title: The independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and the metabolism of atorvastatin.
abstract: To evaluate the independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and atorvastatin metabolism, the relationships among three levels of factors, namely (1) clinical characteristics, CYP3A4/5 genotypes, and miRNAs, (2) CYP3A4 and CYP3A5 mRNAs, and (3) CYP3A activity, as well as their individual impacts on atorvastatin metabolism, were assessed in 55 human liver tissues. MiR-27b, miR-206, and CYP3A4 mRNA respectively accounted for 20.0%, 5.8%, and 9.5% of the interindividual variations in CYP3A activity. MiR-142 was an independent contributor to the expressions of CYP3A4 mRNA (partial R(2) = 0.12, P = 0.002) and CYP3A5 mRNA (partial R(2) = 0.09, P = 0.005) but not CYP3A activity or atorvastatin metabolism. CYP3A activity was a unique independent predictor of variability of atorvastatin metabolism, explaining the majority of the variance in reduction of atorvastatin (60.0%) and formation of ortho-hydroxy atorvastatin (78.8%) and para-hydroxy atorvastatin (83.9%). MiR-27b and miR-206 were found to repress CYP3A4 gene expression and CYP3A activity by directly binding to CYP3A4 3'-UTR, while miR-142 was found to indirectly repress CYP3A activity. Our study indicates that miRNAs play significant roles in bridging the gap between epigenetic effects and missing heritability in CYP3A functionality.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.|Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong 510080, China.
authors.forename: Ju-E
authors.initials: JE
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Tang
authors.affiliation: Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong 510080, China.|Institute of Chinese medical science, Guangdong TCM key Laboratory for metabolism, Guangdong Pharmaceutical University, Guangzhou 510006, China.
authors.forename: Qian-Jie
authors.initials: QJ
authors.lastname: Tang
authors.affiliation: Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong 510080, China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong 510080, China.|Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong 510080, China.|School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.affiliation: Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong 510080, China.|Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wan-Ping
authors.initials: WP
authors.lastname: Zhong
authors.affiliation: Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong 510080, China.
authors.forename: Jin-Xiu
authors.initials: JX
authors.lastname: Meng
authors.affiliation: Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
authors.forename: Hao-Ming
authors.initials: HM
authors.lastname: Lin
authors.affiliation: Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong 510080, China.|Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
authors.forename: Ji-Yan
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong 510080, China.|Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Zhong
mesh_terms: D000328:Adult; D000368:Aged; D000069059:Atorvastatin / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D055815:Young Adult
chemical_list: C555159:MIRN142 microRNA, human; C546087:MIRN206 microRNA, human; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D000069059:Atorvastatin; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human