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Pharmacogenetic determinants of warfarin in the Indian population

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Abstract

Background

Several studies optimized the warfarin dose based on CYP2C9*2, CYP2C9*3, VKORC1 -1639 G > A, CYP4F2 V433M. But, the information on the rare variants is lacking. In this study, we have explored the prevalence of common and rare pharmacogenetic determinants of warfarin and determined their damaging nature.

Methods

We have analyzed 2000 healthy adults using the Infinium global screening array (GSA) for 15 pharmacogenetic determinants of warfarin. In addition, we have elucidated the impact of these variants on protein function, stability, dynamics, evolutionary preservation, and ligand binding propensity.

Results

The GSA Analysis has revealed that CYP4F2 V433M (MAF: 39.425%), VKORC1 -1639 G > A (MAF: 20.5%), CYP2C9*3 (MAF:9.925%), and CYP2C9*2 (MAF:4.575%) are common, while CYP2C9*14 (MAF: 1.475%), CYP2C9*4 (0.175%), CYP2C9*5 (0.125%), and CYP2C9*11 (0.125%) are rare. Position-specific evolutionary preservation (PSEP) analysis has revealed that CYP2C9*4 is possibly damaging, while CYP2C9*5, CYP2C9*11, and CYP2C9*14 are probably damaging. CYP2C9*4 has high thermolability (−10.14 kcal/mol). Among the rare CYP2C9 variants, CYP2C9*4 and CYP2C9*11 exert destabilizing effects and may have increased molecular flexibility, while CYP2C9*5 and CYP2C9*14 exert stabilizing effects and may have decreased molecular flexibility. DNase I footprint analysis has revealed the loss of the E-box consensus sequence due to VKORC1 -1639 G > A polymorphism.

Conclusion

CYP2C9*2, CYP2C9*3, VKORC1 -1639 G > A and CYP4F2 V433M are common; CYP2C9*4, CYP2C9*5, CYP2C9*11, and CYP2C9*14 variants are rare in Indian subjects. All the CYP2C9 variants are found to be damaging. DNase I footprint analysis provided the mechanistic rationale for the association of VKORC1 -1639 G > A with warfarin sensitivity.

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Abbreviations

AFR:

Africans

AMR:

Americans

CUPSAT:

Cologne University Protein Stability Analysis Tool

CYP2C9:

Cytochrome P450 2 C9

CYP4F2:

Cytochrome P450 4 F2

DDIG-in:

Detecting disease-causing genetic variants due to indels

EAS:

East Asians

EUR:

Europeans

GGCX:

Gamma-glutamyl carboxylase

PSEP:

Position-specific evolutionary preservation

MAF:

Minor allele frequency

SAS:

South Asians

SFR:

Shoulder-to-foot ratio

VKORC1:

Vitamin K epoxide reductase complex 1

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Funding

The authors are grateful to the Deanship of Scientific Research, King Saud University for funding through Vice Deanship of Scientific Research Chairs.

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Authors and Affiliations

  1. Department of Biochemical Genetics and Pharmacogenomics, Sandor Speciality Diagnostics Pvt Ltd, Banjara Hills, Road No 3, Hyderabad, 500034, India

    Shaik Mohammad Naushad

  2. Department of Clinical Pharmacology and Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, India

    Vijay Kumar Kutala

  3. Center of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia

    Tajamul Hussain

  4. Research Chair for Biomedical Applications of Nanomaterials, Biochemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia

    Tajamul Hussain & Salman A. Alrokayan

  5. Biochemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia

    Salman A. Alrokayan

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  1. Shaik Mohammad Naushad
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  3. Tajamul Hussain
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  4. Salman A. Alrokayan
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Contributions

SMN and VKK conceptualized and designed the study. SMN, VKK, TH, SAA acquired, analyzed, and interpreted the data. SMN and VKK drafted the manuscript. TH and SAA revised it critically. The final version of the manuscript was approved by all the authors. The accuracy and integrity of the work are ascertained by all the authors.

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Correspondence to Shaik Mohammad Naushad.

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Naushad, S.M., Kutala, V.K., Hussain, T. et al. Pharmacogenetic determinants of warfarin in the Indian population. Pharmacol. Rep 73, 1396–1404 (2021). https://doi.org/10.1007/s43440-021-00297-1

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  • DOI: https://doi.org/10.1007/s43440-021-00297-1

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