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CYP2D6 expression is regulated by polymorphisms that affect splicing and trancription: new biomarkers for CYP2D6 activity
Author(s) -
Wang Danxin,
Poi Ming J,
Sun Xiaochun,
Gaedigk Andrea,
Leeder J. Steven,
Sadee Wolfgang
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.663.6
Subject(s) - snp , cyp2d6 , haplotype , biology , single nucleotide polymorphism , exon , genetics , rna splicing , genotype , rna , gene
Cytochrome P450 2D6 (CYP2D6) metabolizes ~25% of clinical used drugs. CYP2D6 variants are currently used as biomarkers to predict CYP2D6 activity, but the relationship between genotype and phenotype is still ambiguous in most individuals except in poor metabolizers. In this study, we showed common SNP located in exon 6 (rs16947, *2) affects exon 6 splicing, resulting in 2 fold reduction in total CYP2D6 mRNA expression via nonsense‐mediated RNA decay. In addition we identified a novel SNP (E‐SNP) located in an enhancer region over 100 kb downstream of CYP2D6 that increases CYP2D6 transcription 2 fold. Testing in a pediatric cohort of 160 individuals with metabolic activity measured as the ratio of dextromethorphan/metabolites (DM/DX), SNP rs16947 alone is associated with reduced metabolic activity, while haplotype containing both rs16947 and E‐SNP has similar metabolic activity as reference haplotype, indicating gain of function E‐SNP can compensate for the loss of function effect of rs16947. Our data also indicate that the key SNP in *41 rs28371725 does not have independent effect on CYP2D6 mRNA level, the in vivo reduced activity effects associated with *41 was resulted from the lack of E‐SNP in *41 haplotype which also contain rs16947. These results suggest that the combination of rs16947 and E‐SNP may become a new biomarker for predicting CYP2D6 activity. Supported by NIH grant U01 GM092655.