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An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

The objective of this study was to determine the influence of CYP2C9, VKORC1, CYP4F2, and GGCX genetic polymorphisms on mean daily dose of acenocoumarol in South Indian patients and to develop a new pharmacogenetic algorithm based on clinical and genetic factors.

Methods

Patients receiving acenocoumarol maintenance therapy (n = 230) were included in the study. Single nucleotide polymorphisms (SNP) of CYP2C9, VKORC1, CYP4F2, and GGCX were genotyped by real-time polymerase chain reaction (RT-PCR) method.

Results

The mean daily acenocoumarol maintenance dose was found to be 3.7 ± 2.3 (SD) mg/day. The CYP2C9 *1*2, CYP2C9 *1*3, and CYP2C9 *2*3 variant genotypes significantly reduced the dose by 56.7 % (2.0 mg), 67.6 % (1.6 mg), and 70.3 % (1.5 mg) than wild-type carriers 4.1 mg, p < 0.0001. The genetic variants of CYP2C9 and GGCX (rs11676382) were found to be associated with lower acenocoumarol dose, whereas CYP4F2 (rs2108622) was associated with higher doses. Age, body mass index (BMI), variation of CYP2C9, VKORC1, CYP4F2, and GGCX were the major determinants of acenocoumarol maintenance dose, accounting for 61.8 % of its variability (adjusted r 2 = 0.615, p < 0.0001). Among the VKORC1 variants, rs9923231 alone contributed up to 28.6 % of the acenocoumarol dose variation.

Conclusion

VKORC1 rs9923231 polymorphism had the highest impact on acenocoumarol daily dose. A new pharmacogenetic algorithm was established to determine the acenocoumarol dose in South Indian population.

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Acknowledgments

This study was a collaborative project between INSERM UMR775–Bases Moléculaires de la réponse aux xénobiotiques located in the Université Paris-Descartes, Paris, France and Indian council of Medical Research, New Delhi, India. 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 departments of pharmacology, cardiology and CTVS are gratefully acknowledged.

Conflict of interest

All the authors declare that there is no conflict of interest.

Author information

Authors and Affiliations

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

    Dhakchinamoorthi Krishna Kumar & Chandrasekaran Adithan

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

    Deepak Gopal Shewade

  3. Department of Cardiovascular and Thoracic surgery, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India

    B. V. Sai Chandran

  4. Department of Cardiology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India

    Jayaraman Balachander

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

    Marie-Anne Loriot & Philippe Beaune

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

    Marie-Anne Loriot & Philippe Beaune

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  1. Dhakchinamoorthi Krishna Kumar
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  2. Deepak Gopal Shewade
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  3. Marie-Anne Loriot
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Corresponding author

Correspondence to Dhakchinamoorthi Krishna Kumar.

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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, rs2359612 and 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 13 kb)

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Krishna Kumar, D., Shewade, D.G., Loriot, MA. et al. An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population. Eur J Clin Pharmacol 71, 173–181 (2015). https://doi.org/10.1007/s00228-014-1791-x

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  • DOI: https://doi.org/10.1007/s00228-014-1791-x

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