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Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population

  • Pharmacoeconomics
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European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

To determine the influence of genetic polymorphisms on warfarin maintenance dose and to explicate an algorithm using the pharmacogenetic and clinical factors to determine the maintenance and/or starting dose of warfarin in South Indian patients receiving warfarin therapy.

Methods

Patients receiving stabilized warfarin therapy (n = 257) were included in the study. Single nucleotide polymorphisms (SNPs) of CYP2C9 (rs1799853 and rs1057910), VKORC1 (rs9923231, rs7196161, rs2884737, rs9934438, rs8050894, rs2359612 and rs7294), CYP4F2 (rs2108622) and GGCX (rs11676382) were genotyped by the quantitative real time-PCR method.

Results

The mean daily maintenance dose of warfarin was found to be 4.7 ± 2.1 mg/day. Patients with the CYP2C9*1/*2, *1/*3 and *2/*3 variant genotypes required a 51.0 (2.8 mg), 60.9 (2.3 mg) and 62.2 % (2.2 mg) lower daily maintenance dose of warfarin, respectively, than those patients with the CYP2C9*1/*1 wild-type genotype (5.2 mg) (p < 0.0001). The genetic variants of CYP2C9, VKORC1 and GGCX were associated with decreased warfarin dose, except for rs7196161, rs7294 and rs2108622 which were associated with an increased warfarin dose. Genetic variations of CYP2C9 (*2 and *3), VKORC1 (rs9923231, rs7294, rs9934438 and rs2359612), CYP4F2, GGCX and non-genetic factors such as age, body weight, clinical status (post mechanical valve replacement) could explain up to 62.1 % of the overall variation (adjusted r 2 60.2 %, p < 0.0001) in warfarin maintenance dose.

Conclusion

Genetic polymorphisms of CYP2C9, VKORC1, CYP4F2 and GGCX are important predictive factors of warfarin maintenance dose, and the developed algorithm will be useful to predict the required maintenance and/or starting warfarin dose in South Indian populations.

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Acknowledgments

This study was a collaborative project between Institut national de la santé et de la recherche médicale (INSERM) UMR775–Bases Moléculaires de la réponse aux xénobiotiques located in the Université Paris-Descartes, Paris, France and the Indian council of Medical Research (ICMR), New Delhi, India (grant 2011-2012). It was supported by a research grant (ICMR Ref. No. 50/6/2010/BMS, dated 03/11/2010) from the ICMR, New Delhi. The technical staffs of the departments of pharmacology, cardiology and CTVS departments are gratefully acknowledged.

Conflict of interest

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Authors and Affiliations

  1. Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, 605 006, India

    Dhakchinamoorthi Krishna Kumar, Deepak Gopal Shewade & Chandrasekaran Adithan

  2. University Paris Sorbonne Cité, INSERM UMRS 775, Paris, France

    Marie-Anne Loriot & Philippe Beaune

  3. Department of Biochemistry, Georges Pompidou European Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France

    Marie-Anne Loriot & Philippe Beaune

  4. Department of Cardiology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India

    Jayaraman Balachander

  5. Department of Cardiothoracic and Vascular Surgery, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India

    B. V. Sai Chandran

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  1. Dhakchinamoorthi Krishna Kumar
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  2. Deepak Gopal Shewade
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Correspondence to Dhakchinamoorthi Krishna Kumar.

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Suppl. Table 1

Genotype condition for all the SNPs (DOCX 16 kb)

Suppl. Table 2

Assessment of the VKORC1 haplotypes influences on the daily warfarin dose requirement in South Indian patients (DOCX 15 kb)

Supplementary Figure 1

LD pattern of the haplotypes tagSNPs. The single nucleotide polymorphisms in chromosome 16 were positioned according to the order and orientation. Each of the variant is given with their specific chromosomal position and the rsID. LD pattern of the rs9923231, rs7196161, rs2884737, rs1770847, rs9934438, rs8050894, rs23596121and rs7294 in the study population. Red and pink colors represent a very strong LD pattern (D’ > 0.8) and white color represents moderate to low LD (D’ < 0.8 to >0.5). The D’ prime values given inside the color boxes respect to the LD between the SNPs (DOCX 152 kb)

Supplementary Figure 2

Relationship between observed warfarin maintenance dose and estimated maintenance dose determined by multivariate regression analysis (pharmacogenetic algorithm). There is a significant correlation between the predicted and observed warfarin maintenance doses (y = 1.7418 + 0.58914, r 2 = 0.635, p < 0.0001). (DOCX 145 kb)

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Krishna Kumar, D., Shewade, D.G., Loriot, MA. et al. Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population. Eur J Clin Pharmacol 70, 47–56 (2014). https://doi.org/10.1007/s00228-013-1581-x

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