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The influence of genetic polymorphisms and interacting drugs on initial response to warfarin in Chinese patients with heart valve replacement

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

Compared with genetic factors, drug interactions were largely unexplored in warfarin pharmacogenetic studies. This study sought to systematically investigate the effects of genetic polymorphisms of VKORC1, STX4A, CYP2C9, CYP3A4, and GGCX and interacting drugs on the initial responses to warfarin in Chinese patients with heart valve replacement (HVR).

Methods

A retrospective study was conducted in 809 patients starting warfarin therapy after HVR. The relationships between 12 polymorphisms plus 47 drugs and primary outcomes of the time to the first international normalized ratio (INR) ≥ 1.8 and the time to the first INR > 3.5 and the secondary outcomes of the proportion of time INR < 1.8, the proportion of time INR > 3.5, and the daily warfarin dose in the first 28 days after the initiation of warfarin treatment were analyzed.

Results

Genetic polymorphisms and interacting drugs could significantly affect the primary and secondary outcomes. The time to the first INR ≥ 1.8 was significantly influenced by the body surface area (BSA), VKORC1 g.3588G > A allele, and CYP2C9*3 allele, with hazard ratio (HR; 95% confidence interval [CI]) of 0.34 (0.17–0.66), 2.71 (2.2–3.35) and 1.43 (1.07–1.93) respectively. The time to the first INR > 3.5 was affected not only by BSA, VKORC1 g.3588G > A allele, and CYP2C9*3 allele with HR (95%CI) of 0.26 (0.07–0.99), 2.76 (1.61–4.72), and 3.09 (2.02–4.74) respectively, but also by age and interacting drugs, including fluconazole, amiodarone, and simvastatin with HR (95%CI) of 1.02 (1.01–1.04), 2.66 (1.16–6.08), 1.78 (1.17–2.73), and 5.33 (1.67–16.96) respectively.

Conclusions

Not only VKORC1 and CYP2C9 genotypes, but also interacting drugs, had a significant impact on the variability of the initial response to warfarin.

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Acknowledgements

This work has been supported by the National Science Foundation of China (30772620, 81070103, 81072701), and the National Key Basic Research Program (NKBRP) of China (2006CB503806).

Conflict of interest

No conflicts to disclose.

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Author notes

  1. Shi-Long Zhong & Yuan Liu

    Present address: Guangdong Provincial Cardiovascular Institute, Medical Research Center of Guangdong General Hospital, Guangdong Institute of Clinical Pharmacology, Guangdong Academy of Medical Sciences, 96 Dongchuan Road, Guangzhou, GD, 510080, People’s Republic of China

Authors and Affiliations

  1. Guangdong Provincial Cardiovascular Institute, Medical Research Center of Guangdong General Hospital, Guangdong Institute of Clinical Pharmacology, Guangdong Academy of Medical Sciences, 96 Dongchuan Road, Guangzhou, GD, 510080, People’s Republic of China

    Xi-Yong Yu, Dan Xu, Hong-Hong Tan, Qiu-Xiong Lin, Min Yang, Hai-Yan Lao & Shu-Guang Lin

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  1. Shi-Long Zhong
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Correspondence to Xi-Yong Yu or Shu-Guang Lin.

Additional information

Shi-Long Zhong and Yuan Liu made same experimental contribution to the paper

Electronic supplementary material

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Table S1

Primer sequences used in SNaPShot assay for genotyping. (DOC 37 kb)

Table S2

The impact of genotypes on the percentage of time INR < 1.8 or percentage of time INR > 3.5. (DOC 83 kb)

Table S3

The impact of concomitant interacting drugs on the percentage of time INR < 1.8 or percentage of time INR > 3.5. (DOC 71 kb)

Fig. S1

The impact of genotypes and interacting drugs on the time course of daily warfarin doses during the early phase of warfarin therapy. The daily warfarin doses were grouped according to (A) g.3588G>A genotypes in VKORC1, (B) c.1075A>C genotypes in CYP2C9, ©) with or without fluconazole, and (D) with or without amiodarone. (JPEG 656 kb)

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Zhong, SL., Liu, Y., Yu, XY. et al. The influence of genetic polymorphisms and interacting drugs on initial response to warfarin in Chinese patients with heart valve replacement. Eur J Clin Pharmacol 67, 581–590 (2011). https://doi.org/10.1007/s00228-011-0995-6

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  • DOI: https://doi.org/10.1007/s00228-011-0995-6

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