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. 2013 Dec;17(12):932–936. doi: 10.1089/gtmb.2013.0303

Association of Genetic Polymorphisms with Warfarin Dose Requirements in Chinese Patients

Yundan Liang 1,2,*, Zhiyu Chen 3,*, Gang Guo 4, Xuemei Dong 5, Chunting Wu 1, He Li 1, Tong Wang 1, Bingying Xu 1,✉
PMCID: PMC3865618  PMID: 23941071

Abstract

Objective: Warfarin is a commonly used anticoagulant with a narrow therapeutic range and large interindividual differences in dosing requirements. Previously, studies have identified that the interindividual variability was influenced by varieties of factors, including age, body size, vitamin K intake, interacting medications, as well as genetic variants. We aimed to investigate the effect of single-nucleotide polymorphisms (SNPs) on the interindividual variability of warfarin dose requirements in Chinese patients. Methods: The study population consisted of 300 patients with a stable maintenance dose of warfarin. We examined SNPs in eight genes involving in the biotransformation and mode of action of warfarin (i.e., CYP4F2, CYP2C19, APOE, CALU, EPHX1, PROC, CYP2C9, and GGCX) using the SNaPshot assay. Results: The mean daily warfarin dose in patients carrying CYP2C19 rs3814637CC, CYP2C9 rs1057910AA, and GGCX rs699664AA genotype was 3.39, 3.34, and 3.51 mg/day, respectively, which was higher than those carrying CYP2C19 rs3814637TT, CYP2C9 rs1057910CC, and rs699664GG genotype (2.00, 0.81, and 3.09 mg/day, respectively). Conclusion: These findings indicate that individuals carrying the CYP2C19 rs3814637CC or CYP2C9 rs1057910AA or GGCX rs699664AA genotype needed higher warfarin doses in the Chinese population.

Introduction

Warfarin is a commonly used anticoagulant prescribed for patients with chronic atrial fibrillation, deep vein thrombosis, pulmonary embolism, recurrent stroke, and prosthetic heart valves (Oldenburg et al., 2007). However, there are numerous challenges in clinical practice because of interindividual differences in drug responses, a narrow therapeutic range, and the risk of bleeding (Landefeld and Beyth, 1993; Takahashi and Echizen, 2003). Incorrect dosage administration may cause a high risk of either potentially devastating bleeding or failure to prevent thrombosis (Landefeld and Beyth, 1993). The therapeutic response must be monitored by serial determinations of the prothrombin time/international normalized ratio (INR). Several factors have been reported to influence therapeutic warfarin dose requirements, including age, body size, vitamin K intake, interacting medications, as well as genetic variants (Gage et al., 2004; Kamali et al., 2004).

Cytochrome P450 oxidoreductase is a membrane-bound enzyme, which plays critical roles in the metabolism of many drugs, including warfarin (Guengerich, 2008). Recently, pharmacogenomics studies have demonstrated that single-nucleotide polymorphisms (SNPs) in genes involving in warfarin metabolism and action may contribute to interindividual differences in patients' responses to warfarin (Lee et al., 2009; Cen et al., 2010; Pathare et al., 2012; Valentin et al., 2012; Wang et al., 2012; Zhong et al., 2012). Nevertheless, some of the results were not conclusive, even in the same ethnic group. Cen et al. (2010) reported that patients carrying CYP4F2 rs2108622 CT/TT genotypes had a significantly higher stable warfarin dose than those carrying the rs2108622 CC genotype in a Chinese population, whereas Lee et al. (2009) did not find that the CYP4F2 rs2108622 polymorphism influenced warfarin dosage in another Chinese population. Therefore, it is of great value to replicate the association between SNPs and warfarin responses.

In this study, we chose and genotyped SNPs in eight genes involving in the biotransformation and mode of action of warfarin (i.e., CYP4F2, CYP2C19, APOE, CALU, EPHX1, PROC, CYP2C9, and GGCX). We aimed to investigate the effect of these SNPs on the interindividual variability of warfarin dose requirements in Chinese patients.

Materials and Methods

Study population

The study population consisted of 300 unrelated patients who were enrolled from the Yan An Hospital, Kunming Medical University. The study protocol was approved by the University Ethics Committee, and all subjects signed the written informed consent. All the patients were Chinese Han individuals who lived in the Yunnan province of southwest China. The inclusion criteria were age ≥18 years and current treatment with a stable maintenance dose of warfarin. Patients with a history of liver dysfunction (serum transaminase levels greater than 1.5 times the upper limit of normal) or renal dysfunction (serum creatinine levels >120 μM) were excluded. After written informed consent was obtained, EDTA-anticoagulated peripheral blood was collected for genetic analysis and clinical information was recorded through patient interviews (Table 1).

Table 1.

Demographic and Clinical Characteristics of Warfarin-Treated Patients

Characteristics Patients (n=300)
Age (years) 47.9±12.5
Gender
 Male 138
 Female 162
Goal INR range 1.5–3.0
Warfarin dose (mg/day) 3.28±1.19
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Age and warfarin dose are shown as mean±SD.

INR, international normalized ratio; SD, standard deviation.

Genotyping

Genomic DNA was extracted from peripheral blood using the phenol/chloroform method. The SNPs were genotyped using the SNaPshot assay. The resulting data were analyzed using an ABI Prism 3130 DNA analyzer (Applied Biosystems, Foster City, CA). To ensure quality control, DNA sequencing was performed to confirm the results, and they were 100% concordant.

Statistical analysis

Baseline demographic and clinical characteristics were analyzed in patients with warfarin treatment. Data are expressed as numbers for categorical variables and mean±standard deviation for numerical variables. Associations between genotypes and warfarin dose requirements were examined by one-way analysis of variance (ANOVA). All the data were analyzed using the SPSS for windows software package version 15.0 (SPSS, Inc., Chicago, IL). A p-value less than 0.05 was considered as statistical significance.

Results

We analyzed the frequency of 19 SNPs in 300 patients under stable anticoagulation with warfarin. Demographic and clinical characteristics of the patients are summarized in Table 2. Of the 19 SNPs, 3 polymorphisms (i.e., CYP2C19 rs3814637, CYP2C9 rs1057910, and GGCX rs699664) exhibited a significant association with warfarin dose requirements (Table 2). The mean warfarin dose in patients with the CYP2C19 rs3814637CC genotype was 3.39 mg/day, which was higher than that in patients with the CYP2C19 rs3814637TT genotype (2.00 mg/day). The mean warfarin dose in patients with the CYP2C9 rs1057910AA genotype was 3.34 mg/day, which was higher than that in patients with the CYP2C9 rs1057910CC genotype (0.81 mg/day). The mean warfarin dose in patients with the GGCX rs699664AA genotype was 3.51 mg/day, which was higher than that in patients with the GGCX rs699664GG genotype (3.09 mg/day).

Table 2.

Association of Genetic Polymorphisms with Warfarin Dose Requirements in Chinese Patients

Genes SNPs Genotypes n Warfarin dose (mean±SD, mg/day) p-Value
CYP4F2 rs2108622 CC 172 3.26±1.16 0.47
    CT 120 3.31±1.31  
    TT 8 3.66±1.28  
  rs2189784 GG 135 3.22±1.05 0.44
    GA 124 3.35±1.26  
    AA 41 3.34±1.15  
CYP2C19 rs3814637 CC 251 3.39±1.19 <0.001
    CT 43 2.84±1.01  
    TT 5 2.00±0.97  
  rs4417205 CC 154 3.37±1.22 0.32
    CG 105 3.20±1.19  
    GG 41 3.23±1.08  
  rs17879456 GG 162 3.35±1.30 0.30
    GA 118 3.24±1.11  
    AA 20 3.12±1.06  
APOE rs7412 TT 6 2.95±0.54 0.52
    TC 28 3.60±1.60  
    CC 266 3.25±1.15  
  rs429358 CC 6 2.84±0.88 0.30
    CT 17 3.14±1.00  
    TT 277 3.30±1.21  
CALU rs1006023 GG 4 3.03±0.68 0.68
    GT 69 3.25±1.33  
    TT 227 3.29±1.16  
  rs2307040 TT 5 3.40±0.76 0.91
    TC 49 3.27±1.29  
    CC 246 3.28±1.18  
  rs339054 GG 22 3.35±1.34 0.23
    GT 138 3.14±1.16  
    TT 140 3.40±1.19  
EPHX1 rs2292566 AA 23 3.26±1.36 0.35
    AG 129 3.17±1.11  
    GG 148 3.36±1.23  
  rs4653436 AA 6 3.03±1.49 0.37
    AG 85 3.20±1.00  
    GG 209 3.32±1.26  
  rs1877724 TT 32 3.07±0.98 0.40
    TC 117 3.49±1.21  
    CC 151 3.16±1.20  
PROC rs1799809 AA 201 3.33±1.22 0.73
    AG 79 3.16±1.11  
    GG 20 3.32±1.19  
  rs2069910 CC 14 2.98±0.99 0.40
    CT 125 3.39±1.29  
    TT 160 3.23±1.13  
CYP2C9 rs1057910 AA 276 3.34±1.17 <0.001
    AC 22 2.71±1.03  
    CC 2 0.81±0.26  
  rs9332127 GG 281 3.35±1.35 0.63
    GC 19 3.39±1.25  
GGCX rs699664 AA 24 3.51±1.44 0.01
    AG 137 3.46±1.24  
    GG 119 3.09±1.04  
  rs12714145 TT 33 3.35±1.35 0.30
    TC 146 3.39±1.25  
    CC 104 3.20±1.02  
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SNP, single-nucleotide polymorphism.

Discussion

In this study, we genotyped the SNPs in eight genes involving in warfarin metabolism and action (i.e., CYP4F2, CYP2C19, APOE, CALU, EPHX1, PROC, CYP2C9, and GGCX), and examined the contribution of the SNPs to the warfarin maintenance dose required in Chinese patients. We found that individuals carrying the CYP2C19 rs3814637CC or CYP2C9 rs1057910AA or GGCX rs699664AA genotype needed higher warfarin doses when compared with those carrying the CYP2C19 rs3814637TT or CYP2C9 rs1057910CC or GGCX rs699664GG genotype. These findings indicate that personalized dosing guided by genotyping data from CYP2C19 rs3814637 or CYP2C9 rs1057910 or GGCX rs699664 may be a solution for the safety of warfarin therapy.

The cytochrome P450 superfamily is a group of enzymes that plays key roles in the metabolism and bioactivation of many drugs, such as warfarin. Warfarin is metabolized primarily by the liver, with more than one cytochrome P450 isoenzyme involved in the metabolism. Previous studies have identified that CYP2C9 is responsible for the metabolism of 90% of S-warfarin and CYP2C19 for the metabolism of R-warfarin (Shek et al., 1999). At present, management of warfarin therapy in clinical practice is difficult due to large interindividual variability, and the interindividual variability may be explained by the genetic variants of the warfarin metabolizing enzymes (Kimura et al., 2007).

The gene that encodes CYP2C9 is located on chromosome 10q24 in humans (Gray et al., 1995). Previously, several polymorphic variants of the CYP2C9 gene have been identified. Among them, the CYP2C9*2 (R144C, rs1799853) and CYP2C9*3 (I359L, rs1057910) variants were known to influence warfarin dose requirements (Higashi et al., 2002). In this study, we found that CYP2C9 rs1057910CC genotype required lower doses of warfarin in Chinese patients. Our data were consistent with previous results, which reported that the CYP2C9 rs1057910C allele was associated with diminished warfarin clearance and a lower average warfarin dose (Steward et al., 1997; Sanderson et al., 2005; Gan et al., 2011; Eriksson and Wadelius, 2012). As for the CYP2C9*2, Ross et al. (2010) reported that the variant leads to reduced warfarin metabolism and increased risk of bleeding in Caucasian subjects, but is very rare in Chinese. In this study, we failed to detect the CYP2C9*2 in Chinese patients, which confirmed the result of Ross et al. (2010). These results suggested that the CYP2C9 polymorphism exhibited ethnic specificity and association studies investigating the influence of CYP2C9 polymorphism on warfarin dose requirements in different ethnic groups were valuable.

In addition to the CYP2C9 polymorphism, several other genetic variants have been presented to affect interindividual variability in the response to warfarin therapy, such as CYP2C19. Lane et al. (2012) reported that the CYP2C19 rs3814637 genotype had a significant impact on R-warfarin clearance. Indeed, the effect of CYP2C19 on warfarin has been studied extensively (Scordo et al., 2002; Obayashi et al., 2006; Lee et al., 2007; Uno et al., 2008; Lane et al., 2012). However, limited data are shown in the Chinese population, especially in patients living in the southwest region of China. In the current study, we found that CYP2C19 rs3814637 genotype influenced the between-subject variability, which may be used as a reference in developing dosing algorithms.

Gamma-glutamyl carboxylase (GGCX) is known as the vitamin K-dependent carboxylase, which activates a subset of proteins with calcium-binding properties. The GGCX gene is located on chromosome 2p12 in human, consisting of 15 exons (Kuo et al., 1995; Wu et al., 1997). Over the past decades, the association of GGCX polymorphisms with warfarin maintenance-dose requirements has been extensively investigated (Wadelius et al., 2005; Herman et al., 2006; Cha et al., 2007; Kimura et al., 2007; Rieder et al., 2007). Conflicting results, however, was obtained. Wadelius et al. (2005) reported that a common nonsynonymous polymorphism Q325R (rs699664) was not associated with warfarin dose in a Swedish population. In contrast, Kimura et al. (2007) reported that the polymorphism explained 4.6% of the variation in warfarin dose in Japanese patients. In this study, we found that the GGCX rs699664 polymorphism was associated with increased sensitivity to warfarin in Chinese patients, suggesting that it may be used as a predictor of warfarin maintenance dose.

Even though we found that the CYP2C19 rs3814637, CYP2C9 rs1057910, and GGCX rs699664 genotypes were related to the dose of warfarin therapy, there are some limitations in the study. The power is not very strong due to the moderate sample size. Moreover, all the patients included in the study were Chinese, and thus, the results cannot be directly extended to other populations. Further studies with a larger sample size should be conducted to confirm the results.

In conclusion, this study provides evidence that patients with the CYP2C19 rs3814637CC or CYP2C9 rs1057910AA or GGCX rs699664AA genotype required higher warfarin doses in the Chinese population. The genotyping information might help to guide warfarin dosage for clinicians. However, replication studies with a larger sample size and a longer follow-up are needed to obtain an algorithm suitable for the Chinese population.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 30860339). This study was endowed by the National Natural Science Foundation of China, Grant No. 30860339 and Yunnan province science and technology project, Grant No. 2009ZC155M, which is taken charge of by Professor Bingying Xu.

Authors' Contributions

Yundan Liang: Data analysis, statistical analysis, manuscript preparation.

Zhiyu Chen: Literature research, Clinical studies, Manuscript final version approval.

Gang Guo: Experimental studies, Data acquisition, Data analysis, Statistical analysis.

Dong Xuemei: Experimental studies, Data acquisition, Data analysis, Statistical analysis.

Chunting Wu: Experimental studies, Data acquisition, Data analysis, Statistical analysis.

He Li: Experimental studies, Data acquisition, Data analysis, Statistical analysis.

Tong Wang: Experimental studies, Data acquisition, Data analysis, Statistical analysis.

Bingying Xu: Guarantor of integrity of entire study, Study concepts, Study design, Manuscript preparation, Manuscript definition of intellectual content, Manuscript editing, Manuscript revision/review, Manuscript final version approval.

Author Disclosure Statement

The authors of this article have no conflicts of interest with the information presented in any submitted manuscript, including consultancies, stock ownership, or other equity interests, patent licensing arrangements, and payments for conducting or publicizing a study described in the manuscript.

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