Gene copy number variation analysis reveals dosage-insensitive expression of CYP2E1.
Gene copy number variants (CNVs) of CYP2E1 have been described but not functionally characterized. Here we investigated effects of CNVs on hepatic and lymphoblastoid CYP2E1 expression. Using available single-nuleotide polymorphism microarray data and quantitative PCR, CYP2E1 gene duplication and deletion carriers were identified. CYP2E1 mRNA, protein and enzyme activity (chlorzoxazone-6-hydroxylation) phenotypes of CYP2E1 were not associated with gene copy number. Analysis of gene expression in lymphoblastoid cell lines in relation to CNV confirmed this finding in an extrahepatic tissue and for other ethnicities. Further analyses identified a linked haplotype cluster with possible influence on gene expression. In summary, our data suggest a homeostatic, gene dosage-insensitive regulation of CYP2E1 expression by unknown gene dosage compensation mechanisms. This is in striking contrast to well-known structural variations of CYP2A6 and CYP2D6 that have a strong impact on expression and activity. These findings are important in the context of pharmacogenetic prediction.
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|Tuebingen University Hospital, Tuebingen, Germany.
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0000-0003-1564-0433
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Tremmel
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|Tuebingen University Hospital, Tuebingen, Germany.
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K
Klein
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|Tuebingen University Hospital, Tuebingen, Germany.
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S
Winter
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|Tuebingen University Hospital, Tuebingen, Germany.
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E
Schaeffeler
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|Tuebingen University Hospital, Tuebingen, Germany.
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UM
Zanger
D002460:Cell Line; D002753:Chlorzoxazone / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism*; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D017353:Gene Deletion; D018628:Gene Dosage; D020440:Gene Duplication; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D006239:Haplotypes; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D006900:Hydroxylation; D020411:Oligonucleotide Array Sequence Analysis; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone