Characterization of the
            <i>CYP2D6</i>
            Gene Locus and Metabolic Activity in Indo- and Afro-Trinidadians: Discovery of Novel Allelic Variants

Jaime, Lazara Karelia Montané; Lalla, A.; Steimer, Werner; Gaedigk, Andrea

doi:10.2217/pgs.12.207

Cited by 38 publications

(28 citation statements)

References 41 publications

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“…There are also a number of alleles with g.100C>T that are currently labeled as “uncertain” function (e.g., *37 , *52 , *64 , *87 , *94 , and *95 ). Most experts recommended that these alleles should also receive an activity value of 0.25; however, concerns were raised by some of the experts regarding the lack of evidence (i.e., in vitro or in vivo studies) for most of these alleles (e.g., 100C>T in combination with other SNP(s) may obliterate function, or compensate for the decreased function caused by 100C>T) . Thus, other CYP2D6 alleles containing the 100C>T variant besides *10 will be assessed as part of future CPIC guideline development.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the determination of activity for an allele is difficult as is and to discriminate activity on a scale of 10% increments seems impossible as there are no data for the vast majority of alleles at this point in time. Second, there is a broad range of interindividual variability among subjects within the same genotype group and third, even if activity could be determined on a 10% scale, percent activities may still need to be translated into a limited number of phenotyping categories for feasibility of clinical implementation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group

Caudle

Sangkuhl

Whirl‐Carrillo

et al. 2019

Clinical Translational Sci

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400

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Translating CYP2D6 genotype to metabolizer phenotype is not standardized across clinical laboratories offering pharmacogenetic (PGx) testing and PGx clinical practice guidelines, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). The genotype to phenotype translation discordance between laboratories and guidelines can cause discordant cytochrome P450 2D6 (CYP2D6) phenotype assignments and, thus lead to inconsistent therapeutic recommendations and confusion among patients and clinicians. A modified‐Delphi method was used to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts. Experts with diverse involvement in CYP2D6 interpretation (clinicians, researchers, genetic testing laboratorians, and PGx implementers; n = 37) participated in conference calls and surveys. After completion of 7 surveys, a consensus (> 70%) was reached with 82% of the CYP2D6 experts agreeing to the final CYP2D6 genotype to phenotype translation method. Broad adoption of the proposed CYP2D6 genotype to phenotype translation method by guideline developers, such as CPIC and DPWG, and clinical laboratories as well as researchers will result in more consistent interpretation of CYP2D6 genotype.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group

Caudle

Sangkuhl

Whirl‐Carrillo

et al. 2019

Clinical Translational Sci

Self Cite

400

502

View full text Add to dashboard Cite

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“…Furthermore, the study of populations with complex ancestry such as Latin American populations comprises the fact that novel or rare variants (Fohner et al, 2013;Gaedigk et al, 2010) might appear, leading to poor metabolism or reduced function (Montané-Jaime et al, 2013). In the future, sequencing the CYP2D6 gene in these populations might be suitable to detect relevant genetic variants.…”

Section: Discussionmentioning

confidence: 99%

“…During the 16 th century, people from the Iberian Peninsula arrived to different places of America leading current Costa Rican, Latin American, and Caribbean populations to have different degrees of admixture (Gaedigk et al, 2010;Llerena et al, 2012;Montané-Jaime, Lalla, Steimer, & Gaedigk, 2013). Latin American populations are products of a process of admixture, mainly including groups of Amerindian, European and African ancestry (Sans, 2000).…”

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confidence: 99%

Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans

Céspedes-Garro

Jiménez-Arce

Naranjo

et al. 2014

RBT

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CYP2D6 differences have already been demonstrated within Latin American populations by the CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics (RIBEF, as per the acronym in Spanish). However, within the population of Costa Rica, no research has been conducted until now, even though this population has a trihybrid component ancestry that represents an interesting condition. Thus, the present study was aimed to determine the frequency of Ultra-rapid Metabolizers (UMs) and Poor Metabolizers (PMs) in a Costa Rican population, as well as to determine whether there are differences in the CYP2D6-predicted phenotype frequencies among three Costa Rican groups with different ethnic backgrounds. Additionally, these frequencies of PMs and UMs obtained were compared with

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“…High quality genomic DNA (gDNA) was isolated from whole blood and tissues using silica-based spin columns such as the QIAamp® DNA Blood Mini Kit, DNeasy® Blood and Tissue Kit from Qiagen (Valencia, CA) or by a phenol-chloroform-based procedure 22 . Saliva samples were collected from participants at CAMH in Oragene DNA kits (DNA Genotek, Kanata, ON, Canada).…”

Section: Methodsmentioning

confidence: 99%

SNP genotyping using TaqMan® technology: the CYP2D6*17 assay conundrum

Gaedigk

Freeman

Hartshorne

et al. 2015

Sci Rep

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CYP2D6 contributes to the metabolism of many clinically used drugs and is increasingly tested to individualize drug therapy. The CYP2D6 gene is challenging to genotype due to the highly complex nature of its gene locus. TaqMan® technology is widely used in the clinical and research settings for genotype analysis due to assay reliability, low cost, and the availability of commercially available assays. The assay identifying 1023C>T (rs28371706) defining a reduced function (CYP2D6*17) and several nonfunctional alleles, produced a small number of unexpected diplotype calls in three independent sets of samples, i.e. calls suggested the presence of a CYP2D6*4 subvariant containing 1023C>T. Gene resequencing did not reveal any unknown SNPs in the primer or probe binding sites in any of the samples, but all affected samples featured a trio of SNPs on their CYP2D6*4 allele between one of the PCR primer and probe binding sites. While the phenomenon was ultimately overcome by an alternate assay utilizing a PCR primer excluding the SNP trio, the mechanism causing this phenomenon remains elusive. This rare and unexpected event underscores the importance of assay validation in samples representing a variety of genotypes, but also vigilance of assay performance in highly polymorphic genes such as CYP2D6.

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Characterization of the CYP2D6 Gene Locus and Metabolic Activity in Indo- and Afro-Trinidadians: Discovery of Novel Allelic Variants

Abstract: Our study underscores the importance of thoroughly characterizing the genetic make up of unique populations when considering pharmacogenetic testing for individualized therapy.

Cited by 38 publications

References 41 publications

Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group

Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group

Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans

SNP genotyping using TaqMan® technology: the CYP2D6*17 assay conundrum

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