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CYP2D6 metabolizes ∼25% of all clinically used drugs, with numerous genetic polymorphisms affecting enzyme activity and drug response. Clinical utility of current CYP2D6 genotyping is partially compromised the unresolved complex haplotype structure of the CYP2D6 locus. We have identified a distal enhancer single-nucleotide polymorphism rs5758550 that robustly increases CYP2D6 expression, whereas rs16947 (CYP2D6*2), previously considered inert, reduces correct mRNA splicing and expression, thereby affecting presumed activity of other alleles on the *2 haplotype.

CYP2D6 haplotypes with enhancer single-nucleotide polymorphism rs5758550 and rs16947 (*2 allele)