Journal of Clinical Medicine

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18 pages, 2267 KiB

Open AccessArticle

Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate

by Maša Vidmar Golja, Alenka Šmid, Nataša Karas Kuželički, Jurij Trontelj, Ksenija Geršak and Irena Mlinarič-Raščan

J. Clin. Med. 2020, 9(9), 2836; https://doi.org/10.3390/jcm9092836 - 02 Sep 2020

Cited by 19 | Viewed by 5922

Abstract

Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal [...] Read more.

Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (n = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells’ metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices. Full article

(This article belongs to the Special Issue Advances and Challenges in Pharmacogenomics)

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18 pages, 1841 KiB

Open AccessArticle

Design and Early Implementation Successes and Challenges of a Pharmacogenetics Consult Clinic

by Meghan J. Arwood, Eric A. Dietrich, Benjamin Q. Duong, D. Max Smith, Kelsey Cook, Amanda Elchynski, Eric I. Rosenberg, Katherine N. Huber, Ying L. Nagoshi, Ashleigh Wright, Jeffrey T. Budd, Neal P. Holland, Edlira Maska, Danielle Panna, Amanda R. Elsey, Larisa H. Cavallari, Kristin Wiisanen, Julie A. Johnson and John G. Gums

J. Clin. Med. 2020, 9(7), 2274; https://doi.org/10.3390/jcm9072274 - 17 Jul 2020

Cited by 30 | Viewed by 5492

Abstract

Pharmacogenetic testing (PGT) is increasingly being used as a tool to guide clinical decisions. This article describes the development of an outpatient, pharmacist-led, pharmacogenetics consult clinic within internal medicine, its workflow, and early results, along with successes and challenges. A pharmacogenetics-trained pharmacist encouraged [...] Read more.

Pharmacogenetic testing (PGT) is increasingly being used as a tool to guide clinical decisions. This article describes the development of an outpatient, pharmacist-led, pharmacogenetics consult clinic within internal medicine, its workflow, and early results, along with successes and challenges. A pharmacogenetics-trained pharmacist encouraged primary care physicians (PCPs) to refer patients who were experiencing side effects/ineffectiveness from certain antidepressants, opioids, and/or proton pump inhibitors. In clinic, the pharmacist confirmed the need for and ordered CYP2C19 and/or CYP2D6 testing, provided evidence-based pharmacogenetic recommendations to PCPs, and educated PCPs and patients on the results. Operational and clinical metrics were analyzed. In two years, 91 referred patients were seen in clinic (mean age 57, 67% women, 91% European-American). Of patients who received PGT, 77% had at least one CYP2C19 and/or CYP2D6 phenotype that would make conventional prescribing unfavorable. Recommendations suggested that physicians change a medication/dose for 59% of patients; excluding two patients lost to follow-up, 87% of recommendations were accepted. Challenges included PGT reimbursement and referral maintenance. High frequency of actionable results suggests physician education on who to refer was successful and illustrates the potential to reduce trial-and-error prescribing. High recommendation acceptance rate demonstrates the pharmacist’s effectiveness in providing genotype-guided recommendations, emphasizing a successful pharmacist–physician collaboration. Full article

(This article belongs to the Special Issue Advances and Challenges in Pharmacogenomics)

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13 pages, 2363 KiB

Open AccessArticle

A Novel Approach for the Identification of Pharmacogenetic Variants in MT-RNR1 through Next-Generation Sequencing Off-Target Data

by Javier Lanillos, María Santos, Marta Carcajona, Juan María Roldan-Romero, Angel M. Martinez, Bruna Calsina, María Monteagudo, Luis Javier Leandro-García, Cristina Montero-Conde, Alberto Cascón, Paolo Maietta, Sara Alvarez, Mercedes Robledo and Cristina Rodriguez-Antona

J. Clin. Med. 2020, 9(7), 2082; https://doi.org/10.3390/jcm9072082 - 02 Jul 2020

Cited by 1 | Viewed by 2941

Abstract

Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-RNR1 genetic variation, including [...] Read more.

Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-RNR1 genetic variation, including the most relevant ototoxicity variant m.1555A>G, using the off-target reads of 473 research samples, sequenced through a capture-based, custom-targeted panel and whole exome sequencing (WES), and of 1245 diagnostic samples with clinical WES. Sanger sequencing and fluorescence-based genotyping were used for genotype validation. There was a correlation between off-target reads and mitochondrial coverage (r_customPanel = 0.39, p = 2 × 10⁻¹³ and rWES = 0.67, p = 7 × 10⁻²¹). The median read depth of MT-RNR1 m.1555 was similar to the average mitochondrial genome coverage, with saliva and blood samples giving comparable results. The genotypes from 415 samples, including three m.1555G carriers, were concordant with fluorescence-based genotyping data. In clinical WES, median MT-RNR1 coverage was 56×, with 90% of samples having ≥20 reads at m.1555 position, and one m.1494T and three m.1555G carriers were identified with no evidence for heteroplasmy. Altogether, this study shows that obtaining MT-RNR1 genotypes through off-target reads is an efficient strategy that can impulse preemptive pharmacogenetic screening of this mitochondrial gene. Full article

(This article belongs to the Special Issue Advances and Challenges in Pharmacogenomics)

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15 pages, 668 KiB

Open AccessArticle

Adverse Drug Reactions in the Emergency Department: Is There a Role for Pharmacogenomic Profiles at Risk?—Results from the ADRED Study

by Katja S. Just, Harald Dormann, Marlen Schurig, Miriam Böhme, Jochen Fracowiak, Michael Steffens, Catharina Scholl, Thomas Seufferlein, Ingo Gräff, Matthias Schwab and Julia C. Stingl

J. Clin. Med. 2020, 9(6), 1801; https://doi.org/10.3390/jcm9061801 - 09 Jun 2020

Cited by 9 | Viewed by 3120

Abstract

Individual differences in required drug dosages exist based on the pharmacogenomic (PGx) profiles. This study aimed to assess associations between PGx profiles and adverse drug reactions (ADR) that lead to admissions to the emergency department (ED). ADR cases of the prospective multi-center observational [...] Read more.

Individual differences in required drug dosages exist based on the pharmacogenomic (PGx) profiles. This study aimed to assess associations between PGx profiles and adverse drug reactions (ADR) that lead to admissions to the emergency department (ED). ADR cases of the prospective multi-center observational trial in EDs (ADRED study) were analyzed (n = 776) together with the relevant PGx phenotypes of the enzymes CYP2D6, CYP2C19, CYP2C9, and VKORC1. Overall, the allele frequency distribution in this cohort did not differ from the population frequencies. We compared the frequencies of phenotypes in the subgroups with the drugs suspected of certain ADR, in the remaining cases. The frequency distribution of CYP2C19 differed for the ADR bleeding cases suspected of clopidogrel (p = 0.020). In a logistic regression analysis, higher CYP2C19 activity (OR (95% CI): 4.97 (1.73−14.27)), together with age (1.05 (1.02−1.08)), showed an impact on the clopidogrel-suspecting ADRs, when adjusting for the clinical parameters. There was a trend for an association of phenprocoumon-risk profiles (low VKORC1 or CYP2C9 activity) with phenprocoumon-suspecting ADRs (p = 0.052). The PGx impact on serious ADRs might be highest in drugs that cannot be easily monitored or those that do not provoke mild ADR symptoms very quickly. Therefore, patients that require the intake of those drugs with PGx variability such as clopidogrel, might benefit from PGx testing. Full article

(This article belongs to the Special Issue Advances and Challenges in Pharmacogenomics)

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19 pages, 591 KiB

Open AccessArticle

Assessing the Implementation of Pharmacogenomic Panel-Testing in Primary Care in the Netherlands Utilizing a Theoretical Framework

by Cathelijne H. van der Wouden, Ellen Paasman, Martina Teichert, Matty R. Crone, Henk-Jan Guchelaar and Jesse J. Swen

J. Clin. Med. 2020, 9(3), 814; https://doi.org/10.3390/jcm9030814 - 17 Mar 2020

Cited by 20 | Viewed by 4707

Abstract

Despite overcoming many implementation barriers, pharmacogenomic (PGx) panel-testing is not routine practice in the Netherlands. Therefore, we aim to study pharmacists’ perceived enablers and barriers for PGx panel-testing among pharmacists participating in a PGx implementation study. Here, pharmacists identify primary care patients, initiating [...] Read more.

Despite overcoming many implementation barriers, pharmacogenomic (PGx) panel-testing is not routine practice in the Netherlands. Therefore, we aim to study pharmacists’ perceived enablers and barriers for PGx panel-testing among pharmacists participating in a PGx implementation study. Here, pharmacists identify primary care patients, initiating one of 39 drugs with a Dutch Pharmacogenetic Working Group (DPWG) recommendation and subsequently utilizing the results of a 12 gene PGx panel test to guide dose and drug selection. Pharmacists were invited for a general survey and a semi-structured interview based on the Tailored Implementation for Chronic Diseases (TICD) framework, aiming to identify implementation enablers and barriers, if they had managed at least two patients with actionable PGx results. In total, 15 semi-structured interviews were performed before saturation point was reached. Of these, five barrier themes emerged: (1) unclear procedures, (2) undetermined reimbursement for PGx test and consult, (3) insufficient evidence of clinical utility for PGx panel-testing, (4) infrastructure inefficiencies, and (5) HCP PGx knowledge and awareness; and two enabler themes: (1) pharmacist perceived role in delivering PGx, and (2) believed clinical utility of PGx. Despite a strong belief in the beneficial effects of PGx, pharmacists’ barriers remain, an these hinder implementation in primary care. Full article

(This article belongs to the Special Issue Advances and Challenges in Pharmacogenomics)

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Review

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22 pages, 1243 KiB

Open AccessReview

Vaccinomics and Adversomics in the Era of Precision Medicine: A Review Based on HBV, MMR, HPV, and COVID-19 Vaccines

by Jasna Omersel and Nataša Karas Kuželički

J. Clin. Med. 2020, 9(11), 3561; https://doi.org/10.3390/jcm9113561 - 05 Nov 2020

Cited by 19 | Viewed by 5938

Abstract

Precision medicine approaches based on pharmacogenomics are now being successfully implemented to enable physicians to predict more efficient treatments and prevention strategies for a given disease based on the genetic background of the patient. This approach has already been proposed for vaccines, but [...] Read more.

Precision medicine approaches based on pharmacogenomics are now being successfully implemented to enable physicians to predict more efficient treatments and prevention strategies for a given disease based on the genetic background of the patient. This approach has already been proposed for vaccines, but research is lagging behind the needs of society, and precision medicine is far from being implemented here. While vaccinomics concerns the effectiveness of vaccines, adversomics concerns their side effects. This area has great potential to address public concerns about vaccine safety and to promote increased public confidence, higher vaccination rates, and fewer serious adverse events in genetically predisposed individuals. The aim here is to explore the contemporary scientific literature related to the vaccinomic and adversomic aspects of the three most-controversial vaccines: those against hepatitis B, against measles, mumps, and rubella, and against human Papilloma virus. We provide detailed information on the genes that encode human leukocyte antigen, cytokines and their receptors, and transcription factors and regulators associated with the efficacy and safety of the Hepatitis B and Measles, Mumps and Rubella virus vaccines. We also investigate the future prospects of vaccinomics and adversomics of a COVID-19 vaccine, which might represent the fastest development of a vaccine ever. Full article

(This article belongs to the Special Issue Advances and Challenges in Pharmacogenomics)

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33 pages, 1205 KiB

Open AccessReview

Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review

by Sylvia D. Klomp, Martijn L. Manson, Henk-Jan Guchelaar and Jesse J. Swen

J. Clin. Med. 2020, 9(9), 2890; https://doi.org/10.3390/jcm9092890 - 07 Sep 2020

Cited by 83 | Viewed by 9122

Abstract

Phenoconversion is the mismatch between the individual’s genotype-based prediction of drug metabolism and the true capacity to metabolize drugs due to nongenetic factors. While the concept of phenoconversion has been described in narrative reviews, no systematic review is available. A systematic review was [...] Read more.

Phenoconversion is the mismatch between the individual’s genotype-based prediction of drug metabolism and the true capacity to metabolize drugs due to nongenetic factors. While the concept of phenoconversion has been described in narrative reviews, no systematic review is available. A systematic review was conducted to investigate factors contributing to phenoconversion and the impact on cytochrome P450 metabolism. Twenty-seven studies met the inclusion criteria and were incorporated in this review, of which 14 demonstrate phenoconversion for a specific genotype group. Phenoconversion into a lower metabolizer phenotype was reported for concomitant use of CYP450-inhibiting drugs, increasing age, cancer, and inflammation. Phenoconversion into a higher metabolizer phenotype was reported for concomitant use of CYP450 inducers and smoking. Moreover, alcohol, pregnancy, and vitamin D exposure are factors where study data suggested phenoconversion. The studies reported genotype–phenotype discrepancies, but the impact of phenoconversion on the effectiveness and toxicity in the clinical setting remains unclear. In conclusion, phenoconversion is caused by both extrinsic factors and patient- and disease-related factors. The mechanism(s) behind and the extent to which CYP450 metabolism is affected remain unexplored. If studied more comprehensively, accounting for phenoconversion may help to improve our ability to predict the individual CYP450 metabolism and personalize drug treatment. Full article

(This article belongs to the Special Issue Advances and Challenges in Pharmacogenomics)

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34 pages, 887 KiB

Open AccessReview

Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response

by Qingyang Xiao, André Nobre, Pilar Piñeiro, Miguel-Ángel Berciano-Guerrero, Emilio Alba, Manuel Cobo, Volker M. Lauschke and Isabel Barragán

J. Clin. Med. 2020, 9(1), 286; https://doi.org/10.3390/jcm9010286 - 20 Jan 2020

Cited by 42 | Viewed by 8515

Abstract

Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors [...] Read more.

Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates. Full article

(This article belongs to the Special Issue Advances and Challenges in Pharmacogenomics)

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