Pharmacogenomic Determinants of Interindividual Drug Response Variability: From Discovery to Implementation

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (1 November 2020) | Viewed by 77688

Special Issue Editors

1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2. Sema4, Stamford, CT 06902, USA
Interests: clinical genetics; human genomics; pharmacogenomics; cytogenomics; long-read sequencing
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Interests: pharmacogenomics, phenoconversion, oncology, long-read sequencing

Special Issue Information

Dear Colleagues,

Since the term ‘pharmacogenetics’ was first published in the late 1950’s, the field has evolved to genome-wide association studies identifying novel variants implicated in drug response phenotypes, international societies and consortia dedicated to pharmacogenomic research and implementation, clinical practice guidelines, and the increasing availability of pharmacogenomic tests for providers in both hospital and primary care settings.

However, current challenges related to translating pharmacogenomic discoveries into clinical practice include an evolving regulatory landscape, best practices for pharmacogenomic testing and interpretation, ongoing debate over clinical validity/utility, and clinical provider education and adoption. Moreover, the implementation of current pharmacogenomic knowledge introduces novel challenges for the field, including how to manage the interplay between gene-drug and drug-drug interactions and how to interpret rare pharmacogenomic variants of unknown significance.

This Special Issue is a collection of articles showcasing novel and international research in pharmacogenomics, spanning the field from discovery to clinical implementation. Manuscripts on the following topics will be considered for publication and are encouraged: pharmacogenomic association studies; multi-ethnic and diverse population research; variant/haplotype discovery and/or functional characterization; pharmacogenomic technologies, assay validation and experience; phenoconversion and gene-drug-drug interactions; clinical pharmacogenomic implementation and/or utility studies; and clinical provider knowledge, education and adoption research.

Dr. Stuart A. Scott
Dr. Jesse J. Swen
Guest Editors

Manuscript Submission Information

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Keywords

  • Pharmacogenomics
  • Drug response variability
  • Multi-ethnic populations
  • Variant and haplotype discovery
  • Variant function characterization
  • Pharmacogenomic sequencing
  • Pharmacogenomic testing
  • Phenoconversion
  • Clinical pharmacogenomic implementation
  • Pharmacogenomic utility and education

Published Papers (16 papers)

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Editorial

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4 pages, 200 KiB  
Editorial
Pharmacogenomic Determinants of Interindividual Drug Response Variability: From Discovery to Implementation
by Stuart A. Scott and Jesse J. Swen
Genes 2021, 12(3), 393; https://doi.org/10.3390/genes12030393 - 10 Mar 2021
Cited by 1 | Viewed by 1763
Abstract
Since the term “pharmacogenetics” was first published in the late 1950s by Friedrich Vogel, the field has evolved into genome-wide association studies identifying novel variants associated with drug response phenotypes, international societies and consortia dedicated to pharmacogenomic research and clinical implementation, clinical practice [...] Read more.
Since the term “pharmacogenetics” was first published in the late 1950s by Friedrich Vogel, the field has evolved into genome-wide association studies identifying novel variants associated with drug response phenotypes, international societies and consortia dedicated to pharmacogenomic research and clinical implementation, clinical practice guidelines, and the increasing availability of pharmacogenomic tests for healthcare providers in both hospital and primary care [...] Full article

Research

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11 pages, 447 KiB  
Article
Using Personal Genomic Data within Primary Care: A Bioinformatics Approach to Pharmacogenomics
by Rick Overkleeft, Judith Tommel, Andrea W. M. Evers, Johan T. den Dunnen, Marco Roos, Marie-José Hoefmans, Walter E. Schrader, Jesse J. Swen, Mattijs E. Numans and Elisa J. F. Houwink
Genes 2020, 11(12), 1443; https://doi.org/10.3390/genes11121443 - 30 Nov 2020
Cited by 8 | Viewed by 4207
Abstract
One application of personalized medicine is the tailoring of medication to the individual, so that the medication will have the highest chance of success. In order to individualize medication, one must have a complete inventory of all current pharmaceutical compounds (a detailed formulary) [...] Read more.
One application of personalized medicine is the tailoring of medication to the individual, so that the medication will have the highest chance of success. In order to individualize medication, one must have a complete inventory of all current pharmaceutical compounds (a detailed formulary) combined with pharmacogenetic datasets, the genetic makeup of the patient, their (medical) family history and other health-related data. For healthcare professionals to make the best use of this information, it must be visualized in a way that makes the most medically relevant data accessible for their decision-making. Similarly, to enable bioinformatics analysis of these data, it must be prepared and provided through an interface for controlled computational analysis. Due to the high degree of personal information gathered for such initiatives, privacy-sensitive implementation choices and ethical standards are paramount. The Personal Genetic Locker project provides an approach to enable the use of personal genomic data in primary care. In this paper, we provide a description of the Personal Genetic Locker project and show its utility through a use case based on open standards, which is illustrated by the 4MedBox system. Full article
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10 pages, 1220 KiB  
Article
Phased Haplotype Resolution of the SLC6A4 Promoter Using Long-Read Single Molecule Real-Time (SMRT) Sequencing
by Mariana R. Botton, Yao Yang, Erick R. Scott, Robert J. Desnick and Stuart A. Scott
Genes 2020, 11(11), 1333; https://doi.org/10.3390/genes11111333 - 12 Nov 2020
Cited by 4 | Viewed by 5090
Abstract
The SLC6A4 gene has been implicated in psychiatric disorder susceptibility and antidepressant response variability. The SLC6A4 promoter is defined by a variable number of homologous 20–24 bp repeats (5-HTTLPR), and long (L) and short (S) alleles are associated with higher and lower expression, [...] Read more.
The SLC6A4 gene has been implicated in psychiatric disorder susceptibility and antidepressant response variability. The SLC6A4 promoter is defined by a variable number of homologous 20–24 bp repeats (5-HTTLPR), and long (L) and short (S) alleles are associated with higher and lower expression, respectively. However, this insertion/deletion variant is most informative when considered as a haplotype with the rs25531 and rs25532 variants. Therefore, we developed a long-read single molecule real-time (SMRT) sequencing method to interrogate the SLC6A4 promoter region. A total of 120 samples were subjected to SLC6A4 long-read SMRT sequencing, primarily selected based on available short-read sequencing data. Short-read genome sequencing from the 1000 Genomes (1KG) Project (~5X) and the Genetic Testing Reference Material Coordination Program (~45X), as well as high-depth short-read capture-based sequencing (~330X), could not identify the 5-HTTLPR short (S) allele, nor could short-read sequencing phase any identified variants. In contrast, long-read SMRT sequencing unambiguously identified the 5-HTTLPR short (S) allele (frequency of 0.467) and phased SLC6A4 promoter haplotypes. Additionally, discordant rs25531 genotypes were reviewed and determined to be short-read errors. Taken together, long-read SMRT sequencing is an innovative and robust method for phased resolution of the SLC6A4 promoter, which could enable more accurate pharmacogenetic testing for both research and clinical applications. Full article
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21 pages, 1794 KiB  
Article
Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations
by Anca Liliana Cismaru, Deborah Rudin, Luisa Ibañez, Evangelia Liakoni, Nicolas Bonadies, Reinhold Kreutz, Alfonso Carvajal, Maria Isabel Lucena, Javier Martin, Esther Sancho Ponce, Mariam Molokhia, Niclas Eriksson, EuDAC collaborators, Stephan Krähenbühl, Carlo R. Largiadèr, Manuel Haschke, Pär Hallberg, Mia Wadelius and Ursula Amstutz
Genes 2020, 11(11), 1275; https://doi.org/10.3390/genes11111275 - 29 Oct 2020
Cited by 7 | Viewed by 3524
Abstract
Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. [...] Read more.
Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10−7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41–6.68, p = 1.01 × 10−7) and rs4427239 (OR = 5.47, 95%CI: 2.81–10.65, p = 5.75 × 10−7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA. Full article
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11 pages, 958 KiB  
Article
Association between the TPMT*3C (rs1142345) Polymorphism and the Risk of Death in the Treatment of Acute Lymphoblastic Leukemia in Children from the Brazilian Amazon Region
by Darlen Cardoso de Carvalho, Luciana Pereira Colares Leitão, Fernando Augusto Rodrigues Mello Junior, Alayde Vieira Wanderley, Tatiane Piedade de Souza, Roberta Borges Andrade de Sá, Amanda Cohen-Paes, Marianne Rodrigues Fernandes, Sidney Santos, André Salim Khayat, Paulo Pimentel de Assumpção and Ney Pereira Carneiro dos Santos
Genes 2020, 11(10), 1132; https://doi.org/10.3390/genes11101132 - 25 Sep 2020
Cited by 6 | Viewed by 2768
Abstract
Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of [...] Read more.
Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient’s genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population. Full article
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13 pages, 772 KiB  
Article
Effect of CYP3A4*22 and PPAR-α Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention
by Thomas O. Bergmeijer, Alfi Yasmina, Gerrit J. A. Vos, Paul W. A. Janssen, Christian M. Hackeng, Johannes C. Kelder, Shefali S. Verma, Marylyn D. Ritchie, Li Gong, Teri E. Klein, ICPC investigators, Anthonius de Boer, Olaf H. Klungel, Jurriën M. ten Berg and Vera H. M. Deneer
Genes 2020, 11(9), 1068; https://doi.org/10.3390/genes11091068 - 11 Sep 2020
Cited by 2 | Viewed by 2405
Abstract
This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing [...] Read more.
This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: −24.6 PRU [−44.7, −4.6], p = 0.016; A208G GG: −24.6 PRU [−44.3, −4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings. Full article
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10 pages, 437 KiB  
Article
Profile of the Nicotinic Cholinergic Receptor Alpha 7 Subunit Gene Expression is Associated with Response to Varenicline Treatment
by Juliana Rocha Santos, Paulo Roberto Xavier Tomaz, Jaqueline Ribeiro Scholz, Patrícia Viviane Gaya, Tânia Ogawa Abe, José Eduardo Krieger, Alexandre Costa Pereira and Paulo Caleb Júnior de Lima Santos
Genes 2020, 11(7), 746; https://doi.org/10.3390/genes11070746 - 6 Jul 2020
Cited by 2 | Viewed by 1870
Abstract
Introduction: Smoking is considered the leading cause of preventable morbidity and mortality worldwide. Studies have sought to identify predictors of response to smoking cessation treatments. The aim of this study was to analyze a possible association of target gene expression for smoking cessation [...] Read more.
Introduction: Smoking is considered the leading cause of preventable morbidity and mortality worldwide. Studies have sought to identify predictors of response to smoking cessation treatments. The aim of this study was to analyze a possible association of target gene expression for smoking cessation with varenicline. Methods: We included 74 smokers starting treatment with varenicline. Gene expression analysis was performed through the custom RT² Profiler qPCR array assay, including 17 genes. Times for sample collection were before the start of therapy (T0) and two weeks (T2) and four weeks (T4) after the start of treatment. Results: For gene expression analysis, we selected 14 patients who had success and 13 patients resistant to varenicline treatment. Success was considered to be when a patient achieved tobacco abstinence until the fourth week of treatment and resistant was when a patient had not stopped smoking as of the fourth week of treatment. We observed a significant difference for CHRNA7 gene expression: in the resistant group, samples from T2 and T4 had lower expression compared with T0 (fold change: 0.38, P = 0.007; fold change: 0.67, P = 0.004; respectively). Conclusion: This exploratory clinical study, searching for a possible predictor of effectiveness for varenicline, reaffirmed the association of the α7 nAChR subunit for nicotine dependence and smoking therapy effectiveness with varenicline. Full article
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15 pages, 605 KiB  
Article
Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia
by Sunitha Kodidela, Patchava Dorababu, Dimpal N. Thakkar, Biswajit Dubashi, Rajan Sundaram, Niveditha Muralidharan, Ravi Prasad Nidanapu, Anil Aribandi, Suresh Chandra Pradhan and Chakradhara Rao Satyanarayana Uppugunduri
Genes 2020, 11(6), 594; https://doi.org/10.3390/genes11060594 - 28 May 2020
Cited by 13 | Viewed by 3152
Abstract
Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT [...] Read more.
Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3–4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3–4) was seen in 54.9% of patients. The NUDT15c.415T allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5–6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105’T’) carrier status along with NUDT15c.415T allele [HR = 2.7 (1.5–4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15c.415T allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT. Full article
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Review

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24 pages, 755 KiB  
Review
Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics
by Laura M. de Jong, Wim Jiskoot, Jesse J. Swen and Martijn L. Manson
Genes 2020, 11(12), 1509; https://doi.org/10.3390/genes11121509 - 16 Dec 2020
Cited by 60 | Viewed by 6076
Abstract
Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition [...] Read more.
Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes—and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response. Full article
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16 pages, 2507 KiB  
Review
Technologies for Pharmacogenomics: A Review
by Maaike van der Lee, Marjolein Kriek, Henk-Jan Guchelaar and Jesse J. Swen
Genes 2020, 11(12), 1456; https://doi.org/10.3390/genes11121456 - 4 Dec 2020
Cited by 28 | Viewed by 7279
Abstract
The continuous development of new genotyping technologies requires awareness of their potential advantages and limitations concerning utility for pharmacogenomics (PGx). In this review, we provide an overview of technologies that can be applied in PGx research and clinical practice. Most commonly used are [...] Read more.
The continuous development of new genotyping technologies requires awareness of their potential advantages and limitations concerning utility for pharmacogenomics (PGx). In this review, we provide an overview of technologies that can be applied in PGx research and clinical practice. Most commonly used are single nucleotide variant (SNV) panels which contain a pre-selected panel of genetic variants. SNV panels offer a short turnaround time and straightforward interpretation, making them suitable for clinical practice. However, they are limited in their ability to assess rare and structural variants. Next-generation sequencing (NGS) and long-read sequencing are promising technologies for the field of PGx research. Both NGS and long-read sequencing often provide more data and more options with regard to deciphering structural and rare variants compared to SNV panels—in particular, in regard to the number of variants that can be identified, as well as the option for haplotype phasing. Nonetheless, while useful for research, not all sequencing data can be applied to clinical practice yet. Ultimately, selecting the right technology is not a matter of fact but a matter of choosing the right technique for the right problem. Full article
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29 pages, 1030 KiB  
Review
Pharmacogenomics for Primary Care: An Overview
by Victoria Rollinson, Richard Turner and Munir Pirmohamed
Genes 2020, 11(11), 1337; https://doi.org/10.3390/genes11111337 - 12 Nov 2020
Cited by 26 | Viewed by 10074
Abstract
Most of the prescribing and dispensing of medicines happens in primary care. Pharmacogenomics (PGx) is the study and clinical application of the role of genetic variation on drug response. Mounting evidence suggests PGx can improve the safety and/or efficacy of several medications commonly [...] Read more.
Most of the prescribing and dispensing of medicines happens in primary care. Pharmacogenomics (PGx) is the study and clinical application of the role of genetic variation on drug response. Mounting evidence suggests PGx can improve the safety and/or efficacy of several medications commonly prescribed in primary care. However, implementation of PGx has generally been limited to a relatively few academic hospital centres, with little adoption in primary care. Despite this, many primary healthcare providers are optimistic about the role of PGx in their future practice. The increasing prevalence of direct-to-consumer genetic testing and primary care PGx studies herald the plausible gradual introduction of PGx into primary care and highlight the changes needed for optimal translation. In this article, the potential utility of PGx in primary care will be explored and on-going barriers to implementation discussed. The evidence base of several drug-gene pairs relevant to primary care will be outlined with a focus on antidepressants, codeine and tramadol, statins, clopidogrel, warfarin, metoprolol and allopurinol. This review is intended to provide both a general introduction to PGx with a more in-depth overview of elements relevant to primary care. Full article
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13 pages, 1303 KiB  
Review
Genetic Variants Affecting Anti-VEGF Drug Response in Polypoidal Choroidal Vasculopathy Patients: A Systematic Review and Meta-Analysis
by Xando Díaz-Villamarín, David Blánquez-Martínez, Ana Pozo-Agundo, Ana María Pérez-Gutiérrez, José Ignacio Muñoz-Ávila, Alba Antúnez-Rodríguez, Ana Estefanía Fernández-Gómez, Paloma García-Navas, Luis Javier Martínez-González and Cristina Lucía Dávila-Fajardo
Genes 2020, 11(11), 1335; https://doi.org/10.3390/genes11111335 - 12 Nov 2020
Cited by 9 | Viewed by 2593
Abstract
Polypoidal choroidal vasculopathy (PCV) is usually regarded as a subtype of choroidal neovascularization (CNV) that is secondary to age-related macular degeneration (AMD) characterized by choroidal vessel branching, ending in polypoidal lesions. Despite their close association, PCV and neovascular AMD have shown differences, especially [...] Read more.
Polypoidal choroidal vasculopathy (PCV) is usually regarded as a subtype of choroidal neovascularization (CNV) that is secondary to age-related macular degeneration (AMD) characterized by choroidal vessel branching, ending in polypoidal lesions. Despite their close association, PCV and neovascular AMD have shown differences, especially regarding patients’ treatment response. Currently, antivascular endothelial growth factor (anti-VEGF) drugs, such as ranibizumab, bevacizumab and aflibercept, have demonstrated their efficacy in CNV patients. However, in PCV, anti-VEGF treatments have shown inconclusive results. Many genetic polymorphisms have been associated with a variable response in exudative/wet AMD patients. Thus, the aim of this study is to explore the genetic variants affecting anti-VEGF drug response in PCV patients. In this regard, we performed a systematic review and meta-analysis. We found four variants (CFH I62V, CFH Y402H, ARMS2 A69S, and HTRA1-62A/G) that have been significantly related to response. Among them, the ARMS2 A69S variant is assessed in our meta-analysis. In conclusion, in order to implement anti-VEGF pharmacogenetics in clinical routines, further studies should be performed, distinguishing physio-pathogenic circumstances between PCV and exudative AMD and the combined effect on treatment response of different genetic variants. Full article
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22 pages, 2032 KiB  
Review
A Review of the Important Role of CYP2D6 in Pharmacogenomics
by Christopher Taylor, Ian Crosby, Vincent Yip, Peter Maguire, Munir Pirmohamed and Richard M. Turner
Genes 2020, 11(11), 1295; https://doi.org/10.3390/genes11111295 - 30 Oct 2020
Cited by 125 | Viewed by 14223
Abstract
Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small [...] Read more.
Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, CYP2D6 genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside. Full article
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10 pages, 684 KiB  
Review
Digital Health Applications for Pharmacogenetic Clinical Trials
by Hetanshi Naik, Latha Palaniappan, Euan A. Ashley and Stuart A. Scott
Genes 2020, 11(11), 1261; https://doi.org/10.3390/genes11111261 - 26 Oct 2020
Cited by 7 | Viewed by 2968
Abstract
Digital health (DH) is the use of digital technologies and data analytics to understand health-related behaviors and enhance personalized clinical care. DH is increasingly being used in clinical trials, and an important field that could potentially benefit from incorporating DH into trial design [...] Read more.
Digital health (DH) is the use of digital technologies and data analytics to understand health-related behaviors and enhance personalized clinical care. DH is increasingly being used in clinical trials, and an important field that could potentially benefit from incorporating DH into trial design is pharmacogenetics. Prospective pharmacogenetic trials typically compare a standard care arm to a pharmacogenetic-guided therapeutic arm. These trials often require large sample sizes, are challenging to recruit into, lack patient diversity, and can have complicated workflows to deliver therapeutic interventions to both investigators and patients. Importantly, the use of DH technologies could mitigate these challenges and improve pharmacogenetic trial design and operation. Some DH use cases include (1) automatic electronic health record-based patient screening and recruitment; (2) interactive websites for participant engagement; (3) home- and tele-health visits for patient convenience (e.g., samples for lab tests, physical exams, medication administration); (4) healthcare apps to collect patient-reported outcomes, adverse events and concomitant medications, and to deliver therapeutic information to patients; and (5) wearable devices to collect vital signs, electrocardiograms, sleep quality, and other discrete clinical variables. Given that pharmacogenetic trials are inherently challenging to conduct, future pharmacogenetic utility studies should consider implementing DH technologies and trial methodologies into their design and operation. Full article
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14 pages, 1743 KiB  
Review
Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT
by Pierre-Olivier Harmand and Jérôme Solassol
Genes 2020, 11(10), 1212; https://doi.org/10.3390/genes11101212 - 16 Oct 2020
Cited by 14 | Viewed by 5382
Abstract
Chronic inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. Both are characterized by inflammation of part of the digestive tract lining. Azathioprine (AZA) is a well-known immunosuppressant that has been known for many years for its ability to provide long-term disease [...] Read more.
Chronic inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. Both are characterized by inflammation of part of the digestive tract lining. Azathioprine (AZA) is a well-known immunosuppressant that has been known for many years for its ability to provide long-term disease remission in IBDs, but has important side effects, most of which are related to a single nucleotide polymorphism in the gene for thiopurine methyltransferase (TPMT), which ensures the degradation and efficacy of AZA. Since a direct correlation between TPMT gene polymorphisms and the haematological toxicity of the AZA treatment has been widely demonstrated, TPMT genotyping has been made necessary prior to any introduction of AZA. The monitoring of thiopurine metabolites presents one of the factors that limit wide adaptation of these thiopurines in clinical practice. Thus, identifying patients with asymmetric metabolism could help clinicians provide an ideal treatment recommendation to improve response and reduce adverse effects. Here, we review the role of AZA in the treatment of IBD and discuss the usefulness of TPMT genotyping to guide clinical decision-making. In addition, we report the identification of a new molecular alteration, never described, TPMT mutation affecting the TPMT activity and responsible for deleterious side effects in a clinical case of a 20-year-old woman patient. Full article
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Review
Comparison of the Impact of Pharmacogenetic Variability on the PK of Slow Release and Immediate Release Tacrolimus Formulations
by Teun van Gelder, Oumaima Etsouli, Dirk Jan Moes and Jesse J. Swen
Genes 2020, 11(10), 1205; https://doi.org/10.3390/genes11101205 - 15 Oct 2020
Cited by 7 | Viewed by 2669
Abstract
Tacrolimus-modified release formulations allow for once-daily dosing, and adherence is better compared to the twice-daily immediate release formulation. When patients are switched from one formulation to another, variable changes in drug concentrations are observed. Current data suggest that the changes in drug exposure [...] Read more.
Tacrolimus-modified release formulations allow for once-daily dosing, and adherence is better compared to the twice-daily immediate release formulation. When patients are switched from one formulation to another, variable changes in drug concentrations are observed. Current data suggest that the changes in drug exposure are larger in patients who express the CYP3A5 enzyme (CYP3A5 *1/*3 or *1/*1) compared to nonexpressers (CYP3A5*3/*3). Possibly, these differences are due to the fact that in the upper region of the small intestine CYP3A activity is higher, and that this expression of CYP3A decreases towards the more distal parts of the gut. Modified release formulations may therefore be subject to a less presystemic metabolism. However, the full implications of pharmacogenetic variants affecting the expression and function of drug transporters in the gut wall and of enzymes involved in phase I and phase II metabolism on the different formulations are incompletely understood, and additional studies are required. Conclusions: In all patients in whom the formulation of tacrolimus is changed, drug levels need to be checked to avoid clinically relevant under- or overexposure. In patients with the CYP3A5 expresser genotype, this recommendation is even more important, as changes in drug exposure can be expected. Full article
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