title: Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective.
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.
authors.affiliation: Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, India.|Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: P
authors.initials: P
authors.lastname: Talwar
authors.affiliation: Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, India.|Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: N
authors.initials: N
authors.lastname: Kanojia
authors.affiliation: Nucleic Acids Research Laboratory, Department of Chemistry, University of Delhi (North Campus), Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Mahendru
authors.affiliation: Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: R
authors.initials: R
authors.lastname: Baghel
authors.affiliation: Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.|Department of Paediatrics, Division of Pneumonology and Immunology, Charité University Medical Centre, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Grover
authors.affiliation: Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: G
authors.initials: G
authors.lastname: Arora
authors.affiliation: Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, India.|Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: G K
authors.initials: GK
authors.lastname: Grewal
authors.affiliation: Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Parween
authors.affiliation: Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: A
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: M
authors.initials: M
authors.lastname: Singh
authors.affiliation: Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Vig
authors.affiliation: Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Kushwaha
authors.affiliation: Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi, India.
authors.forename: K
authors.initials: K
authors.lastname: Bala
authors.affiliation: Nucleic Acids Research Laboratory, Department of Chemistry, University of Delhi (North Campus), Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Kukreti
authors.affiliation: Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, India.|Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
authors.forename: R
authors.initials: R
authors.lastname: Kukreti
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D057809:HEK293 Cells; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007194:India / Q000453:epidemiology; D061986:MCF-7 Cells; D008297:Male; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D011401:Promoter Regions, Genetic; D044469:Racial Groups / Q000235:genetics; D012008:Recurrence; D014162:Transfection; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1