Common CYP2D6 polymorphisms affecting alternative splicing and transcription: Long-range haplotypes with two regulatory variants modulate CYP2D6 activity

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Abstract

Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of 25% of clinically used drugs. Genetic polymorphisms cause substantial variation in CYP2D6 activity and serve as biomarkers guiding drug therapy. However, genotype-phenotype relationships remain ambiguous except for poor metabolizers carrying null alleles, suggesting the presence of yet unknown genetic variants. Searching for regulatory CYP2D6 polymorphisms, we find that a SNP defining the CYP2D6*2 allele, rs16947 [R296C, 17-60% minor allele frequency (MAF)], previously thought to convey normal activity, alters exon 6 splicing, thereby reducing CYP2D6 expression at least 2-fold. In addition, two completely linked SNPs (rs5758550/rs133333,MAF 13-42%) increase CYP2D6 transcription more than 2-fold, located in a distant downstream enhancer region (>100 kb) that interacts with the CYP2D6promoter. In high linkage disequilibrium (LD)with each other, rs16947andtheenhancerSNPsform haplotypes that affect CYP2D6 enzyme activity in vivo. In a pediatric cohort of 164 individuals, rs16947 alone (minor haplotype frequency 28%)was associated with reduced CYP2D6 metabolic activity (measured as dextromethorphan/ metabolite ratios), whereas rs5758550/rs133333 alone (frequency 3%) resulted in increased CYP2D6 activity, while haplotypes containing both rs16947andrs5758550/rs133333 were similar to the wild-type. Other alleles used in biomarker panels carrying these variants such as CYP2D6*41 require re-evaluation of independent effects on CYP2D6 activity. The occurrence of two regulatory variants of high frequency and in high LD, residing on a long haplotype, highlights the importance of gene architecture, likely shaped by evolutionary selection pressures, in determining activity of encoded proteins. © The Author 2013. Published by Oxford University Press. All rights reserved.

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Wang, D., Poi, M. J., Sun, X., Gaedigk, A., Leeder, J. S., & Sadee, W. (2014). Common CYP2D6 polymorphisms affecting alternative splicing and transcription: Long-range haplotypes with two regulatory variants modulate CYP2D6 activity. Human Molecular Genetics, 23(1), 268–278. https://doi.org/10.1093/hmg/ddt417

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