中国汉族人群CYP2C9和VKORC1基因多态性对华法林用药的影响

目的 探讨中国汉族人群细胞色素氧化酶P450 2C9(CYP2C9)基因以及维生素K环氧化物还原酶复合体1(VKORC1)基因多态性对华法林用药的影响。方法 首先抽取无抗凝障碍的汉族人群受试者200例利用基因测序法进行CYP2C9 和VKORC1基因分型(正常对照组)。并收集临床使用华法林稳定维持剂量的汉族人群患者114例(服用华法林药物组),记录患者年龄、性别、身高、体质量以及体表面积等,检测基因型并结合体征差异及临床稳定剂量进行分析。结果 正常对照组的CYP2C9基因型检测有CYP2C9*1/*1型186例(93%),未发现CYP2C9*1/*2型,CYP2C9*1/*3型14例(7%); VKORC1-1639A/G基因型:AA型179例(89.5%),GA型21例(10.5%),未发现GG型(0.0%); 服用华法林药物组的CYP2C9*1/*1型104例(91.2%),CYP2C9*1/*3型10例(8.8%),CYP2C9*1/*1型患者华法林平均维持剂量高于CYP2C9*1/*3型患者[(2.13±0.83)mg/dvs(1.61±1.17)mg/d,P＜0.05]。VKORC1(-1639G＞A)基因型检测有102例患者为突变纯合子AA型(89.5%),12例患者为杂合子GA型(10.5%),未发现纯合子GG型患者,GA型患者华法林平均维持剂量明显高于AA型[(3.34±1.07)mg/d vs(1.63±0.45)mg/d,P＜0.01]。正常人群组与服用华法林药物组基因型在CYP2C9*3(1075C/A)(P=0.926)和VKORCl -1639A/G突变上的差异无统计学意义(P=0.812)。结论 中国汉族人群存在CYP2C9*3 A/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基因多态性与华法林剂量关系的研究

目的研究江苏徐州地区汉族人细胞色素P450(CYP)2C9和维生素K环氧化物还原酶复合体1(VKORC1)基因型与华法林剂量的关系,为华法林个体化给药方案提供建议。方法采用聚合酶链反应-连接酶检测反应(PCR-LDR)技术检测100名汉族健康受试者及200例临床使用华法林的患者CYP2C9和VKORC1基因型。结果健康受试者CYP2C9基因型中91例为*1/*1型,9例为*1/*3型;VKORC1基因型中17例为GA型,83例为AA型。200例临床使用华法林的患者CYP2C9基因型检测有179例为*1/*1型,21例为*1/*3型,未发现*2突变;VKORC1(1639GA)基因型中168例为突变纯合子AA型,32例为杂合子GA型,未发现GG型;VKORC1(1639GA)基因AA型患者的华法林维持剂量为(2.59±0.83)mg/d,明显低于GA型[(4.51±0.79)mg/d];CYP2C9基因*1/1*型华法林维持剂量为(3.01±1.12)mg/d,明显高于*1/*3型[(2.19±0.32)mg/d,P0.05]。结论 CYP2C9和VKORC1基因型的多变量个体化给药方案对临床提高华法林使用的安全性有潜在的意义。     

重庆地区CYP2C9和VKORC1基因多态性与华法令药物敏感性的相关研究

目的探讨重庆地区CYP2C9和VKORC1基因多态性频率分布及与华法令药物敏感性的相关性。方法收集陆军军医大学大坪医院2017年2月至2018年12月CYP2C9和VKORC1基因多态性检测患者657例作为研究对象,采用基因芯片杂交法检测CYP2C9及VKORC1基因多态性。结果 (1)重庆地区共检测出8种基因型,主要以*1/*1AA为主,频率为73.52%;(2)重庆地区人群以华法令敏感型(*1/*1AA、*1/*3GA、*1/*2AA、*1/*2GA、*1/*3GG)为主,频率为74.73%,华法令建议起始剂量3.0～4.0mg;(3)CYP2C9和VKORC1基因多态性分布在性别、疾病间差异无统计学意义(P0.05)。结论重庆地区CYP2C9和VKORC1基因型以*1/*1 AA为主,其中华法令敏感型占74.73%,建议华法令用药前进行CYP2C9和VKORC1基因检测便于指导华法令用药。     

LNA-taqman探针实时荧光PCR快速检测CYP4F2-C1347T,CYP2C9*3,VKORC1-C1173T与VKORC1-G1639A基因多态性方法的建立

目的建立一种基于LNA-taqman探针实时荧光PCR检测华法林剂量相关基因型维生素K单氧酶CYP4F2,维生素K环氧化物还原酶复合体亚单位1(VKORC1)和细胞色素P4502C9(CYP2C9)的方法。方法针对CYP4F2-1347CT,CYP2C9*3,VKORC1-1173CT与VKORC1-1639GA四个单核苷酸多态性(SNP)位点,分别设计一套等位基因特异性探针与引物,并对LNA-taqman探针特异性进行评价。提取150例接受华法林治疗患者外周血样本基因组DNA进行检测,同时对部分实时荧光PCR产物样品进行验证。结果 (1)LNA-taqman探针检测方法特异性高,没有交叉性。(2)150例患者中,CYP4F2-1347CT基因型CC,CT和TT分别有87,56和7例,各占58%,37.3%和4.7%;CYP2C9*3基因型*1/*1和*1/*3分别有142和8例,各占94.7%和5.3%,未检出纯合子*3/*3基因型;VKORC1-1173CT基因型TT,TC和CC分别有127,20和3例,各占84.7%,13.3%和2%;VKORC1-1639GA基因型AA,AG和GG分别有124,23和3例,各占82.7%,15.3%和2%。结论基于LNA-taqman探针的实时荧光PCR分型方法具有操作简便,价格低廉,结果准确可靠等特点,适于临床实验室对CYP4F2,CYP2C9*3,VKORC1的基因分型。     

CYP2C9和VKORC1基因多态性在高寒地区汉族人群中的分布情况分析

目的探究CYP2C9和VKORC1基因多态性在我国高寒地区汉族人群中的分布情况,比较其与同纬度不同国家及我国低纬度汉族人群的差异。方法在高寒地区汉族人群中收集服用华法林的受试者210例,收集患者相关临床病例资料并检测患者的CYP2C9和VKORC1基因型。结果210例受试者CYP2C9的基因型*1/*1、*1/*3和*2/*3频率分别为96.2%、3.3%和0.5%;*1/*1基因型频率高于法国、加拿大、俄罗斯、瑞典和西班牙国家人群(P0.05),*1/*3和*2/*3低于上述国家(P0.05)。VKORC1基因AA、GA和GG的基因型频率分别为81.0%、17.6%和1.4%;AA基因型频率高于法国、加拿大、俄罗斯、瑞典和西班牙国家人群而GG基因型频率低于上述国家人群(P0.05)。CYP2C9和VKORC1基因型与我国广州、湖北、江苏、华南等低纬度地区分布差异无统计学意义(P0.05)。结论 CYP2C9和VKORC1基因型在我国高寒地区汉族人群中以对华法林敏感性较高的类型居多。同纬度不同国家人群上述基因多态性分布差异较大,我国不同纬度汉族人群上述基因多态性分布无差异性。     

基于CYP2C9与VKORC1基因多态性的心脏瓣膜置换术后华法林个体化给药剂量预测的3种模型算法比较

目的了解泸州及周边地区汉族人群CYP2C9与VKORC1基因多态性分布情况并评价3种常用华法林剂量预测算法的差异。方法选取2018年6月至2019年7月在西南医科大学附属医院心脏大血管外科行心脏瓣膜置换术的120例泸州及周边地区汉族患者为研究对象,用PCR-微阵列基因芯片法检测其CYP2C9430、CYP2C91075与VKORC1-1639位点的基因型,对3个基因位点基因型的分布情况进行分析。基于基因检测结果与患者生理、病理信息,分别用国际华法林药物基因组协会(IWPC)公式、Warfarin Dosing网站、中国公式计算患者个体化剂量,对比3种算法计算剂量的差异。结果CYP2C91075位点AA与AC型的患者分别占90.83%和9.17%,VKORC1-1639位点AA、AG、GG型的患者分别占88.33%、10.83%和0.83%,未检出CYP2C9*2。检出的5种基因型组合中华法林计算剂量最高的基因型为CYP2C9*1/*1&VKORC1 GG。中国公式的计算剂量与国际公认的IWPC公式与Warfarin Dosing网站的计算剂量相关度均较高。结论泸州及周边地区汉族人群中存在CYP2C91075与VKORC1-1639位点的基因多态性,建议患者服用华法林前先进行该组基因位点的多态性检测,利用计算因素更全面的中国公式与Warfarin Dosing网站计算剂量,并在后期持续监测国际标准化比值以获得更好的预后。     

CYP2C9及VKORC1基因多态性对心脏瓣膜置换术后华法林抗凝治疗策略的影响

目的评价CYP2C9及VKORC1基因多态性检测对心脏瓣膜置换术后华法林抗凝治疗策略的影响。方法随机选取380例心脏瓣膜置换术患者,190例行CYP2C9和VKORC1基因多态性检测(基因检测组),另190例不作相关检测(对照组),记录患者服用华法林稳定剂量、国际标准化比值(INR)达标时间和住院时间。结果 190例行基因多态性检测的患者中CYP2C9*1/*1型170例(89.5%),*1/*3型19例(10.0%),*3/*3型1例(0.5%);VKORC1 AA型155例(81.6%),AG型35例(18.4%),未检出GG型。基因检测组INR达标时间[(4.0±1.7)d]低于对照组[(4.6±2.1)d](P0.01),2个组住院时间差异无统计学意义(P0.05)。结论 CYP2C9及VKORC1基因多态性检测对于抗凝治疗初期临床策略的制定起重要作用,可缩短患者INR达标时间,有助于减少患者出血及栓塞风险。     

非瓣膜病心房颤动患者VKORC1及CYP2C9基因多态性与华法林临床应用的关系的探究

探究非瓣膜病心房颤动患者VKORC1及CYP2C9基因多态性与华法林临床应用的关系。回顾性分析我院2014年5月~2016年5月收治的140例非瓣膜病心房颤动患者的一般资料,测定华法林初始剂量和基础国际标准化比率(INR),抽取静脉血检测CYP2C9与VKORC1基因多态性,通过随访记录华法林初始服用至INR达标时间、华法林平均日用量及总用量。本组CYP2C9和VKORC1等位基因A型、基因型AA型较多;CYP2C9和VKORC1不同基因型患者体质指数及INR的对比无统计学差异(P0.05);CYP2C9AA型INR达标时间长,华法林总用量较高,与AC型和CC型比较具有显著差异(P0.05);VKORC1 AA型INR达标时间短,华法林总用量较低,与AG型和GG型比较具有显著差异(P0.05)。非瓣膜病心房颤动患者初次服用华法林进行抗凝治疗,VKORC1基因AA型和CYP2C9基因AC/CC患者INR达标时间短,华法林总用量较少。非瓣膜性房颤患者华法林口服剂量个体差异较大,用药前应进行基因多态性检测,以此为临床用药进行指导。     

荧光PCR-熔解曲线法检测新疆回族人群CYP2C9和VKORC1基因多态性研究

目的应用荧光PCR-熔解曲线法检测新疆回族人群细胞色素P450酶2C9(CYP2C9)和维生素K环氧化物还原酶复合体亚单位1(VKORC1)基因多态性,研究新疆回族人群CYP2C9和VKORC1基因分布及基因突变频率情况,并评价荧光PCR-熔解曲线法临床使用的适用性。方法采用荧光PCR-熔解曲线法和测序法对比检测CYP2C9*2、CYP2C9*3和VKORC1(-1639G/A)的基因多态性。结果 228例新疆回族人群中,共检测出CYP2C9*1/*1标本199例,CYP2C9*1/*2标本2例,CYP2C9*1/*3标本26例,CYP2C9*3/*3标本1例,未检测出CYP2C9*2/*2和CYP2C9*2/*3标本。VKORC1(-1639G/A)检测出2种等位基因G和A,其中VKORC1-1639G/G型标本检出2例,VKORC1-1639G/A型标本检出39例,VKORC1-1639A/A型标本检出187例,与测序法对比检测比较,荧光PCR-熔解曲线法与测序法检测结果完全一致。结论新疆回族人群同样具有CYP2C9基因*2、*3位点和VKORC1基因-1639位点的多态性,其发生频率与新疆维吾尔族及其他地域人群的具有一定差异,所采用的荧光PCR-熔解曲线法用于基因多态性检测可满足临床检测要求。     

华南地区汉族人群心脑血管相关基因多态性分析

目的了解心脑血管相关基因细胞色素P450酶(CYP)2C19、CYP2C9、维生素K环氧化物还原酶复合体1(VKORC1)和乙醛脱氢酶2(ALDH2)基因的单核苷酸多态性频率在华南地区汉族人群分布的情况。方法采用芯片技术对252例心脑血管疾病患者的CYP2C19、ALDH2、CYP2C9以及VKORC1位点基因多态性进行检测,并统计男女间基因型频率的差异。结果 CYP2C19的野生型*1/*1占42.5%,突变型*1/*2占36.9%,*1/*3占7.9%,*2/*2占9.9%,*2/*3占1.6%,*3/*3占1.2%,在男女人群间各类基因型的发生率差异无统计学意义(P0.05);CYP2C9只检测到2种等位基因CYP2C9*1/*1和CYP2C9*1/*3,男性基因频率分别为98.6%和1.4%,女性基因频率分别为90.1%和9.9%,在男女人群间的分布差异有统计学意义(P0.05);VKORC1有3种基因型AA、AG和GG,频率分别为80.6%、18.7%和0.8%,在男女人群间的分布差异无统计学意义(P0.05);ALDH2有3种基因型GG、GL和LL型,频率分别为55.2%、37.3%和7.5%,在男女人群间的分布差异无统计学意义(P0.05)。结论 CYP2C9的多态性分布与性别有关,CYP2C19、VKORC1和ALDH2的多态性分布与性别无关。     

Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes

BACKGROUND: CYP2C9 polymorphisms are associated with decreased S-warfarin clearance and lower maintenance dosage. Decreased expression of VKORC1 resulting from the -1639G>A substitution has also been implicated in lower warfarin dose requirements. We investigated the additional contribution of this polymorphism to the variance in warfarin dose. METHODS: Sixty-five patients with stable anticoagulation were genotyped for CYP2C9 and VKORC1 with Tag-It allele-specific primer extension technology. Plasma S-warfarin concentrations and warfarin maintenance dose were compared among patients on the basis of the VKORC1 -1639G>A genotype. RESULTS: Eighty percent of CYP2C9*1/*1 patients stabilized on <4.0 mg/day warfarin had at least 1 VKORC1 -1639A allele. Mean warfarin doses (SD) were 6.7 (3.3), 4.3 (2.2), and 2.7 (1.2) mg/day for patients with the VKORC1 -1639GG, GA, and AA genotypes, respectively. Steady-state plasma concentrations of S-warfarin were lowest in patients with the VKORC1 -1639AA genotype and demonstrated a positive association with the VKORC1 -1639G allele copy number (trend P = 0.012). A model including VKORC1 and CYP2C9 genotypes, age, sex, and body weight accounted for 61% of the variance in warfarin daily maintenance dose. CONCLUSIONS: The VKORC1 -1639A allele accounts for low dosage requirements of most patients without a CYP2C9 variant. Higher plasma S-warfarin concentrations corresponding to increased warfarin maintenance dosages support a hypothesis for increased expression of the VKORC1 -1639G allele. VKORC1 and CYP2C9 genotypes, age, sex, and body weight account for the majority of variance in warfarin dose among our study population.     

VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients

OBJECTIVES: To compare the genetic and clinical factors that cause large interpatient variability and ethnic differences in warfarin efficacy, we investigated variations of the VKORC1, CYP2C9, and CYP2C19 genes in Japanese subjects. Furthermore, we evaluated the genetic variations and clinical data as contributors of variation in warfarin maintenance dose. METHODS: Gene variations of VKORC1, CYP2C9, and CYP2C19 in 125 patients treated with warfarin and 114 healthy subjects were analyzed. The daily dose of warfarin, concentrations of S- and R-warfarin in plasma, and prothrombin time expressed as the international normalized ratio were used as the pharmacokinetic and pharmacodynamic indices. Data were evaluated by a multivariate analysis method. RESULTS: Three missense mutations (47 G>C, 113 A>C, and 1338 A>G) in VKORC1 were newly identified in the Japanese population. The 113 A>C (Asp38Ser) variant decreased the warfarin dose requirement from 3.33 +/- 1.54 mg/d (n = 122) to 1.5 mg/d (n = 1). The variants -1639 G>A in the 5'-upstream region, 1173 C>T in intron 1, and 1542 G>C in intron 2 were in complete linkage disequilibrium, and the frequency of the -1639 G>A variation was only 0.8%, which contrasts with the frequency (39.8%-45.8%) reported previously for white persons. The dose of warfarin was larger in the VKORC1 -1639 GA genotype group (4.55 +/- 1.75 mg/d, P < .001) than in the -1639 AA group (2.94 +/- 1.15 mg/d). The mean daily dose of warfarin was lower in subjects with CYP2C9*1/*3 (1.86 +/- 0.80 mg/d, P = .007) than in subjects with CYP2C9*1/*1 (3.36 +/- 1.43 mg/d). When the relative contributions of the VKORC1 variants, CYP2C9*2, CYP2C9*3, CYP2C19*2, and CYP2C19*3, as well as the clinical characteristics of the patients, diagnoses, and concurrent medications, were compared, the VKORC1 -1639 GA genotype group accounted for 16.5% and CYP2C9 variants accounted for 13.4% of variation in warfarin dose. CONCLUSION: The ethnic difference in warfarin maintenance dose was mainly dependent on the linked VKORC1 variants. Genotyping of -1639 G>A of the VKORC1 gene could be clinically important for predicting individual variability in anticoagulant responses to warfarin.     

Warfarin metabolism and anticoagulant effect: a prospective, observational study of the impact of CYP2C9 genetic polymorphism in the presence of drug-disease and drug-drug interactions

BACKGROUND: Cytocbrome P450 (CYP) 2C9 polymorphism affects the warfarin dosage requirement in stable outpatients. However, it is not known whether the CYP2C9 genotype contributes to the variability in warfarin dosage in the presence of drug-disease and drug-drug interactions. OBJECTIVE: The aim of this study was to examine the effects of CYP2C9 genetic polymorphism on warfarin dosage requirements in patients with severe comorbid conditions and those treated with medications that potentially interact with warfarin. METHODS: This prospective, observational study was conducted at Hadassah University Hospital, Jerusalem, Israel. Data from consecutive patients treated with warfarin for at least 3 months and admitted to the internal medicine ward were eligible for inclusion. Clinical data, international normalized ratio (INR), and warfarin dosage were recorded from medical records. The CYP2C9 genotype was determined using polymerase chain reaction restriction fragment length polymorphism, and plasma concentrations of (S)- and (R)-warfarin were determined by high-performance liquid chromatography using chiral methods. RESULTS: One hundred nineteen subjects (52% women) were studied. Mean age was 65.8 years (95% CI, 63.1-68.4), and weight was 74.9 kg (95% CI, 72.1-77.7). The mean warfarin dosage was 33% lower in patients with the CYP2C9-*1/*3 genotype (mean [SEM], 0.045 [0.006] mg/kg x d(-1)) compared with the CYP2C9-*1/*1 genotype (0.067 [0.004] mg/kg x d(-1)) (P=0.008); an intermediate value was found for the CYP2C9-*1/*2 genotype (0.062 [0.008] mg/kg x d(-1)). However, despite the lower dosage, INR was significantly higher in patients with the *1/*3 genotype (mean [95% CI], 3.29 [2.44-4.14]) (n=18) compared with the *1/*1 genotype (2.52 [2.34-2.71]) (n=64) (P=0.029). In addition to genotype, older age, congestive heart failure (CHF), and treatment with antibiotics were associated with lower warfarin dosages, whereas treatment with drug-metabolism inducers was associated with higher warfarin dosages. In addition, the ratios of (S)- to (R)-warfarin concentrations were significantly higher in patients with *1/*3 compared with those in patients with the *1/*1 genotype. CONCLUSIONS: In this study population of patients with severe comorbid conditions and those treated with medications that potentially interact with warfarin, CYP2C9 *1/*3 genotype, older age, CHF, and the use of antibiotics were associated with lower warfarin dosage requirements. The CYP2C9*1/*3 genotype, compared with CYP2C9 *1/*1, was associated with 33% lower mean warfarin dosage requirements and higher INR values, which were higher than the upper therapeutic range of INR (ie, 3). Genetic CYP2C9 polymorphism contributed to the variability in warfarin dosage requirements in the presence of drug-disease and drug-drug interactions.     

Standard warfarin dose in a patient with the CYP2C9*3/*3 genotype leads to hematuria

BackgroundPatients with certain CYP2C9 genetic variants have increased sensitivity to warfarin and are at increased risk of over-coagulation with standard warfarin dose. We report over-anticoagulation and hematuria manifest as a slow increase in the international normalized ratio (INR) due to warfarin treatment in a patient with the CYP2C9*3/*3 allele.CaseA 58-y-old man with paroxysmal atrial fibrillation received a standard warfarin dose of 2.0 mg/day. Because INR was 2.00 one week after treatment initiation, he was discharged from the hospital. One month later, hematuria was present and INR had increased to 7.26. Although in normal cases (R)-warfarin plasma concentrations are higher than (S)-warfarin, this patient had the opposite warfarin enantiomer plasma concentration profile.ConclusionsIncreased anticoagulation was due to an increased concentration of (S)-warfarin, the more active warfarin enantiomer. INR response to warfarin in this CYP2C9*3/*3 patient was slow. The later INR response appears to be strongly affected by CYP2C9 variants. He also had the VKORC1 ?1639G > A AA genotype, requiring a lower warfarin dose. In this case, increased risk of bleeding could have been identified by prospective genotyping of CYP2C9 and VKORC1 prior to initiating warfarin therapy.     

VKORC1-1639G／A基因多态性与华法林应用剂量关系的研究

目的探讨维生素K环氧化物还原酶复合物1基因（VKORC1）-1639G／A多态性对中国汉族人华法林应用剂量的影响。方法应用PCR—RFLP法检测129例长期口服华法林的患者和198例健康对照者VKORC1-1639G／A多态性，比较VKORC1不同基因型间平均华法林剂量。结果病例组VKORC1-1639AA、AG、GG基因型频率分别为74．4％（96／129）、23．3％（30／129）、2．3％（3／129），等位基因A和G频率分别为86％和14％。病例组与健康对照者VKORC1-1639G／A多态性分布差异无统计学意义（P〉0．05）。VKORC1-1639不同基因型患者所需华法林平均剂量差异有显著统计学意义（P〈0．（301），AA型剂量[（1．444±0．282）mg／INR]显著低于AG型[（1．629±0．258）mg／INR，P=0．002]和GG型患者[（2．031±0．087）mg／INR，P=0．017]。结论中国人华法林应用剂量偏低可能与VKORC1-1639AA型占多数有关。     

Low dose requirement for warfarin treatment in a patient with CYP2C9*3/*13 genotype

BackgroundCytochrome P450 2C9 (CYP2C9) is the major isoform of the CYP2C subfamily, and is involved in the metabolism of many clinically important therapeutic agents. Here we describe a patient who was intolerant of warfarin treatment because of impaired drug metabolism related to the CYP2C9*3/*13 genotype and high warfarin sensitivity associated with the VKORC1 1173TT genotype.CaseA 64-year-old Korean man had taken warfarin for treatment of an occluded left subclavian artery and atrial fibrillation. Although the warfarin doses prescribed were not high (14 mg/week) during the induction of anticoagulation, the prothrombin time (PT) was elevated to over 120 s after two weeks of warfarin therapy. For this patient, a very low dose of warfarin (4 mg/week) was required in order to achieve target INR values.ConclusionsTo the best of our knowledge, this is the first report of a patient with CYP2C9*3/*13 and VKORC1 1173TT genotypes who had slower than normal warfarin metabolism, resulting in the need to administer an extremely low dose of warfarin in order to achieve the target INR value. Our report reinforces the relevance of pharmacogenetic testing to explain warfarin dose variability and to enable individualized dosage adjustments for improved warfarin treatment outcomes.     

Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin

What is known and Objectives: Testing for cytochrome P450‐2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles is recommended by the FDA for dosing of warfarin. However, dose prediction models derived from data obtained in one population may not be applicable to another. We therefore studied the impact of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dose requirement in Malaysia. Methods: Patients who were attending clinics at our hospital and prescribed warfarin with stabilized INR levels of 2–4 were selected. DNA was extracted from blood samples and subsequently genotyped for CYP2C9*1, *2, *3, VKORC1 (G‐1639A) and VKORC1 C1173T. Linear regression modelling using age, CYP2C9 and VKORC1 genotypes, sex, weight and height was undertaken to define a warfarin dosing algorithm. An initial model was developed using data from one cohort of patients and validated using data from a second cohort. Results and Discussion: A model which included age and variants of CYP2C9 and VKORC1 account for about 37% of the variability in warfarin dose required to achieve INR of 2–4. Among the parameters evaluated, only VKORC1 (G‐1639A) and (C1173T) alleles, and age correlated with warfarin dose at 6 month. The mean dose predicted using the algorithm derived from cohort 1 was lower than the actual dose for cohort 2 (3·30 mg, SD 0·84 vs. 3·45 mg, SD 1·42). There was no relationship between INR values and the dose taken by the patients. Race, sex, weight and height did not correlate with dose. What is new and Conclusion: This study identifies factors which affect warfarin dosing in the Malaysia population. However, our best model does not account sufficiently for the variability in dose requirements for it to be used in dose prediction for the individual patient. Other important influential factors affecting warfarin dose requirement remain to be identified.     

Frequency of CYP2C9 polymorphisms affecting warfarin metabolism in a large anticoagulant clinic cohort

OBJECTIVES: To assess allele frequency and genotype distribution of CYP2C9 polymorphisms in patients (n = 189) attending an anticoagulant clinic in comparison to control patients (n = 177) and also to assess if the patients with variant genotypes require lower doses of warfarin. METHODS: Genotyping of the common CYP2C9 variants *2 and *3 was carried out by multiplexed PCR-RFLP while the *5 and *6 allele variants were genotyped by singleton PCR-RFLP. DNA sequencing was used to confirm genotype in all specimens with *3, *4 and *6 alleles. RESULTS: CYP2C9 allele frequencies in patients were 0.81 for *1, 0.11 for *2 and 0.08 for *3, compared to 0.88, 0.08 and 0.04, respectively, in controls. Patients with *1/*3 and *X/*X (where *X is *2 or *3) genotypes required 32 to 67% less warfarin in comparison to patients with the normal *1/*1 genotype. Other alleles were observed in less than 1% of subjects. CONCLUSIONS: Allele frequencies and genotypes for CYP2C9*2 and *3 variants in patients on warfarin are not statistically different from controls whether or not they are stratified for ethnicity. Less common genotypes (*4, *5, *6) do not contribute significantly to warfarin sensitivity among patients attending a routine anticoagulation clinic. CYP2C9 genotype predicts warfarin dosage even in an uncontrolled, retrospective survey of unselected patients on warfarin therapy.