title: Genome-wide association study reveals a complex genetic architecture underpinning-induced CYP3A4 enzyme activity.
abstract: Atypical cytochrome P450 3A4 (CYP3A4) enzyme activity-induced and inhibited-is thought to be the driver of numerous poor or adverse therapeutic responses to up to 50 % of all commonly prescribed drugs. We carried out a genome-wide association study to identify common genetic variants associated with variation in induced CYP3A4 activity. A total of 310 twins were included in this study. Each participant had already completed a 14 days course of St John's Wort to induce CYP3A4, which was quantified through the metabolic ratio of exogenous 3-hydroxyquinine to quinine. We failed to detect any genome-wide significant associations (P < 1 × 10(-8)) with variation in induced CYP3A4 activity although several genomic regions were highlighted which may play minor roles. We report the first GWAS of variation in induced CYP3A4 activity and our preliminary results indicate a complex genetic architecture underpinning induced CYP3A4 enzyme activity.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, King's College London, Lambeth Palace Rd, London, SE1 7EH, UK.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Rahmioglu
authors.forename: James
authors.initials: J
authors.lastname: Heaton
authors.forename: Gail
authors.initials: G
authors.lastname: Clement
authors.forename: Raj
authors.initials: R
authors.lastname: Gill
authors.forename: Gabriela
authors.initials: G
authors.lastname: Surdulescu
authors.forename: Karolina
authors.initials: K
authors.lastname: Zlobecka
authors.forename: Dylan
authors.initials: D
authors.lastname: Hodgkiss
authors.forename: Norman W
authors.initials: NW
authors.lastname: Smith
authors.forename: Kourosh R
authors.initials: KR
authors.lastname: Ahmadi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000652:urine; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D004790:Enzyme Induction; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D020902:Hypericum; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D010641:Phenotype; D028321:Plant Preparations / Q000494:pharmacology; D011802:Quinidine / Q000031:analogs & derivatives / Q000652:urine; D011803:Quinine / Q000652:urine; D013379:Substrate Specificity; D014427:Twins / Q000235:genetics*
chemical_list: D015415:Biomarkers; D028321:Plant Preparations; C013569:3-hydroxyquinidine; D011803:Quinine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine