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

The Pharmacogenomics Journal volume 17, pages 242–251 (2017)Cite this article

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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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References

  1. Schwarz D, Kisselev P, Ericksen SS, Szklarz GD, Chernogolov A, Honeck H et al. Arachidonic and eicosapentaenoic acid metabolism by human CYP1A1: highly stereoselective formation of 17(R),18(S)-epoxyeicosatetraenoic acid. Biochem Pharmacol 2004; 67: 1445–1457.

    Article  CAS  PubMed  Google Scholar 

  2. Debier C, Larondelle Y . Vitamins A and E: metabolism, roles and transfer to offspring. Br J Nutr 2005; 93: 153–174.

    Article  CAS  PubMed  Google Scholar 

  3. Tsuchiya Y, Nakajima M, Yokoi T . Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett 2005; 227: 115–124.

    Article  CAS  PubMed  Google Scholar 

  4. Gonzalez FJ . The molecular biology of cytochrome P450s. Pharmacol Rev 1988; 40: 243–288.

    CAS  PubMed  Google Scholar 

  5. Shimada T, Yun CH, Yamazaki H, Gautier JC, Beaune PH, Guengerich FP . Characterization of human lung microsomal cytochrome P-450 1A1 and its role in the oxidation of chemical carcinogens. Mol Pharmacol 1992; 41: 856–864.

    CAS  PubMed  Google Scholar 

  6. Ma Q, Lu AY . CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies. Drug Metab Dispos 2007; 35: 1009–1016.

    Article  CAS  PubMed  Google Scholar 

  7. Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT . Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 2003; 144: 3382–3398.

    Article  CAS  Google Scholar 

  8. Logothetis J, Harner R, Morrell F, Torres F . The role of estrogens in catamenial exacerbation of epilepsy. Neurology 1959; 9: 352–360.

    Article  CAS  PubMed  Google Scholar 

  9. Backstrom T, Jorpes P . Serum phenytoin, phenobarbital, carbamazepine, albumin; and plasma estradiol, progesterone concentrations during the menstrual cycle in women with epilepsy. Acta Neurol Scand 1979; 59: 63–71.

    Article  CAS  PubMed  Google Scholar 

  10. Grover S, Talwar P, Baghel R, Kaur H, Gupta M, Gourie-Devi M et al. Genetic variability in estrogen disposition: potential clinical implications for neuropsychiatric disorders. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 1391–1410.

    Article  CAS  PubMed  Google Scholar 

  11. Sowers MR, Wilson AL, Kardia SR, Chu J, McConnell DS . CYP1A1 and CYP1B1 polymorphisms and their association with estradiol and estrogen metabolites in women who are premenopausal and perimenopausal. Am J Med 2006; 119: S44–S51.

    Article  CAS  PubMed  Google Scholar 

  12. Kravitz HM, Janssen I, Lotrich FE, Kado DM, Bromberger JT . Sex steroid hormone gene polymorphisms and depressive symptoms in women at midlife. Am J Med 2006; 119: S87–S93.

    Article  CAS  PubMed  Google Scholar 

  13. Grover S, Talwar P, Gourie-Devi M, Gupta M, Bala K, Sharma S et al. Genetic polymorphisms in sex hormone metabolizing genes and drug response in women with epilepsy. Pharmacogenomics 2010; 11: 1525–1534.

    Article  CAS  PubMed  Google Scholar 

  14. Indian Genome Variation Consortium. Genetic landscape of the people of India: a canvas for disease gene exploration. J Genet 2008; 87: 3–20.

    Article  Google Scholar 

  15. Grover S, Bala K, Sharma S, Gourie-Devi M, Baghel R, Kaur H et al. Absence of a general association between ABCB1 genetic variants and response to antiepileptic drugs in epilepsy patients. Biochimie 2010; 92: 1207–1212.

    Article  CAS  PubMed  Google Scholar 

  16. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rosenbloom KR, Sloan CA, Malladi VS, Dreszer TR, Learned K, Kirkup VM et al. ENCODE data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res 2013; 41: D56–D63.

    Article  CAS  PubMed  Google Scholar 

  18. Alcina A, Fedetz M, Fernandez O, Saiz A, Izquierdo G, Lucas M et al. Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis. J Med Genet 2013; 50: 25–33.

    Article  CAS  PubMed  Google Scholar 

  19. Ward LD, Kellis M . HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 2012; 40: D930–D934.

    Article  CAS  PubMed  Google Scholar 

  20. Puglisi JD, Tinoco I Jr . Absorbance melting curves of RNA. Methods Enzymol 1989; 180: 304–325.

    Article  CAS  PubMed  Google Scholar 

  21. Cantor CR, Warshaw MM, Shapiro H . Oligonucleotide interactions. 3. Circular dichroism studies of the conformation of deoxyoligonucleotides. Biopolymers 1970; 9: 1059–1077.

    Article  CAS  PubMed  Google Scholar 

  22. NCBI Resource Coordinators. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 2014; 42: D7–D17.

    Article  Google Scholar 

  23. Hall TA . BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symposium Series 1999; 41: 95–98.

    CAS  Google Scholar 

  24. Narang A, Roy RD, Chaurasia A, Mukhopadhyay A, Mukerji M, Dash D . IGVBrowser—a genomic variation resource from diverse Indian populations. Database (Oxford) 2010; 2010: baq022.

    Article  Google Scholar 

  25. Xodo LE, Manzini G, Quadrifoglio F, van der Marel GA, van Boom JH . Oligodeoxynucleotide folding in solution: loop size and stability of B-hairpins. Biochemistry 1988; 27: 6321–6326.

    Article  CAS  PubMed  Google Scholar 

  26. Xodo LE, Manzini G, Quadrifoglio F, Yathindra N, van der Marel GA, van Boom JH . A facile duplex-hairpin interconversion through a cruciform intermediate in a linear DNA fragment. J Mol Biol 1989; 205: 777–781.

    Article  CAS  PubMed  Google Scholar 

  27. Marky LA, Blumenfeld KS, Kozlowski S, Breslauer KJ . Salt-dependent conformational transitions in the self-complementary deoxydodecanucleotide d(CGCAATTCGCG): evidence for hairpin formation. Biopolymers 1983; 22: 1247–1257.

    Article  CAS  PubMed  Google Scholar 

  28. Vorlickova M, Kejnovska I, Bednarova K, Renciuk D, Kypr J . Circular dichroism spectroscopy of DNA: from duplexes to quadruplexes. Chirality 2012; 24: 691–698.

    Article  CAS  PubMed  Google Scholar 

  29. Kypr J, Vorlickova M . Graphical analysis of circular dichroic spectra distinguishes between two-state and gradual alterations in DNA conformation. Gen Physiol Biophys 1986; 5: 415–421.

    CAS  PubMed  Google Scholar 

Download references

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.

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Authors and 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. Department of Chemistry, Nucleic Acids Research Laboratory, 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. P Talwar
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  14. K Bala
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Correspondence to R Kukreti.

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Talwar, P., Kanojia, N., Mahendru, S. et al. Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective. Pharmacogenomics J 17, 242–251 (2017). https://doi.org/10.1038/tpj.2016.1

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

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