Special Issue "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)

Special Issue Editors

Guest Editor
Dr. Erika Cecchin

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

Department of Life Science, Universita degli Studi di Trieste, Trieste, Italy
Website | E-Mail
Interests: molecular strategies; therapy personalization; immunomodulators; anti-cancer agents

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

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Keywords

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

Published Papers (9 papers)

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Research

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Open AccessArticle
Pharmacist-Initiated Pre-Emptive Pharmacogenetic Panel Testing with Clinical Decision Support in Primary Care: Record of PGx Results and Real-World Impact
Received: 29 March 2019 / Revised: 1 May 2019 / Accepted: 8 May 2019 / Published: 29 May 2019
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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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Open AccessArticle
Outcome Definition Influences the Relationship between Genetic Polymorphisms of ERCC1, ERCC2, SLC22A2 and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients
Received: 16 April 2019 / Accepted: 7 May 2019 / Published: 10 May 2019
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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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Open AccessArticle
MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia
Received: 26 March 2019 / Revised: 16 April 2019 / Accepted: 20 April 2019 / Published: 24 April 2019
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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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Open AccessArticle
Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants
Received: 19 February 2019 / Revised: 1 April 2019 / Accepted: 1 April 2019 / Published: 4 April 2019
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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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Open AccessArticle
FARMAPRICE: A Pharmacogenetic Clinical Decision Support System for Precise and Cost-Effective Therapy
Received: 28 February 2019 / Revised: 26 March 2019 / Accepted: 1 April 2019 / Published: 4 April 2019
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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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Open AccessArticle
Diagnostic and Therapeutic Strategies for Fluoropyrimidine Treatment of Patients Carrying Multiple DPYD Variants
Genes 2018, 9(12), 585; https://doi.org/10.3390/genes9120585
Received: 9 November 2018 / Revised: 26 November 2018 / Accepted: 26 November 2018 / Published: 28 November 2018
Cited by 1 | PDF Full-text (542 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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Open AccessArticle
Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy
Genes 2018, 9(12), 578; https://doi.org/10.3390/genes9120578
Received: 15 October 2018 / Revised: 21 November 2018 / Accepted: 21 November 2018 / Published: 27 November 2018
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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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Open AccessReview
Pharmacogenetics in the Treatment of Cardiovascular Diseases and Its Current Progress Regarding Implementation in the Clinical Routine
Received: 8 February 2019 / Revised: 25 March 2019 / Accepted: 26 March 2019 / Published: 1 April 2019
Cited by 1 | PDF Full-text (376 KB) | HTML Full-text | XML Full-text
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)
Open AccessFeature PaperReview
Pharmacogenomic and Pharmacotranscriptomic Profiling of Childhood Acute Lymphoblastic Leukemia: Paving the Way to Personalized Treatment
Received: 4 February 2019 / Revised: 23 February 2019 / Accepted: 25 February 2019 / Published: 1 March 2019
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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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