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摘要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 R2 = 0.12,P = 0.002)and CYP3A5 mRNA(partial R2 = 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.