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Pharmacogenomics and Personalized Medicine
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Pharmacogenomics and Personalized Medicine

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 (31 January 2019) | Viewed by 62496

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Erika Cecchin

E-Mail Website
Guest Editor
IRCCS Centro Di Riferimento Oncologico Aviano, Experimental and Clinical Pharmacology Unit, Aviano, Italy
Interests: pharmacogenetics and pharmacogenomics; anti-cancer drug pharmacology
Special Issues, Collections and Topics in MDPI journals
Dr. Gabriele Stocco

E-Mail Website
Guest Editor
Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
Interests: pharmacogenomics; pediatric patients; acute lymphoblastic leukemia; inflammatory bowel disease; juvenile idiopathic arthritis; antimetabolites; anti-TNF agents; epigenetics; pharmacokinetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Precision medicine has the ultimate goal to exactly match each therapeutic intervention with the patient’s molecular profile. Pharmacogenomics is one of the emerging approaches to the problem, tailoring drug selection and dosing based on the patient’s genetic features. In recent years, several pharmacogenetic guidelines have been published by international scientific consortia, but the up-take in the clinical practice is still poor. Many international coordinated efforts are ongoing to overcome existing barriers to pharmacogenomic implementation. On the other hand, existing validated pharmacogenomic markers can explain only a minor part of the observed clinical variability in therapeutic outcomes. New investigational approaches are warranted, including the study of the pharmacogenomic role of immune system genetics and of previously-neglected rare genetic variants, reported to account for a large part of the inter-individual variability in drug metabolism.

In this Special Issue, we welcome reviews, new methods, and original articles covering many aspects of pharmacogenomics. These include, but are not limited to, clinical implementation of pharmacogenomics in clinical practice, development of tools or infrastructure to support this process, research of new pharmacogenomics markers to increase drug efficacy and safety, the role of immunogenetics in the precision medicine field, the impact of rare genetic variants in the pharmacogenomics, and innovative models for pharmacogenomic studies. We look forward to your contributions.

Dr. Erika Cecchin
Dr. Gabriele Stocco
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Pharmacogenomics
  • Precision medicine
  • Implementation
  • Genetic markers
  • Rare variants
  • Innovative models

Published Papers (12 papers)

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Editorial

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5 pages, 183 KiB  
Editorial
Pharmacogenomics and Personalized Medicine
by Erika Cecchin and Gabriele Stocco
Genes 2020, 11(6), 679; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11060679 - 22 Jun 2020
Cited by 34 | Viewed by 7053
Abstract
Pharmacogenomics is one of the emerging approaches to precision medicine, tailoring drug selection and dosing to the patient’s genetic features. In recent years, several pharmacogenetic guidelines have been published by international scientific consortia, but the uptake in clinical practice is still poor. Many [...] Read more.
Pharmacogenomics is one of the emerging approaches to precision medicine, tailoring drug selection and dosing to the patient’s genetic features. In recent years, several pharmacogenetic guidelines have been published by international scientific consortia, but the uptake in clinical practice is still poor. Many coordinated international efforts are ongoing in order to overcome the existing barriers to pharmacogenomic implementation. On the other hand, existing validated pharmacogenomic markers can explain only a minor part of the observed clinical variability in the therapeutic outcome. New investigational approaches are warranted, including the study of the pharmacogenomic role of the immune system genetics and of previously neglected rare genetic variants, reported to account for a large part of the inter-individual variability in drug metabolism. In this Special Issue, we collected a series of articles covering many aspects of pharmacogenomics. These include clinical implementation of pharmacogenomics in clinical practice, development of tools or infrastractures to support this process, research of new pharmacogenomics markers to increase drug efficacy and safety, and the impact of rare genetic variants in pharmacogenomics. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)

Research

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16 pages, 3701 KiB  
Article
Focal Recurrent Copy Number Alterations Characterize Disease Relapse in High Grade Serous Ovarian Cancer Patients with Good Clinical Prognosis: A Pilot Study
by Matteo Dugo, Andrea Devecchi, Loris De Cecco, Erika Cecchin, Delia Mezzanzanica, Marialuisa Sensi and Marina Bagnoli
Genes 2019, 10(9), 678; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10090678 - 05 Sep 2019
Cited by 9 | Viewed by 3411
Abstract
High grade serous ovarian cancer (HGSOC) retains high molecular heterogeneity and genomic instability, which currently limit the treatment opportunities. HGSOC patients receiving complete cytoreduction (R0) at primary surgery and platinum-based therapy may unevenly experience early disease relapse, in spite of their clinically favorable [...] Read more.
High grade serous ovarian cancer (HGSOC) retains high molecular heterogeneity and genomic instability, which currently limit the treatment opportunities. HGSOC patients receiving complete cytoreduction (R0) at primary surgery and platinum-based therapy may unevenly experience early disease relapse, in spite of their clinically favorable prognosis. To identify distinctive traits of the genomic landscape guiding tumor progression, we focused on the R0 patients of The Cancer Genome Atlas (TCGA) ovarian serous cystadenocarcinoma (TCGA-OV) dataset and classified them according to their time to relapse (TTR) from surgery. We included in the study two groups of R0-TCGA patients experiencing substantially different outcome: Resistant (R; TTR ≤ 12 months; n = 11) and frankly Sensitive (fS; TTR ≥ 24 months; n = 16). We performed an integrated clinical, RNA-Sequencing, exome and somatic copy number alteration (sCNA) data analysis. No significant differences in mutational landscape were detected, although the lack of BRCA-related mutational signature characterized the R group. Focal sCNA analysis showed a higher frequency of amplification in R group and deletions in fS group respectively, involving cytobands not commonly detected by recurrent sCNA analysis. Functional analysis of focal sCNA with a concordantly altered gene expression identified in R group a gain in Notch, and interferon signaling and fatty acid metabolism. We are aware of the constraints related to the low number of OC cases analyzed. It is worth noting, however, that the sCNA identified in this exploratory analysis and characterizing Pt-resistance are novel, deserving validation in a wider cohort of patients achieving complete surgical debulking. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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17 pages, 11769 KiB  
Article
Quantifying Risk Pathway Crosstalk Mediated by miRNA to Screen Precision drugs for Breast Cancer Patients
by Yingqi Xu, Shuting Lin, Hongying Zhao, Jingwen Wang, Chunlong Zhang, Qun Dong, Congxue Hu, Desi Shang, Li Wang and Yanjun Xu
Genes 2019, 10(9), 657; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10090657 - 28 Aug 2019
Cited by 3 | Viewed by 2706
Abstract
Breast cancer has become the most common cancer that leads to women’s death. Breast cancer is a complex, highly heterogeneous disease classified into various subtypes based on histological features, which determines the therapeutic options. System identification of effective drugs for each subtype remains [...] Read more.
Breast cancer has become the most common cancer that leads to women’s death. Breast cancer is a complex, highly heterogeneous disease classified into various subtypes based on histological features, which determines the therapeutic options. System identification of effective drugs for each subtype remains challenging. In this work, we present a computational network biology approach to screen precision drugs for different breast cancer subtypes by considering the impact intensity of candidate drugs on the pathway crosstalk mediated by miRNAs. Firstly, we constructed and analyzed the subtype-specific risk pathway crosstalk networks mediated by miRNAs. Then, we evaluated 36 Food and Drug Administration (FDA)-approved anticancer drugs by quantifying their effects on these subtype-specific pathway crosstalk networks and combining with survival analysis. Finally, some first-line treatments of breast cancer, such as Paclitaxel and Vincristine, were optimized for each subtype. In particular, we performed precision screening of subtype-specific therapeutic drugs and also confirmed some novel drugs suitable for breast cancer treatment. For example, Sorafenib was applicable for the basal subtype treatment, Irinotecan was optimum for Her2 subtype treatment, Vemurafenib was suitable for the LumA subtype treatment, and Vorinostat could apply to LumB subtype treatment. In addition, the mechanism of these optimal therapeutic drugs in each subtype of breast cancer was further dissected. In summary, our study offers an effective way to screen precision drugs for various breast cancer subtype treatments. We also dissected the mechanism of optimal therapeutic drugs, which may provide novel insight into the precise treatment of cancer and promote researches on the mechanisms of action of drugs. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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16 pages, 2348 KiB  
Article
Pharmacist-Initiated Pre-Emptive Pharmacogenetic Panel Testing with Clinical Decision Support in Primary Care: Record of PGx Results and Real-World Impact
by Cathelijne H. van der Wouden, Paul C. D. Bank, Kübra Özokcu, Jesse J. Swen and Henk-Jan Guchelaar
Genes 2019, 10(6), 416; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10060416 - 29 May 2019
Cited by 53 | Viewed by 5034
Abstract
Logistics and (cost-)effectiveness of pharmacogenetic (PGx)-testing may be optimized when delivered through a pre-emptive panel-based approach, within a clinical decision support system (CDSS). Here, clinical recommendations are automatically deployed by the CDSS when a drug-gene interaction (DGI) is encountered. However, this requires record [...] Read more.
Logistics and (cost-)effectiveness of pharmacogenetic (PGx)-testing may be optimized when delivered through a pre-emptive panel-based approach, within a clinical decision support system (CDSS). Here, clinical recommendations are automatically deployed by the CDSS when a drug-gene interaction (DGI) is encountered. However, this requires record of PGx-panel results in the electronic medical record (EMR). Several studies indicate promising clinical utility of panel-based PGx-testing in polypharmacy and psychiatry, but is undetermined in primary care. Therefore, we aim to quantify both the feasibility and the real-world impact of this approach in primary care. Within a prospective pilot study, community pharmacists were provided the opportunity to request a panel of eight pharmacogenes to guide drug dispensing within a CDSS for 200 primary care patients. In this side-study, this cohort was cross-sectionally followed-up after a mean of 2.5-years. PGx-panel results were successfully recorded in 96% and 68% of pharmacist and general practitioner (GP) EMRs, respectively. This enabled 97% of patients to (re)use PGx-panel results for at least one, and 33% for up to four newly initiated prescriptions with possible DGIs. A total of 24.2% of these prescriptions had actionable DGIs, requiring pharmacotherapy adjustment. Healthcare utilization seemed not to vary among those who did and did not encounter a DGI. Pre-emptive panel-based PGx-testing is feasible and real-world impact is substantial in primary care. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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17 pages, 567 KiB  
Article
Outcome Definition Influences the Relationship between Genetic Polymorphisms of ERCC1, ERCC2, SLC22A2 and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients
by Zulfan Zazuli, Leila S. Otten, Britt I. Drögemöller, Mara Medeiros, Jose G. Monzon, Galen E. B. Wright, Christian K. Kollmannsberger, Philippe L. Bedard, Zhuo Chen, Karen A. Gelmon, Nicole McGoldrick, Abhijat Kitchlu, Susanne J. H. Vijverberg, Rosalinde Masereeuw, Colin J. D. Ross, Geoffrey Liu, Bruce C. Carleton and Anke H. Maitland-van der Zee
Genes 2019, 10(5), 364; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10050364 - 10 May 2019
Cited by 21 | Viewed by 4538
Abstract
Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than [...] Read more.
Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009–2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI: 0.08–0.70; p = 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI: 1.96–9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI: 1.69–15.16; p = 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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12 pages, 2408 KiB  
Article
MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia
by Neha S. Bhise, Abdelrahman H. Elsayed, Xueyuan Cao, Stanley Pounds and Jatinder K. Lamba
Genes 2019, 10(4), 319; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10040319 - 24 Apr 2019
Cited by 6 | Viewed by 3933
Abstract
Nucleoside analog, cytarabine (ara-C) is the mainstay of acute myeloid leukemia (AML) chemotherapy. Cytarabine and other nucleoside analogs require activation to the triphosphate form (ara-CTP). Intracellular ara-CTP levels demonstrate significant inter-patient variation and have been related to therapeutic response in AML patients. Inter-patient [...] Read more.
Nucleoside analog, cytarabine (ara-C) is the mainstay of acute myeloid leukemia (AML) chemotherapy. Cytarabine and other nucleoside analogs require activation to the triphosphate form (ara-CTP). Intracellular ara-CTP levels demonstrate significant inter-patient variation and have been related to therapeutic response in AML patients. Inter-patient variation in expression levels of drug transporters or enzymes involved in the activation or inactivation of cytarabine and other analogs is a prime mechanism contributing to development of drug resistance. Since microRNAs (miRNAs) are known to regulate gene-expression, the aim of this study was to identify miRNAs involved in regulation of messenger RNA expression levels of cytarabine pathway genes. We evaluated miRNA and gene-expression levels of cytarabine metabolic pathway genes in 8 AML cell lines and The Cancer Genome Atlas (TCGA) data base. Using correlation analysis and functional validation experiments, our data demonstrates that miR-34a-5p and miR-24-3p regulate DCK, an enzyme involved in activation of cytarabine and DCTD, an enzyme involved in metabolic inactivation of cytarabine expression, respectively. Further our results from gel shift assays confirmed binding of these mRNA-miRNA pairs. Our results show miRNA mediated regulation of gene expression levels of nucleoside metabolic pathway genes can impact interindividual variation in expression levels which in turn may influence treatment outcomes. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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12 pages, 1093 KiB  
Article
Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants
by Marianna Lucafò, Gabriele Stocco, Stefano Martelossi, Diego Favretto, Raffaella Franca, Noelia Malusà, Angela Lora, Matteo Bramuzzo, Samuele Naviglio, Erika Cecchin, Giuseppe Toffoli, Alessandro Ventura and Giuliana Decorti
Genes 2019, 10(4), 277; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10040277 - 04 Apr 2019
Cited by 13 | Viewed by 3346
Abstract
The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months [...] Read more.
The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn’s disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio (LME p = 0.041) and 30% decrease in clinical efficacy (LME p = 0.0031). GSTA1 variant (12.8% of patients) showed a trend (p = 0.046, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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13 pages, 1167 KiB  
Article
FARMAPRICE: A Pharmacogenetic Clinical Decision Support System for Precise and Cost-Effective Therapy
by Rossana Roncato, Lisa Dal Cin, Silvia Mezzalira, Francesco Comello, Elena De Mattia, Alessia Bignucolo, Lorenzo Giollo, Simone D’Errico, Antonio Gulotta, Luca Emili, Vincenzo Carbone, Michela Guardascione, Luisa Foltran, Giuseppe Toffoli and Erika Cecchin
Genes 2019, 10(4), 276; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10040276 - 04 Apr 2019
Cited by 10 | Viewed by 4563
Abstract
Pharmacogenetic (PGx) guidelines for the precise dosing and selection of drugs remain poorly implemented in current clinical practice. Among the barriers to the implementation process is the lack of clinical decision support system (CDSS) tools to aid health providers in managing PGx information [...] Read more.
Pharmacogenetic (PGx) guidelines for the precise dosing and selection of drugs remain poorly implemented in current clinical practice. Among the barriers to the implementation process is the lack of clinical decision support system (CDSS) tools to aid health providers in managing PGx information in the clinical context. The present study aimed to describe the first Italian endeavor to develop a PGx CDSS, called FARMAPRICE. FARMAPRICE prototype was conceived for integration of patient molecular data into the clinical prescription process in the Italian Centro di Riferimento Oncologico (CRO)-Aviano Hospital. It was developed through a coordinated partnership between two high-tech companies active in the computerization of the Italian healthcare system. Introducing FARMAPRICE into the clinical setting can aid physicians in prescribing the most efficacious and cost-effective pharmacological therapy available. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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13 pages, 542 KiB  
Article
Diagnostic and Therapeutic Strategies for Fluoropyrimidine Treatment of Patients Carrying Multiple DPYD Variants
by Carin A. T. C. Lunenburg, Linda M. Henricks, André B. P. Van Kuilenburg, Ron H. J. Mathijssen, Jan H. M. Schellens, Hans Gelderblom, Henk-Jan Guchelaar and Jesse J. Swen
Genes 2018, 9(12), 585; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9120585 - 28 Nov 2018
Cited by 7 | Viewed by 11186
Abstract
DPYD genotyping prior to fluoropyrimidine treatment is increasingly implemented in clinical care. Without phasing information (i.e., allelic location of variants), current genotype-based dosing guidelines cannot be applied to patients carrying multiple DPYD variants. The primary aim of this study is to examine diagnostic [...] Read more.
DPYD genotyping prior to fluoropyrimidine treatment is increasingly implemented in clinical care. Without phasing information (i.e., allelic location of variants), current genotype-based dosing guidelines cannot be applied to patients carrying multiple DPYD variants. The primary aim of this study is to examine diagnostic and therapeutic strategies for fluoropyrimidine treatment of patients carrying multiple DPYD variants. A case series of patients carrying multiple DPYD variants is presented. Different genotyping techniques were used to determine phasing information. Phenotyping was performed by dihydropyrimidine dehydrogenase (DPD) enzyme activity measurements. Publicly available databases were queried to explore the frequency and phasing of variants of patients carrying multiple DPYD variants. Four out of seven patients carrying multiple DPYD variants received a full dose of fluoropyrimidines and experienced severe toxicity. Phasing information could be retrieved for four patients. In three patients, variants were located on two different alleles, i.e., in trans. Recommended dose reductions based on the phased genotype differed from the phenotype-derived dose reductions in three out of four cases. Data from publicly available databases show that the frequency of patients carrying multiple DPYD variants is low (< 0.2%), but higher than the frequency of the commonly tested DPYD*13 variant (0.1%). Patients carrying multiple DPYD variants are at high risk of developing severe toxicity. Additional analyses are required to determine the correct dose of fluoropyrimidine treatment. In patients carrying multiple DPYD variants, we recommend that a DPD phenotyping assay be carried out to determine a safe starting dose. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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13 pages, 1442 KiB  
Article
Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy
by Laith N. AL-Eitan, Ayah Y. Almasri and Rame H. Khasawneh
Genes 2018, 9(12), 578; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9120578 - 27 Nov 2018
Cited by 27 | Viewed by 4419
Abstract
Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) [...] Read more.
Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) within the CYP2C9 and VKORC1 genes. This study confirmed a genetic association of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472 SNPs with warfarin sensitivity. This study also found an association between CYP2C9 and VKORC1 genetic haplotype blocks and warfarin sensitivity. The initial warfarin dose was significantly related to the CYP2C9*3 polymorphism and the four VKORC1 SNPs (p < 0.001). There were significant associations between rs4086116 SNP and TAT haplotype within CYP2C9 gene and rs17708472 SNP and CCGG haplotype within VKORC1 gene and warfarin responsiveness. However, possessing a VKORC1 variant allele was found to affect the international normalized ratio (INR) outcomes during initiation of warfarin therapy. In contrast, there was a loose association between the CYP2C9 variant and INR measurements. These findings can enhance the current understanding of the great variability in response to warfarin treatment in Arabs. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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Review

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25 pages, 376 KiB  
Review
Pharmacogenetics in the Treatment of Cardiovascular Diseases and Its Current Progress Regarding Implementation in the Clinical Routine
by Cristina Lucía Dávila-Fajardo, Xando Díaz-Villamarín, Alba Antúnez-Rodríguez, Ana Estefanía Fernández-Gómez, Paloma García-Navas, Luis Javier Martínez-González, José Augusto Dávila-Fajardo and José Cabeza Barrera
Genes 2019, 10(4), 261; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10040261 - 01 Apr 2019
Cited by 11 | Viewed by 4941
Abstract
There is a special interest in the implementation of pharmacogenetics in clinical practice, although there are some barriers that are preventing this integration. A large part of these pharmacogenetic tests are focused on drugs used in oncology and psychiatry fields and for antiviral [...] Read more.
There is a special interest in the implementation of pharmacogenetics in clinical practice, although there are some barriers that are preventing this integration. A large part of these pharmacogenetic tests are focused on drugs used in oncology and psychiatry fields and for antiviral drugs. However, the scientific evidence is also high for other drugs used in other medical areas, for example, in cardiology. In this article, we discuss the evidence and guidelines currently available on pharmacogenetics for clopidogrel, warfarin, acenocoumarol, and simvastatin and its implementation in daily clinical practice. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
31 pages, 1010 KiB  
Review
Pharmacogenomic and Pharmacotranscriptomic Profiling of Childhood Acute Lymphoblastic Leukemia: Paving the Way to Personalized Treatment
by Sonja Pavlovic, Nikola Kotur, Biljana Stankovic, Branka Zukic, Vladimir Gasic and Lidija Dokmanovic
Genes 2019, 10(3), 191; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10030191 - 01 Mar 2019
Cited by 29 | Viewed by 5930
Abstract
Personalized medicine is focused on research disciplines which contribute to the individualization of therapy, like pharmacogenomics and pharmacotranscriptomics. Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. It is one of the pediatric malignancies with the highest cure rate, but still [...] Read more.
Personalized medicine is focused on research disciplines which contribute to the individualization of therapy, like pharmacogenomics and pharmacotranscriptomics. Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. It is one of the pediatric malignancies with the highest cure rate, but still a lethal outcome due to therapy accounts for 1–3% of deaths. Further improvement of treatment protocols is needed through the implementation of pharmacogenomics and pharmacotranscriptomics. Emerging high-throughput technologies, including microarrays and next-generation sequencing, have provided an enormous amount of molecular data with the potential to be implemented in childhood ALL treatment protocols. In the current review, we summarized the contribution of these novel technologies to the pharmacogenomics and pharmacotranscriptomics of childhood ALL. We have presented data on molecular markers responsible for the efficacy, side effects, and toxicity of the drugs commonly used for childhood ALL treatment, i.e., glucocorticoids, vincristine, asparaginase, anthracyclines, thiopurines, and methotrexate. Big data was generated using high-throughput technologies, but their implementation in clinical practice is poor. Research efforts should be focused on data analysis and designing prediction models using machine learning algorithms. Bioinformatics tools and the implementation of artificial i Lack of association of the CEP72 rs924607 TT genotype with intelligence are expected to open the door wide for personalized medicine in the clinical practice of childhood ALL. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
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