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Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs

Abstract

Cytochrome P450 3A4 (CYP3A4) metabolizes 50% of all clinically used drugs. Although CYP3A4 expression varies widely between individuals, the contribution of genetic factors remains uncertain. In this study, we measured allelic CYP3A4 heteronuclear RNA (hnRNA) and mRNA expression in 76 human liver samples heterozygous for at least one of eight marker SNPs and found marked allelic expression imbalance (1.6–6.3-fold) in 10/76 liver samples (13%). This was fully accounted for by an intron 6 SNP (rs35599367, C>T), which also affected mRNA expression in cell culture on minigene transfections. CYP3A4 mRNA level and enzyme activity in livers with CC genotype were 1.7- and 2.5-fold, respectively, greater than in CT and TT carriers. In 235 patients taking stable doses of atorvastatin, simvastatin, or lovastatin for lipid control, carriers of the T allele required significantly lower statin doses (0.2–0.6-fold, P=0.019) than non-T carriers for optimal lipid control. These results indicate that intron 6 SNP rs35599367 markedly affects expression of CYP3A4 and could serve as a biomarker for predicting response to CYP3A4-metabolized drugs.

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Acknowledgements

This study was supported by a grant from Eli Lilly and a grant from National Institute of Allergy and Infectious Diseases NIH/NIAID (1R21AI074399 to DW). GEC was supported by National Heart, Lung, and Blood Institute NIH/NHLBI career development grant (K23 HL004483).

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Wang, D., Guo, Y., Wrighton, S. et al. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 11, 274–286 (2011). https://doi.org/10.1038/tpj.2010.28

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