PharmVar Tutorial on <i>CYP2D6</i> Structural Variation Testing and Recommendations on Reporting

Turner, Amy J.; Nofziger, Charity; Ramey, Bronwyn E.; Ly, Reynold C.; Bousman, Chad A.; Agúndez, José A. G.; Sangkuhl, Katrin; Whirl‐Carrillo, Michelle; Vanoni, Simone; Dunnenberger, Henry M.; Ruaño, Gualberto; Kennedy, Martin A.; Phillips, Michael S.; Hachad, Houda; Klein, Teri E.; Moyer, Ann M.; Gaedigk, Andrea

doi:10.1002/cpt.3044

Cited by 13 publications

(1 citation statement)

References 88 publications

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“…Furthermore, we discovered a more than two-fold higher frequency of homozygous carriers (*5/*5) in AFR individuals (0.43%) compared to individuals within the other groups (ranging from 0.11% AMR ancestry to 0.16% EAS ancestry). We observed that whilst the frequency of the *5 allele in the East Asian cohort (5.2%) was iden\cal to that reported in PharmGKB 29 , it was higher than the es\mate from a recent CYP2D6 SV-focused study 3 . Iden$cal gene duplica$ons and mul$plica$ons CYP2D6 duplica\on and mul\plica\on SV events are key to predic\ng the UM category (Supplementary Table 5) and we iden\fied 16,144 carriers (3.4% of the overall popula\on).…”

Section: Cyp2d6 Genotyping and Phenotyping Callingsupporting

confidence: 47%

Genetic ancestral patterns inCYP2D6alleles: structural variants, rare variants, and clinical associations in 479,144 UK Biobank genomes

Jiang,

Hu,

Zou

et al. 2024

Preprint

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Cytochrome P450 2D6 (CYP2D6) is involved in metabolising over 20% of clinical drugs, yet its genetic variation across ancestries is underexplored in large-scale whole-genome sequencing (WGS) datasets. We analysed WGS data from 479,144 UK Biobank participants, identifying 95 distinct CYP2D6 star alleles across five biogeographic groups. Of these, 48 alleles had currently unknown effects. These alleles were more prevalent in African, admixed American, and South Asian groups (~5%) compared to European and East Asian groups (~2%), affecting the ability to provide pharmacogenomics recommendations across ancestries. We identified 99,656 (20.8%) individuals carrying CYP2D6 structural variations and predicted the CYP2D6 ultra-rapid metaboliser phenotype to be most common in Africans (4.5%) and rarest in East Asians (0.32%). Less than half (45.7%) of rare protein-truncating variant carriers were categorised as poor or intermediate metabolisers, indicating an underrepresentation of rare functional variants in the current CYP2D6 star allele evaluation. Phenome-wide association studies confirmed links with narcotic allergies and found new associations with plasma BAFFR and BAFF proteins, offering insights for the BAFF-targeted clinical therapy. Collectively, this largest WGS study of CYP2D6 to date highlights the importance of leveraging all genetic variations for pharmacogenomic insights affecting therapeutic safety and development.

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Section: Cyp2d6 Genotyping and Phenotyping Callingsupporting

confidence: 47%

Genetic ancestral patterns inCYP2D6alleles: structural variants, rare variants, and clinical associations in 479,144 UK Biobank genomes

Jiang,

Hu,

Zou

et al. 2024

Preprint

View full text Add to dashboard Cite

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Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta‐Blocker Therapy

Duarte,

Thomas,

Lee

et al. 2024

Clin Pharma and Therapeutics

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Beta‐blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta‐blocker exposure and response. We searched and summarized the strength of the evidence linking beta‐blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta‐blockers or for any beta‐blocker and the other five genes evaluated (updates at www.cpicpgx.org).

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Influence of CYP2C19 and CYP2D6 on side effects of aripiprazole and risperidone: A systematic review

de Brabander,

Kleine Schaars,

van Amelsvoort

et al. 2024

Journal of Psychiatric Research

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PharmVar Tutorial on CYP2D6 Structural Variation Testing and Recommendations on Reporting

Cited by 13 publications

References 88 publications

Genetic ancestral patterns inCYP2D6alleles: structural variants, rare variants, and clinical associations in 479,144 UK Biobank genomes

Genetic ancestral patterns inCYP2D6alleles: structural variants, rare variants, and clinical associations in 479,144 UK Biobank genomes

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta‐Blocker Therapy

Influence of CYP2C19 and CYP2D6 on side effects of aripiprazole and risperidone: A systematic review

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