Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians

McLellan, Roman A.; Oscarson, Mikael; Seidegård, Janeric; Evans, David A.; Ingelman‐Sundberg, Magnus

doi:10.1097/00008571-199706000-00003

Cited by 187 publications

(97 citation statements)

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“…The high frequency of haplotypes with duplications in Syria (*1 Â N þ *2 Â N ¼ 7.8%) agrees with previous observations of high frequencies of duplications in the Near East and in Africa. 14,15 …”

Section: Haplotype Determinationmentioning

confidence: 99%

“…12,13 The high frequency of these haplotypes in certain populations is hard to account for under a simple mutation-selection model. Haplotypes containing multiple gene copies were found at high frequencies only in specific regions like Ethiopia (29%) 14 and Saudi Arabia (21%), 15 while their frequency in the rest of the world ranges between 1 and 3%.…”

Section: Introductionmentioning

confidence: 99%

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Molecular diversity at the CYP2D6 locus in the Mediterranean region

et al. 2004

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Despite the importance of cytochrome P450 in the metabolism of many drugs, several aspects of molecular variation at one of the main loci coding for it, CYP2D6, have never been analysed so far. Here we show that it is possible to rapidly and efficiently genotype the main European allelic variants at this locus by a SNaPshot method identifying chromosomal rearrangements and nine single-nucleotide polymorphisms. Haplotypes could be reconstructed from data on 494 chromosomes in six populations of the Mediterranean region. High levels of linkage disequilibrium were found within the chromosome region screened, suggesting that CYP2D6 may be part of a genomic recombination block, and hence that, aside from unequal crossingover that led to large chromosomal rearrangements, its haplotype diversity essentially originated through the accumulation of mutations. With the only, albeit statistically insignificant, exception of Syria, haplotype frequencies do not differ among the populations studied, despite the presence among them of three well-known genetic outliers, which could be the result of common selective pressures playing a role in shaping CYP2D6 variation over the area of Europe that we surveyed.

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Section: Haplotype Determinationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular diversity at the CYP2D6 locus in the Mediterranean region

et al. 2004

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“…The frequency of poor and ultra-rapid metabolizers in a given population varies based on ethnicity, with CYP2D6 ultrarapid metabolizers occurring in as many as 20% to 30% of some African and Arab populations. [27][28][29] The guideline specifies that it is safe to prescribe the labelrecommended dose of codeine to CYP2D6 extensive metabolizers and intermediate metabolizers, noting that intermediate metabolizers may not achieve adequate pain control, and a change in analgesic may be warranted per patient response.Although we acknowledge that multiple enzymes are involved in the metabolism of codeine (Fig 1), including CYP3A4 and the glucuronidating enzymes UGT1A1 and UGT2B7, the only pharmacogene currently rated by CPIC as actionable for codeine prescribing is CYP2D6, a rating based on a high standard of evidence in peer-reviewed literature. 26 After the FDA boxed warning was added to codeine products in 2013, a controversial regulatory development changed the landscape of opioid prescribing.…”

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confidence: 99%

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

et al. 2016

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After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations. abstractDepartments of a Pharmaceutical Sciences, b Hematology, and c Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee; and d Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin Dr Gammal collected data, carried out the initial analyses, and drafted the initial manuscript; Drs Crews, Haidar, and Hoffman are coinvestigators on the PG4KDS study; they supervised the collection and analysis of data and critically reviewed and revised the manuscript; Dr Baker created the clinical decision support alerts, collected data, and critically reviewed the manuscript; Drs Barker, Estepp, Wang, and Weiss critically reviewed and revised the manuscript; Ms Pei designed and conducted the statistical analysis; Dr Broeckel supervises all PG4KDS-related genotyping; Dr Relling conceptualized and designed the PG4KDS study, supervised the collection and analysis of data, and critically reviewed and revised the manuscript; Dr Hankins conceptualized and designed the study and critically reviewed and revised the manuscript; and all authors approved the fi nal manuscript as submitted. The use of codeine in pediatric medicine has been questioned following reports of postoperative deaths in children who were prescribed codeine and the subsequent US Food and Drug Admin...

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“…However, when we added the haplotype information from the five microsatellite loci, we were able to distinguish the two samples (p ϭ 0.047), illustrating the greater resolving power available with the compound haplotypes. We compared our data with previously published data on CYP2D6 allele frequencies in Western Europeans (n ϭ 3292) [38] and Saudi Arabians (n ϭ 202) [9]. Our British sample did not differ significantly from the Western European sample (p ϭ 0.487 using exact test), despite the very high Western European sample size.…”

Section: Resultsmentioning

confidence: 84%

“…Several studies have suggested that variation in CYP2D6 can affect neurological disease susceptibility [7] as well as being a potential modulator of cancer risk [8]. Evolutionary interest in CYP2D6 arises because of the primary role that DMEs have in the metabolism of dietary toxins such as alkaloids [9].…”

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confidence: 99%

High-throughput analysis of informative CYP2D6 compound haplotypes

et al. 2003

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We describe a high-throughput protocol for detecting key polymorphisms in the drug-metabolizing enzyme gene CYP2D6 and a number of linked microsatellites that is both fast and relatively inexpensive to perform. This approach employs GeneScan technology to enable a researcher to determine rapidly the status of seven simple nucleotide polymorphisms in CYP2D6 and also to assay repeat number variation at five closely linked dinucleotide microsatellite loci. The method requires only three PCRs and two GeneScan runs per sample. We anticipate that this will be of value to researchers in three different ways: (1) rapid discrimination of common CYP2D6 alleles, (2) high-resolution haplotyping for association studies involving chromosome 22q13.1 using microsatellite variation, and (3) generation of compound haplotypes for investigating the evolution of CYP2D6 variation. We also report compound haplotype frequencies for an Ashkenazi Jewish and a British sample. © 2003 Elsevier Science (USA). All rights reserved.Keywords: CYP2D6; Pharmacogenetics; Genotyping; Haplotype; Microsatellites; SNPs; Jews; British; Population; Variation It is now clear that much of the observed variation in drug efficacy and safety has a hereditary basis, arising from polymorphisms in genes coding for drug-metabolizing enzymes (DMEs). The frequency of DME alleles can vary greatly between different human populations, and this has implications for both medical and evolutionary studies. Consequently, there has been growing academic and commercial interest in the extent, nature, and causes of DME variation. However, it is currently unknown to what extent interpopulation variability is due to selection, drift, or other processes. Studies seeking to elucidate this have been held back by the absence of efficient low-cost high-throughput procedures for characterizing variability at the molecular level in and around DME loci. Ultimately, the identification of the molecular basis of pharmacogenetically relevant variation combined with the technology to screen individuals for the presence of specific alleles allows for the prediction of drug response and individualized treatment.Polymorphism in debrisoquine/sparteine oxidation is arguably the most highly studied pharmacogenetic trait. The DNA sequence encoding the enzyme has been localized to the 4.3-kb, nine-exon cytochrome P450 2D6 (CYP2D6) gene found at chromosome 22q13.1. To date more than 48 mutations and 53 alleles of CYP2D6 have been characterized in European populations [1]. The poor metabolizer (PM) phenotype follows an autosomal recessive pattern of inheritance [2]. An allele duplication consisting of multiple functional copies of CYP2D6 confers the ultrarapid metabolizer (URM) phenotype [3]. Individuals who demonstrate normal levels of CYP2D6 activity are referred to as extensive metabolizers. Intermediate metabolizers (IMs) typically produce lower than normal levels of functional enzyme.Medical interest in CYP2D6 polymorphism arises because the CYP2D6 enzyme has been found to process more t...

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Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians

Cited by 187 publications

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Molecular diversity at the CYP2D6 locus in the Mediterranean region

Molecular diversity at the CYP2D6 locus in the Mediterranean region

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

High-throughput analysis of informative CYP2D6 compound haplotypes

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