Original Article | Published:

Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective

The Pharmacogenomics Journal volume 17, pages 242251 (2017) | Download Citation

Abstract

CYP1A1 gene is involved in estrogen metabolism, and previously, we have reported association of variant rs2606345 with altered anti-epileptic drugs (AED) response in North Indian women with epilepsy (WWE). The present study aims to replicate the pharmacogenetic association, perform functional characterization and study its distribution within ethnically diverse Indian population. The variant was genotyped in 351 patients to assess the pharmacogenetic association and 552 healthy individuals belonging to 24 different ethnic groups to examine the distribution in Indian population. We observed significant overrepresentation of ‘A’ allele and ‘AA’ genotype in poor responders in WWE at Bonferroni-corrected significance levels. The recessive allele was found to lower the promoter activity by ~70–80% which was further substantiated by thermally less stable hairpin formed by it (ΔTm=7 °C). Among all ethnic groups, west Indo–European (IE-W-LP2) subpopulation showed highest genotypic frequency of the variant making women from this community more prone to poor AED response. Our results indicate that rs2606345 influences drug response in WWE by lowering CYP1A1 expression.

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Acknowledgements

We thank Professor Samir K Brahmachari (CSIR) and Dr Rajesh Gokhale, Institute of Genomics and Integrative Biology (CSIR) for their vision and constant support. Financial support from the Council of Scientific and Industrial Research (CSIR) (BSC0123) is duly acknowledged. SK acknowledges the support from the R & D grant of University Of Delhi. We are grateful to Dr Mitali Mukerji (IGIB) and Dr Abhay Sharma for their unconditional support. We appreciate Dr Neeru Saini, Dr Malabika Datta for their support in sharing reagents, instruments and technical expertise. Dr Anurag Agarwal helped us in the critical evaluation of the manuscript. We thank Ms Chitra Rawat for helping in phenotyping of the patients. PT, AS and NK acknowledge CSIR, Government of India for providing their fellowships. GKG and SV acknowledge DBT and ICMR, Government of India for providing their fellowships, respectively. We thank the anonymous reviewers for their helpful suggestions in improving the manuscript.

Author information

Affiliations

  1. Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, India

    • P Talwar
    • , N Kanojia
    • , G K Grewal
    •  & R Kukreti
  2. Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India

    • P Talwar
    • , N Kanojia
    • , R Baghel
    • , S Grover
    • , G Arora
    • , G K Grewal
    • , S Parween
    • , A Srivastava
    • , M Singh
    • , S Vig
    •  & R Kukreti
  3. Nucleic Acids Research Laboratory, Department of Chemistry, University of Delhi (North Campus), Delhi, India

    • S Mahendru
    •  & S Kukreti
  4. Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi, India

    • S Kushwaha
    • , S Sharma
    •  & K Bala
  5. Department of Paediatrics, Division of Pneumonology and Immunology, Charité University Medical Centre, Berlin, Germany

    • S Grover

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  1. Indian Genome Variation Consortium

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to R Kukreti.

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DOI

https://doi.org/10.1038/tpj.2016.1

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj)