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CYP2D6 Pharmacogenomics: From Genotype to Phenotype Simon Kung, M.D. Associate Professor of Psychiatry Mayo Clinic

CYP2D6 Common Alleles Allele Frequency (Caucasians) Allele Functional Status Activity Level *1 Normal 1 39% *2 Normal 1 28% *3 None 1.3% *4 None 18% *5 None 2.8% *9 Decreased 0.5 2.1% *10 Decreased 0.5 2.9% *41 Decreased 0.5 7.7% Duplications Increased >1 2.7% Hicks, J. K., Sangkuhl, K., Swen, J. J., Ellingrod, V. L., Müller, D. J., Shimoda, K., ... & Dunnenberger, H. M. (2017). Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clinical Pharmacology & Therapeutics, 102(1), 37-44.

Africans and Middle Easterners: Allele Frequency and Geography Allele Frequency (Caucasians) Allele Functional Status East Asians: Allele frequency is 0.5%. *1 Normal 39% *2 Normal 28% *3 None 1.3% *4 None 18% *5 None 2.8% Africans and Middle Easterners: Allele frequency is 7%. *9 Decreased 2.1% *10 Decreased 2.9% *41 Decreased 7.7% Duplications Increased 2.7% Hicks, J. K., Sangkuhl, K., Swen, J. J., Ellingrod, V. L., Müller, D. J., Shimoda, K., ... & Dunnenberger, H. M. (2017). Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clinical Pharmacology & Therapeutics, 102(1), 37-44.

Metabolizer Phenotype Mapping Genotype to Phenotype Metabolizer Phenotype Genotype *4/*4 Poor Intermediate *1/*4 Normal (extensive) *1/*1 Ultrarapid Duplications Hicks, J. K., Sangkuhl, K., Swen, J. J., Ellingrod, V. L., Müller, D. J., Shimoda, K., ... & Dunnenberger, H. M. (2017). Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clinical Pharmacology & Therapeutics, 102(1), 37-44.

CYP2D6 Relative Percentages Metabolizer Percentages 5-10% Poor Intermediate 2-11% Normal (extensive) 77-92% Ultrarapid 1-7% Hicks, J. K., Sangkuhl, K., Swen, J. J., Ellingrod, V. L., Müller, D. J., Shimoda, K., ... & Dunnenberger, H. M. (2017). Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clinical Pharmacology & Therapeutics, 102(1), 37-44. Porcelli, S., Drago, A., Fabbri, C., Gibiino, S., Calati, R., & Serretti, A. (2011). Pharmacogenetics of antidepressant response. Journal of psychiatry & neuroscience: JPN, 36(2), 87.

Key Points P450 2D6 is highly polymorphic, and it does vary across geography. About 10% of Caucasians are poor metabolizers, and up to 7% are ultrarapid metabolizers. In Africa and the Middle East, there is a higher prevalence of ultrarapid metabolizers.

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