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Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers

The Pharmacogenomics Journal volume 9, pages 208–217 (2009)Cite this article

Abstract

The basis for interindividual variation in the CYP1A2 gene expression is not fully understood and the known genetic polymorphisms in the gene provide no explanation. We investigated whether the CYP1A2 gene expression is regulated by DNA methylation and displays allele-specific expression (ASE) using 65 human livers. Forty-eight percent of the livers displayed ASE not associated to the CYP1A2 mRNA levels. The extent of DNA methylation of a CpG island including 17 CpG sites, close to the translation start site, inversely correlated with hepatic CYP1A2 mRNA levels (P=0.018). The methylation of two separate core CpG sites was strongly associated with the CYP1A2 mRNA levels (P=0.005) and ASE phenotype (P=0.01), respectively. The CYP1A2 expression in hepatoma B16A2 cells was strongly induced by treatment with 5-aza-2′-deoxycytidine. In conclusion, the CYP1A2 gene expression is influenced by the extent of DNA methylation and displays ASE, mechanisms contributing to the large interindividual differences in CYP1A2 gene expression.

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Abbreviations

CYP1A2:

cytochrome P450, family 1, subfamily A, polypeptide 2

ASE:

allele-specific expression

CpG:

cytosine-guanine

SNP:

single nucleotide polymorphism

EROD:

7-ethoxyresorufin

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Acknowledgements

This study was financially supported by the Swedish Research Council for Medicine, the Swedish Research Council for Science and Technology, and by Torsten and Ragnar Söderbergs Stiftelser.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden

    Roza Ghotbi, Gunnel Tybring, Leif Bertilsson & Eleni Aklillu

  2. Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden

    Alvin Gomez & Magnus Ingelman-Sundberg

  3. Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden

    Lili Milani & Ann-Christine Syvänen

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  1. Roza Ghotbi
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Correspondence to Eleni Aklillu.

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Ghotbi, R., Gomez, A., Milani, L. et al. Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers. Pharmacogenomics J 9, 208–217 (2009). https://doi.org/10.1038/tpj.2009.4

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