The effect of the CYP2D6 genotype on the maintenance dose of metoprolol in a chronic Dutch patient population

Poulussen, Fenna C.P.; Peters, Bas J M; Hua, K. H.; Houthuizen, Patrick; Grouls, R. J. E.; Deenen, Maarten J.

doi:10.1097/fpc.0000000000000381

Cited by 9 publications

(6 citation statements)

References 17 publications

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“…CYP2D6*41 is also prevalent in African (9.7%), European (7.4%), American (3.7%) and East Asian (2.2%) populations albeit at overall lower frequencies. Notably, however, CYP2D6*41 frequencies can be substantially higher than the respective superpopulation averages, as observed in Ethiopia (22.9%) (Aklillu et al 2002 ), Italy (15.2%) (Carano et al 2018 ) and the Netherlands (15%) (Poulussen et al 2019 ).…”

Section: Cyp2d6mentioning

confidence: 96%

“…The splicing variant CYP2D6*41 (rs28371725) is globally common with highest frequencies being reported in Notably, however, CYP2D6*41 frequencies can be substantially higher than the respective superpopulation averages, as observed in Ethiopia (22.9%) (Aklillu et al 2002), Italy (15.2%) (Carano et al 2018) and the Netherlands (15%) (Poulussen et al 2019).…”

Section: Cyp2d6mentioning

confidence: 99%

“…In contrast to the LOF alleles CYP2D6*3 , *4 and *6 , deletion of CYP2D6 ( CYP2D6*5 ) is most common in Africa, East Asia and Oceania with frequencies pivoting around 5–6% (Gaedigk et al 2017 ). In Europe, CYP2D6*5 prevalence is overall lower with a South-East to North-West gradient, ranging from 1% in Croatia (Ganoci et al 2017 ) to 7.2% in Netherlands (Poulussen et al 2019 ). Frequencies of CYP2D6*5 are similarly low in the Americas (2.1%), as well as in South Asian populations (3.2%) with national frequencies up to 5.1% in Malaysia (Teh et al 2001 ).…”

Section: Cyp2d6mentioning

confidence: 99%

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Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health

Zhou

Lauschke

2021

Hum Genet

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Both safety and efficacy of medical treatment can vary depending on the ethnogeographic background of the patient. One of the reasons underlying this variability is differences in pharmacogenetic polymorphisms in genes involved in drug disposition, as well as in drug targets. Knowledge and appreciation of these differences is thus essential to optimize population-stratified care. Here, we provide an extensive updated analysis of population pharmacogenomics in ten pharmacokinetic genes (CYP2D6, CYP2C19, DPYD, TPMT, NUDT15 and SLC22A1), drug targets (CFTR) and genes involved in drug hypersensitivity (HLA-A, HLA-B) or drug-induced acute hemolytic anemia (G6PD). Combined, polymorphisms in the analyzed genes affect the pharmacology, efficacy or safety of 141 different drugs and therapeutic regimens. The data reveal pronounced differences in the genetic landscape, complexity and variant frequencies between ethnogeographic groups. Reduced function alleles of CYP2D6, SLC22A1 and CFTR were most prevalent in individuals of European descent, whereas DPYD and TPMT deficiencies were most common in Sub-Saharan Africa. Oceanian populations showed the highest frequencies of CYP2C19 loss-of-function alleles while their inferred CYP2D6 activity was among the highest worldwide. Frequencies of HLA-B*15:02 and HLA-B*58:01 were highest across Asia, which has important implications for the risk of severe cutaneous adverse reactions upon treatment with carbamazepine and allopurinol. G6PD deficiencies were most frequent in Africa, the Middle East and Southeast Asia with pronounced differences in variant composition. These variability data provide an important resource to inform cost-effectiveness modeling and guide population-specific genotyping strategies with the goal of optimizing the implementation of precision public health.

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Section: Cyp2d6mentioning

confidence: 96%

Section: Cyp2d6mentioning

confidence: 99%

Section: Cyp2d6mentioning

confidence: 99%

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Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health

Zhou

Lauschke

2021

Hum Genet

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“…Interesting examples that demonstrate the power of this design include the relationship of metoprolol maintenance dose in heart failure patients with CYP2D6 genotype 56,57 (Fig. 2).…”

Section: How To Increase the Reliability Of Pharmacogenomic Studiesmentioning

confidence: 99%

Emerging strategies to bridge the gap between pharmacogenomic research and its clinical implementation

Lauschke

Ingelman‐Sundberg

2020

npj Genom. Med.

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The genomic inter-individual heterogeneity remains a significant challenge for both clinical decision-making and the design of clinical trials. Although next-generation sequencing (NGS) is increasingly implemented in drug development and clinical trials, translation of the obtained genomic information into actionable clinical advice lags behind. Major reasons are the paucity of sufficiently powered trials that can quantify the added value of pharmacogenetic testing, and the considerable pharmacogenetic complexity with millions of rare variants with unclear functional consequences. The resulting uncertainty is reflected in inconsistencies of pharmacogenomic drug labels in Europe and the United States. In this review, we discuss how the knowledge gap for bridging pharmacogenomics into the clinics can be reduced. First, emerging methods that allow the high-throughput experimental characterization of pharmacogenomic variants combined with novel computational tools hold promise to improve the accuracy of drug response predictions. Second, tapping of large biobanks of therapeutic drug monitoring data allows to conduct high-powered retrospective studies that can validate the clinical importance of genetic variants, which are currently incompletely characterized. Combined, we are confident that these methods will improve the accuracy of drug response predictions and will narrow the gap between variant identification and its utilization for clinical decision-support.

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“…Pharmacogenetics is a research field studying how interindividual genetic differences contribute to drug efficacy and safety, aiding physicians in drug selection and dose adjustment 1,2 . Variants in CYP2D6 and CYP2C19 genes have been shown to affect the metabolism of antidepressants, antipsychotics, analgesics such as codeine and tramadol, the antiplatelet agent clopidogrel and antiarrhythmic drugs, for example 3,4,5,6,7,8 . Although involved in the metabolism of 25% of all available drugs, research of the CYP2D6 locus at 22q13.2 has been limited by its complexity 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

Häkkinen

Kiiski

Lähteenvuo

et al. 2020

Preprint

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PurposeWe constructed a CYP2D6 copy-number imputation panel by combining copy-number information to GWAS chip data. In addition, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland.MethodsWe combined GWAS chip and CYP2D6 copy-number variation (CNV) data from the Breast Cancer Pain Genetics study (BrePainGen) to construct an imputation panel (N=902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9,262 non-related individuals passing genotype data quality control procedures. The panel performance was evaluated by genotyping the CNV from a subset (N=297) of SUPER-Finland participants.ResultsCYP2D6 CNV was imputed correctly in 272 (92%) individuals. Sensitivity and specificity for detecting a duplication were 0.986 and 0.946, respectively. Sensitivity and specificity for detecting a deletion using imputation were 0.886 and 0.966, respectively. Based on imputation, the frequency of a CYP2D6 duplication and deletion in the whole SUPER-Finland sample with 9,262 non-related individuals passing quality control were 8.5% and 2.7%, respectively. We confirm the higher frequency of CYP2D6 ultrarapid metabolizers in Finland compared with non-Finnish Europeans. Additionally, we confirm a 21-fold enrichment of the UGT1A1 decreased function variant rs4148323 (also known as 211G>A, G71R or UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland.ConclusionOur results demonstrate that imputation of CYP2D6 CNV is possible. The methodology is not accurate enough to be used in clinical decision making, but it enables studying CYP2D6 in large biobanks with genome-wide data. In addition, it allows for researchers to recontact patients with certain pharmacogenetic variations through biobanks. We show that bottle-necked populations may have pharmacogenetically important variants with allele frequencies very different from the main ancestral group. Future studies should assess whether these differences are large enough to cause clinically significant changes in trial results across different ancestral groups.

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The effect of the CYP2D6 genotype on the maintenance dose of metoprolol in a chronic Dutch patient population

Cited by 9 publications

References 17 publications

Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health

Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health

Emerging strategies to bridge the gap between pharmacogenomic research and its clinical implementation

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

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