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Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin

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Abstract

This study was designed to evaluate the effect of the warfarin dose-associated genotypes, CYP2C9*3 (rs1057910), VKORC1 −1639 G/A (rs9923231), and CYP4F2 1347 C/T (rs2108622), on hemorrhagic complications in Han Chinese patients. Consecutively recruited patients requiring more than 1 year of warfarin treatment were followed from the initiation of warfarin anticoagulation for at least 3 months. CYP2C9*3, VKORC1 −1639 G/A, and CYP4F2 1347 C/T were genotyped by sequencing. The association between genotypes and warfarin hemorrhagic complications was evaluated using Cox proportional hazard regression, adjusted for demographic and clinical factors. Of 312 eligible patients obtaining stable warfarin anticoagulation in 3 months, 11 major and 69 minor hemorrhages occurred over 147 person-years. The CYP2C9*3 genotype conferred an increased risk of all [hazard ratio (HR) 3.07, 95 % confidence interval (CI) 1.57–6.01] and minor hemorrhage (HR 3.28, 95 % CI 1.62–6.65), but not major hemorrhage (HR 0.44, 95 % CI 0.04–4.72). CYP2C9*3 also conferred an increased risk of over-anticoagulation with international normalization ratio (INR) ≥4 (HR 2.92, 95 % CI 1.08–7.85). VKORC1 −1639 G/A, and CYP4F2 rs2108622 did not confer significant increase in risk for hemorrhage or over-anticoagulation. Kaplan–Meier curves showed that time to all hemorrhagic events was significantly shorter for patients with CYP2C9*3 genotype than non-carriers (P = 0.001), but not for patients with VKORC1 −1639 G/A or CYP4F2 rs2108622 genotype (P = 0.3 and 0.2). CYP2C9*3 may be the main genetic factor in hemorrhagic complications in Chinese patients under warfarin anticoagulation.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 30971259). We are grateful to all the patients who participated in the study. We thank Ting Yang for her untiring efforts with patient recruitment and follow-up, and the staff of the Institute of Geriatric Cardiology, General Hospital of Chinese People’s Liberation Army for their help with identification of potential participants.

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There are no competing interests to declare.

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Authors and Affiliations

  1. Institute of Geriatric Cardiology, General Hospital of Chinese People’s Liberation Army, No. 28 Fu Xing Road, Beijing, 100853, China

    Cong Ma, Yuxiao Zhang, Qiang Xu, Jie Yang, Yan Zhang, Lei Gao, Bin Xu, Hongjuan Wang, Yang Li, Caiyi Lu & Tong Yin

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  1. Cong Ma
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  2. Yuxiao Zhang
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  3. Qiang Xu
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  4. Jie Yang
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Correspondence to Caiyi Lu or Tong Yin.

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Cong Ma and Yuxiao Zhang contributed equally to the manuscript as co-first authors.

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Ma, C., Zhang, Y., Xu, Q. et al. Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin. Int J Hematol 96, 719–728 (2012). https://doi.org/10.1007/s12185-012-1205-8

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