论:基于CYP2C9和VKORC1基因多态性建立的华法林稳定剂量预测公式,能帮助指导华法林在老年房颤患者中的抗凝治疗。     

亚洲人群VKORC1-1639G>A基因多态性对华法林平均日剂量影响的系统评价和Meta分析

目的:评价亚洲人群VKORC1-1639G>A基因多态性对华法林平均日剂量的影响。方法:计算机检索相关中英文数据库,用RevMan 5.0.23软件进行Meta分析。结果:纳入16篇研究(n=3 016),10篇英文,6篇中文。VKORC1-1639G>A基因型发生频率在各人群间存在差异。与VKORC1-1639AA组相比,-1639GG组、-1639GA组和-1639GA+GG组患者平均日剂量分别高出113%[95%C(I70%,156%)]、52%[95%C(I30%,73%)]和72%[95%C(I48%,96%)]。敏感性分析以及人群间的亚组分析均表明,上述结果稳定、可信。结论:VKORC1-1639G>A的基因多态性与华法林剂量个体间差异显著相关,对华法林药效的影响存在种族差异。     

VKORC1基因多个单核苷酸位点基因多态性对华法林维持剂量的影响

目的探讨维生素K环氧化物还原酶复合物1(VKORC1)基因多个单核苷酸位点基因多态性对中国汉族人华法林维持剂量的影响。方法应用多聚酶链反应-限制性内切酶长度片段多态性(PCR-RFLP)方法对125例长期口服华法林患者的VKORC1-1639G/A、1173C/T、497T/G位点多态性进行检测,其他资料通过临床随访获得。结果 125例中国汉族人检出VKORC1-1639AA(87.2%)、AG(12%)、GG(0.8%)型的频率分别与1173TT、TC、CC型完全相同。VKORC1-1639A/G(1173T/C)的AA(TT)型患者所需华法林维持剂量低于AG(TC)/GG(CC)型[(2.65±0.90)mg/dvs.(4.88±2.12)mg/d](P<0.01);497T/G基因多态性则对华法林维持剂量影响不大。结论 VKORC1-1639或1173位点基因多态性与华法林维持剂量关系密切,且AA基因型或TT基因型占多数可能是中国汉族人群所需华法林剂量普遍较低的重要原因。     

基因多态性对华法林个体化药量作用的临床分析

目的探讨细胞色素氧化酶P450（CYP2C9）和环氧化物还原酶复合体（VKORC1）基因型与华法林个体化剂量的关系。方法应用PCR-RFLP方法,检测临床长期口服华法林患者（362例）的VKORC1-1639及CYP2C9-1061A/C多态性,并按其基因型分组,分别比较VKORC1和CYP2C9不同基因型间的平均华法林剂量。结果病例检测出VKORC1-1639 AA基因型273例（75.4%）、AC基因型81例（22.3%）及CC基因型8例（2.3%）。CYP2C9基因检测AA型321例（88.7%）、AG基因型34例（9.5%）、GG型7例（1.8%）。两组VKORC1和CYP2C9各基因型分布差异无统计学意义（P〉0.05）。VKORC1不同基因型间患者所需华法林平均剂量GA、GG组明显高于AA组（P〈0.01）。携带CYP2C9基因型的患者（AG＋GG）组华法林平均剂量要低于AA组（P〈0.05）。结论华法林应用剂量偏低可能与VKORC G-C和CYP2C9 A-G转变有关。VKORC1 AA型占多数可能是中国汉族人群所需华法林剂量普遍较低的重要原因。     

基于Warfarindosing网站预测汉族人群华法林给药剂量与实际剂量的相关性研究

目的考察基于Warfarindosing网站预测汉族人群华法林剂量与实际剂量的相关性。方法选取某院2017年7月至2018年11月住院期间行华法林基因检测的108例汉族患者,记录其基本信息和华法林等用药情况,利用原位杂交荧光染色DNA测序的方法检测CYP2C9*3和VKORC1(-1639G>A)的基因型,并应用Warfarindosing网站预测患者华法林剂量,比较预测剂量与实际剂量差异。结果行基因检测的108例汉族患者中,以CYP2C9*1/*1 VKORC1AA基因型为主(71.30%),其次为CYP2C9*1/*1 VKORC1GA基因型(19.44%)。47例患者服用华法林,其中CYP2C9*1/*1 VKORC1 AA型患者实际剂量在预测剂量范围内的比例为82.85%(29/35),高于CYP2C9*1/*1 VKORC1 GA型患者实际初始剂量在预测剂量范围内的比例70.00%(7/10)。在院INR达标的23例患者中,CYP2C9*1/*1 VKORC1 AA型和CYP2C9*1/*1 VKORC1 GA型预测周剂量分别为(21.37±5.15)、(31.73±8.85)mg,实际维持周剂量分别为(21.29±6.26)、(27.00±6.00)mg,CYP2C9*1/*1 VKORC1 AA型预测的维持周剂量与实际维持周剂量差异无统计学意义,而CYP2C9*1/*1 VKORC1 GA型预测的维持周剂量显著大于实际维持周剂量。结论基于Warfarindosing网站预测汉族人华法林用药剂量具有一定的参考价值,可适用于汉族人群,尤其对CYP2C9*1/*1 VKORC1 AA型汉族患者华法林的周剂量预测准确性较高,具有较大的临床参考意义;但对于汉族CYP2C9*1/*1 VKORC1 GA基因型患者华法林的剂量预测亦存在局限性,有待于进一步临床研究。     

中国汉族人孕烷X受体基因NR1I2的单核苷酸多态性

目的了解中国健康汉族人孕烷X受体基因NR1I2的单核苷酸多态性分布以明确种族差异。方法用PCR扩增后直接测序的方法,检测NR1I2基因2和4外显子及1,2,4和5内含子的单核苷酸突变。结果中国健康汉族人NR1I2基因2和4外显子均未发现已报道的单核苷酸突变,外显子1和内含子1,2,4和5检测到单核苷酸突变9种,分别为-24446C>A,-24381A>C,-24113G>A,252A>G,275A>G,4760G>A,7635G>A,7637C>T和7675C>T,等位基因频率分别为2.4%,20.8%,20.8%,33.3%,31.0%,68.5%,31.7%,1.6%和10.6%,其中7637C>T未见在任何文献和单核苷酸多态性数据库中报道,为新发现突变。结论中国健康汉族人NR1I2内含子1,2,4和5位置检测到9种单核苷酸突变,且突变频率较高,与白人和美国黑人比较,单核苷酸突变的发生位点和发生频率存在显著性差异。     

POR基因多态性与华法林维持剂量关系的研究

目的探讨POR基因多态性与华法林维持剂量的相关性。方法共纳入185例中国汉族人工心脏机械瓣膜置换术患者,采用Sequenom MassARRAYSystem检测VKORC1及POR相关SNPs,采用PCR-RFLP法检测CYP2C9*3基因型。采用ANOVA或t检验考察目的 SNPs与患者华法林维持剂量的关系。结果在CYP2C9*1*1携带者中,POR rs17685 T等位基因携带者(TT型和CT型)华法林维持剂量明显高于CC型携带者(3.50±1.07)mg·d-1vs(3.14±0.94)mg·d-1,P=0.03。在CYP2C9*1*1及VKORC1 rs9934438 GA/GG携带者中,POR rs17685 T等位基因携带者(TT型和CT型)的华法林维持剂量明显高于CC型携带者(4.76±0.90)mg·d-1vs(4.08±1.03)mg·d-1,P=0.04。未发现POR rs2868177与华法林维持剂量存在相关性。结论在中国汉族人工心脏机械瓣膜置换术患者中,POR rs17685 T突变与华法林剂量上调相关,该基因型检测将有助于指导华法林的临床合理应用。     

Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis

The aim of this study was to investigate the impact of genetic polymorphisms in the metabolic and cellular transport pathway of methotrexate (MTX) on the clinical outcome of MTX monotherapy in Japanese rheumatoid arthritis (RA) patients. Fifty-five patients were treated with MTX monotherapy at a dose of 4-10 mg/week. The total concentration of MTX-polyglutamates (MTX-PGs) was measured at steady-state in red blood cells (RBCs) by high performance liquid chromatography. The genotype at 16 polymorphic sites in 11 genes (ABCB1, ABCG2, ABCC2, RFC1, PCFT, SLCO1B1, MTHFR, GGH, ATIC, MTR, and MTRR) was analyzed. No significant association between the total concentration of MTX-PGs in RBCs and clinical outcome was found. However, patients with the ABCB1 3435TT genotype had a significantly lower mean disease activity score (DAS) 28 than did patients with the ABCB1 3435CC genotype (p = 0.02). Similarly, patients with the ABCB1 2677AA/AT/TT genotypes had a significantly lower mean DAS28 than did patients with the ABCB1 2677GG/GA/GT genotypes (p = 0.04). The patients with the MTHFR 1298AA genotype had a significantly lower mean DAS28 than those with the MTHFR 1298AC/CC genotypes (p = 0.04). In conclusion, the ABCB1 3435C>T, ABCB1 2677G>A/T, and MTHFR 1298A>C polymorphisms influenced the efficacy of MTX monotherapy.     

<Emphasis Type="Italic">VKORC1</Emphasis> and <Emphasis Type="Italic">CYP2C9</Emphasis> polymorphisms are associated with warfarin dose requirements in Turkish patients

OBJECTIVES: The objective of this study was to determine the quantitative influence of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP 2C9) polymorphisms on warfarin dose requirements in Turkish patients. METHODS: A total of 205 patients taking warfarin for >2 months were enrolled in the study. Deoxyribonucleic acid (DNA) samples from these patients were genotyped for polymorphisms in VKORC1 and CYP2C9 genes. A linear regression analysis was used to determine the independent effects of genetic and non-genetic factors on mean warfarin dose requirements. RESULTS: The VKORC1 promoter polymorphism (3673 G>A) was associated with differences in weekly mean varfarin dose: for GG genotype the dose was 43.18 mg/week, for GA genotype 33.78 mg/week and for AA genoype 25.83 mg/week (P < 0.0001). Patients who carried VKORC1 and CYP2C9 variants needed a 40% lower mean weekly warfarin dose compared to wild types. Variables associated with lower warfarin dose requirements were VKORC1 3673 AA or GA genotype (both P < 0.0001), one or two CYP2C9 variant alleles (both P < 0.0001), increasing age (P < 0.0001) and non-indication of venous thromboembolism for warfarin therapy (P = 0.002). CONCLUSION: Polymorphisms in VKORC1 and CYP2C9 genes were important determinants of warfarin dose requirements in Turkish patients.     

基因多态性对华法林稳态剂量和模型预测剂量的相关性研究

目的：研究扬州地区汉族人群CYP2C9、VKORC1基因型、性别、年龄、身高、体质量与华法林稳态剂量及计算机模型预测剂量的相关性。方法：收集扬州地区汉族人群使用华法林的患者,采用基因测序的方法检测CYP2C9和VKORC1基因型,同时记录患者的年龄、性别、身高、体质量、国家化标准比值（INR）、胺碘酮使用情况临床资料,并对这些临床资料进行相关分析及多元回归分析。结果：CYP2C9基因型检测有102例为野生AA型（91.9%）,8例为杂合子AC型（7.21%）,1例为突变CC型（0.9%）。VKORC1基因型检测有96例为突变纯合子AA型（86.49%）,13例为杂合子GA型（11.71%）,2例为野生GG型（1.80%）,所有基因型分布符合Hardy-Weinberg遗传平衡。VKORC1 AA型患者华法林剂量明显低于较AG型,CYP2C9*3 AC型明显低于AA型（P<0.05）。对患者年龄、身高、体质量及不同基因型、模型预测剂量及稳态剂量进行相关性分析和多元回归分析,提示患者的年龄、体质量、CYP2C9和VKORC1基因多态性与华法林个体剂量相关,而相关性分析提示性别和身高对华法林剂量差异无统计学意义。本研究提示模型预测剂量与实际稳态剂量的相关系数为0.732,配对t检验预估剂量与稳态剂量之间无显著性差异。随访显示不良反应发生率为10.81%,均为轻微出血,所有基因型中AC/AA型患者出血发生率最高。结论：扬州地区汉族人群存在CYP2C9和VKORC1基因多态性,应用CYP2C9和VKORC1基因多态性和模型可以准确估测华法林剂量。     

基因多态性对华法林抗凝治疗维持剂量的影响

目的研究中国汉族人群细胞色素P450酶4F2基因(cytochrome P-450 4F2.CYP4F2)多态性分布,并探讨其与华法林抗凝维持剂量的关系。方法采集112例心脏机械瓣膜置换术后服用华法林抗凝已达稳定剂量、凝血酶原时间国际标准化比值INR在目的范围(1.5-2.5)病人的外周血,采用用聚合酶链式反应(polymerase chain reaction,PCR)基因测序的方法检测CYP4F2 rs2108622基因位点的基因型和等位基因频率,探讨华法林抗凝维持剂量与该基因多态性的关系。结果在所有的样本中,CYP4F2 rs2108622基因共检出C(73.1%)和T(26.9%)2种等位基因,检出基因有CC、TT和CT 3种基因型,其基因频率分别为54.1%、41.2和4.7%,人群中CYP4F2 rs2108622基因多态性分布在性别和年龄上无差异;TT基因型患者所需华法林维持剂量最高(4.7±0.99)mg/d,其次为CT基因型患者(3.70±0.85)mg/d,最少的是CC基因型患者(2.46±0.75)mg/d。结论中国汉族人群CYP4F2 rs2108622基因位点具有遗传多态性,其基因型在华法林抗凝治疗中具有重要指导意义。     

MDR1 C1236T和G2677T/A基因多态性对肾移植受者他克莫司血药浓度影响的Meta分析

目的：系统评价多药耐药基因1（MDR1）C1236T和G2677T/A多态性对肾移植受者他克莫司（FK506）血药浓度的影响,为临床个体化应用FK506提供循证参考。方法：计算机检索PubMed、Embase、Cochrane Library、CNKI数据库和万方数据库,检索时限均为建库起至2020年11月。收集MDR1（C1236T,G2677T/A）基因多态性对肾移植受者FK506血药浓度影响的研究,用Rev Man 5.3软件进行Meta分析。结果：共纳入12篇（中文5篇,英文7篇）相关研究,共计1 083例患者。其中,涉及C1236T的研究为9项,涉及G2677T/A的研究为10项。Meta分析结果显示：MDR1 C1236T基因型方面：MDR1 C1236T基因中CC型患者与CT型比较,FK506血药浓度/校正剂量值差异无统计学意义[SMD＝2.18,95% CI （-2.84,7.19）,P=0.40];MDR1 C1236T基因中CC型患者与TT型比较,FK506血药浓度/校正剂量值差异无统计学意义[SMD＝6.02,95% CI （-4.12,16.17）,P=0.24];MDR1 C1236T基因中CT型患者与TT型比较,FK506血药浓度/校正剂量值差异无统计学意义[SMD＝-0.13,95% CI （-7.71,7.44）,P=0.97]。MDR1 G2677T/A基因型方面：MDR1 G2677T/A基因中GG型患者FK506血药浓度/校正剂量值显著低于GA+GT型[SMD＝-6.91,95% CI （-12.39,-1.42）,P=0.01],亚组分析结果显示：术后12月[SMD＝-18.62,95% CI （-23.41,-13.82）,P<0.000 01],MDR1 G2677T/A基因中GG型患者FK506血药浓度/校正剂量值显著低于GA+GT型;MDR1 G2677T/A基因中GG型患者FK506血药浓度/校正剂量值显著低于TT+TA+AA[SMD＝-9.15,95% CI （-16.68,-1.61）,P=0.02],亚组分析结果显示：术后12月[SMD＝-19.81,95% CI （-39.29,-0.32）,P=0.05],MDR1 G2677T/A基因中GG型患者FK506血药浓度/校正剂量值显著低于TT+TA+AA;MDR1 G2677T/A基因中GA+GT型患者FK506血药浓度/校正剂量值与TT+TA+AA型比较,差异无统计学意义[SMD＝-4.56,95% CI （-9.32,0.19）,P=0.06]。结论：MDR1G2677T/A基因多态性与FK506血药浓度/校正剂量值有一定的相关性,且GA+GT或者TT+TA+AA型>GG型,而MDR1 C1236T基因多态性与肾移植受者FK506血药浓度/校正剂量值无相关性。     

Influence of CYP2C9 and vitamin k oxide reductase complex (VKORC)1 polymorphisms on time to determine the warfarin maintenance dose

Polymorphisms in cytochrome P450 (CYP) 2C9 and the vitamin K oxide reductase complex subunit 1 (VKORC1) greatly affect the maintenance dose of warfarin. To prevent adverse events, immediate dose adjustment is required. The purpose of this study was to investigate the influence of these polymorphisms on the time taken to determine the warfarin maintenance dose for individual patients, and to assess the advantages of genotype-based dosing on initial anticoagulant therapy. We analyzed the genotypes of CYP2C9 and VKORC1 from 72 patients. The number of days taken to determine the maintenance dose was compared with the genotypes. The time taken to determine the maintenance dose of warfarin in group A (CYP2C9*1/*1, VKORC1 -1639AA), B (*1/*1, - 1639GA), C (*1/*3, - 1639AA), and D (*1/*3, - 1639GA) patients was 19 +/- 19, 28 +/- 28, 27 +/- 20 and 7 days, respectively. We analyzed the relationship between the initial dose of warfarin and the number of days required to determine the maintenance dose based on the VKORC1 genotypes. Patients with the VKORC1 - 1639AA genotype and who were initially treated with more than 3mg warfarin, required approximately 2 weeks for the maintenance dose to be determined. Patients with the VKORC1 - 1639GA genotype and the same initial warfarin dosage required approximately a month; however, patients initially treated with 5 mg of warfarin only required 9.5 +/- 5.3 days. We found a tendency that the time taken to determine the warfarin maintenance dose depends on the genotypes. Genotype-based dosing may improve initial anticoagulant therapy.     

广州地区CYP2C9/VKORC1基因多态性及行个体化治疗患者凝血指标的改变

目的：调查广州地区汉族人群与华法林代谢相关的CYP2C9/VKORC1基因多态性分布特征,并了解经验用药患者与根据基因型进行个体化抗凝治疗患者凝血指标（TT、PT、PT-INR、FIB）的改变。方法：选取2015年1月至12月住院或门诊676例患者,采用基因芯片法进行CYP2C9/VKORC1基因多态性检测,分析基因型频率和等位基因频率,了解广州地区汉族人群CYP2C9/VKORC1基因多态性分布特征和凝血情况。随机选取初期2.5~3 mg·d^-1经验用药组（A组）服用华法林患者91例;经验用药一段时间后进行了CYP2C9/VKORC1基因多态性检测,并根据基因型行个体化用药（B组）。2组患者均按要求定期检测凝血指标。结果：广州地区汉族人群CYP2C9/VKORC1基因型*1*1/AA占74.567%;*1*1/GA占16.57%;*1*3/AA占6.21%;*1*3/GA和*1*1/GG各占1.18%;*1*2/AA和*1*3/AA各占0.15%。凝血指标（TT、PT、PT-INR、FIB）A组依次为（13.97±1.43）s、（16.74±8.34）s、（1.47±0.77）INR、（3.34±0.90）s,B组依次为（13.76±1.17）s、（21.71±11.40）s、（1.96±0.90）INR、（3.63±0.92）s;经配对资料t检验,TT 2组间无显著差异（P>0.05）;PT和PT-INR 2组间均有非常显著差异（P<0.01）;FIB A组与B组间有显著差异（P<0.05）。A组、B组患者在治疗过程中PT-INR控制在2~3 INR抗凝治疗理想范围的分别占13.6%和23.57%,经χ²检验有显著差异（P<0.05）。结论：广州地区汉族人群CYP2C9/VKORC1呈基因多态性,因此华法林按传统经验用药抗凝治疗模式存在一定的盲目性和潜在的危险性,以基因为导向的个体化抗凝治疗为临床在调整华法林抗凝治疗方案提供了科学依据,减少不良事件的发生率。     

Dose-dependent effects of the 3435 C>T genotype of ABCB1 gene on the steady-state plasma concentration of fluvoxamine in psychiatric patients

This study investigated effects of the 3435 C>T genotype of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1, MDR1) gene on the steady-state plasma concentration of fluvoxamine (FLV). METHODS: Sixty-two psychiatric patients were treated with different doses (50, 100, 150, and 200 mg/d) of FLV. Blood samples were collected after at least 2 weeks of treatment with the same daily dose to obtain steady-state concentrations of FLV, and 3435 C>T genotype was determined by polymerase chain reaction. RESULTS: FLV concentration-to-dose ratio was significantly different among 3435 C>T genotype groups at the 200 mg/d dose (P = 0.019). A post-hoc analysis revealed that FLV concentration-to-dose ratio was significantly higher in the TT genotype group as compared with the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.861 vs 0.434, P = 0.026). FLV concentration-to-dose ratio was significantly higher in the CT + TT genotype group than the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.618 vs 0.434, P = 0.031). At 50, 100, and 150 mg/d dose, FLV concentration-to-dose ratios were not significantly different among 3435 C>T genotype groups. At 50, 100, and 150 mg/d dose, no significant differences were found in FLV concentration-to-dose ratios between the CT + TT genotype group and CC genotype group. CONCLUSIONS: This study suggests that pharmacokinetics of FLV depend on ABCB1 gene polymorphism only at the 200 mg/d dose.