ArticleHuman molecular genetics2014
Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 123 citations in OpenAlex.
- Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype-Derived Activity Scores.CPT: pharmacometrics & systems pharmacology · 2020Trial
- The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial.Scientific reports · 2020Trial
- In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles.British journal of clinical pharmacology · 2015Trial
- Lower Dose-Normalized Tacrolimus Exposure in CYP3A5*6 vs. *3 Loss-of-Function Allele Carriers: A Longitudinal Retrospective Real-World Study in Kidney Transplant Recipients.Clinical pharmacology and therapeutics · 2026Article
- Alternative Splicing Regulation in Metabolic Disorders.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2025Review
- Impact of CYP2D6*2, CYP2D6*35, rs5758550, and related haplotypes on risperidone clearance in vivo.European journal of clinical pharmacology · 2024Article
- Novel Independent Trans- and Cis-Genetic Variants Associated with CYP2D6 Expression and Activity in Human Livers.Drug metabolism and disposition: the biological fate of chemicals · 2024Article
- PharmVar Tutorial on CYP2D6 Structural Variation Testing and Recommendations on Reporting.Clinical pharmacology and therapeutics · 2023Review
- Genetic polymorphisms of GGT1 gene (rs8135987, rs5751901 and rs2017869) are associated with neoadjuvant chemotherapy efficacy and toxicities in breast cancer patients.BMC medical genomics · 2023Article
- Pharmacogenomics: Driving Personalized Medicine.Pharmacological reviews · 2023Review
- Does ethnicity impact CYP2D6 genotype-phenotype relationships?Clinical and translational science · 2023Article
- PEACOCK: a machine learning approach to assess the validity of cell type-specific enhancer-gene regulatory relationships.NPJ systems biology and applications · 2023Article
- Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole.Clinical pharmacology and therapeutics · 2023Article
- Comparing feature selection and machine learning approaches for predictingFrontiers in neuroinformatics · 2023Article
- Genetic polymorphisms are associated with individual susceptibility to dexmedetomidine.Frontiers in genetics · 2023Article
- A frequent CYP2D6 variant promotes skipping of exon 3 and reduces CYP2D6 protein expression in human liver samples.Frontiers in pharmacology · 2023Article
- Article
- From Croatian Roma to 1000 Genomes: The Story of theJournal of personalized medicine · 2022Article
- From pharmacogenetics to pharmaco-omics: Milestones and future directions.HGG advances · 2022Review
- Transgenic HepaRG cells expressing CYP2D6 as an improved model of primary human hepatocytes.Pharmacology research & perspectives · 2022Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
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 CYP2D6 promoter. In high linkage disequilibrium (LD) with each other, rs16947 and the enhancer SNPs form 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 rs16947 and rs5758550/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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.