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Special Issue "Pharmacogenetics and Personalized Medicine 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 30 September 2020.

Special Issue Editors

Dr. Gloria Ravegnini
E-Mail
Guest Editor
L’Oreal-UNESCO for Women and Science, Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, Bologna, Italy
Special Issues and Collections in MDPI journals
Prof. Dr. Sabrina Angelini
E-Mail Website
Guest Editor
Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio, n 48, IT-40126, Bologna, Italy
Interests: Pharmacogenetic studies; biomarkers of effect and susceptibility in populations exposed to pollutants; epidemiological studies in populations exposed to ionizing radiation
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

The accomplishment of the Human Genome Project, followed by the availability of high-throughput technologies, has led to a dramatic change in biomedical research. In particular, the emergency of new tools for genome analysis has contributed to our knowledge of the molecular mechanisms defining pathways that might reasonably influence therapy and response. This knowledge has paved the way to the development of personalized medicine, which aims to determine unique individuals’ molecular characteristics, select better treatments, and reduce possible drug adverse reactions. Despite personalized medicine being an attractive strategy in disease treatment (there is a great interest in the development of powerful approaches to be incorporated into clinical practice), persistent gaps do exist between published research and clinical application.

Topics of this Special Issue include, but are not limited to:

  • Genetic variability related to drug toxicity and efficacy
  • Genomic and proteomic profiling
  • ncRNA profiles to predict prognosis and outcome
  • Liquid biopsy
  • Microbiome and drug response
  • Methylation profiles to predict prognosis and outcome
  • Multi-omics approaches to the study of treatment response
  • Epigenetic changes as determinants of drug response and resistance
  • Novel genomic targets for drug development

Pharmacometabonomics as a promising tool for monitoring therapy effectiveness on the basis of mathematical models of pre-dose metabolite profiles

Dr. Gloria Ravegnini
Prof. Dr. Sabrina Angelini
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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • pharmacogenetics and pharmacogenomics
  • personalized medicine
  • lncRNA
  • miRNA
  • circRNA
  • methylation
  • epigenetics
  • microbiome
  • liquid biopsy
  • circulating biomarkers

Published Papers (7 papers)

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Research

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Open AccessArticle
Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
Int. J. Mol. Sci. 2020, 21(7), 2308; https://doi.org/10.3390/ijms21072308 (registering DOI) - 26 Mar 2020
Abstract
Although several pharmacogenetic (PGx) predispositions affecting drug efficacy and safety are well established, drug selection and dosing as well as clinical trials are often performed in a non-pharmacogenetically-stratified manner, ultimately burdening healthcare systems. Pre-emptive PGx testing offers a solution which is often performed [...] Read more.
Although several pharmacogenetic (PGx) predispositions affecting drug efficacy and safety are well established, drug selection and dosing as well as clinical trials are often performed in a non-pharmacogenetically-stratified manner, ultimately burdening healthcare systems. Pre-emptive PGx testing offers a solution which is often performed using microarrays or targeted gene panels, testing for common/known PGx variants. However, as an added value, whole-genome sequencing (WGS) could detect not only disease-causing but also pharmacogenetically-relevant variants in a single assay. Here, we present our WGS-based pipeline that extends the genetic testing of Mendelian diseases with PGx profiling, enabling the detection of rare/novel PGx variants as well. From our in-house WGS (PCR-free 60× PE150) data of 547 individuals we extracted PGx variants with drug-dosing recommendations of the Dutch Pharmacogenetics Working Group (DPWG). Furthermore, we explored the landscape of DPWG pharmacogenes in gnomAD and our in-house cohort as well as compared bioinformatic tools for WGS-based structural variant detection in CYP2D6. We show that although common/known PGx variants comprise the vast majority of detected DPWG pharmacogene alleles, for better precision medicine, PGx testing should move towards WGS-based approaches. Indeed, WGS-based PGx profiling is not only feasible and future-oriented but also the most comprehensive all-in-one approach without generating significant additional costs. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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Open AccessArticle
Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients
Int. J. Mol. Sci. 2020, 21(3), 858; https://doi.org/10.3390/ijms21030858 - 29 Jan 2020
Abstract
Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may [...] Read more.
Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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Open AccessArticle
Clinical and Genetic Factors Associated with Resistance to Treatment in Patients with Schizophrenia: A Case-Control Study
Int. J. Mol. Sci. 2019, 20(19), 4753; https://doi.org/10.3390/ijms20194753 - 25 Sep 2019
Cited by 1
Abstract
Objectives: To assess clinical and genetic factors affecting response to treatment in a sample of patients with schizophrenia (treatment-resistant patients versus treatment responders). We also aimed at examining if these factors are different when we consider two different resistance classifications (the positive and [...] Read more.
Objectives: To assess clinical and genetic factors affecting response to treatment in a sample of patients with schizophrenia (treatment-resistant patients versus treatment responders). We also aimed at examining if these factors are different when we consider two different resistance classifications (the positive and negative syndrome scale, PANSS and the brief psychiatric rating scale, BPRS). Material and Methods: A case-control study included treatment-resistant patients and good responders. Patients were stratified in two groups based on the established criteria for treatment-resistant schizophrenia using BPRS and PANSS. The study was approved by the ethical committees (references: CEHDF1017; HPC-017-2017) and all patients/legal representatives gave their written consent. Clinical factors were assessed. DNA was obtained using a buccal swab and genotyping for OPRM1, COMT, DRD2 et MTHFR genes using the Lightcycler® (Roche). Results: Some discrepancies between the BPRS and PANSS definitions were noted in our study when assessing the patients’ psychopathological symptoms and response to treatment. The multivariable analysis, taking the presence versus absence of treatment resistance as the dependent variable, showed that that family history of schizophrenia, university studies, time since the beginning of treatment and chlorpromazine equivalent dose as well as the COMT gene are associated with resistance to treatment. In addition, a gender-related difference was noted for COMT SNP; men with at least one Met allele were more prone to be resistant to treatment than Val/Val patients. Conclusion: Uncovering the clinical and genetic factors associated with resistance to treatment could help us better treat our schizophrenic patients in a concept of personalized medicine. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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Open AccessArticle
Association between Polymorphisms of OCT1 and Metabolic Response to Metformin in Women with Polycystic Ovary Syndrome
Int. J. Mol. Sci. 2019, 20(7), 1720; https://doi.org/10.3390/ijms20071720 - 07 Apr 2019
Cited by 3
Abstract
Insulin-sensitizer treatment with metformin is widely used in polycystic ovary syndrome (PCOS). However, the treatment effectiveness shows individual differences in PCOS patients. Organic cation transporter (OCT) 1 and 2 have been reported to mediate metformin transport in the liver and kidney, respectively. In [...] Read more.
Insulin-sensitizer treatment with metformin is widely used in polycystic ovary syndrome (PCOS). However, the treatment effectiveness shows individual differences in PCOS patients. Organic cation transporter (OCT) 1 and 2 have been reported to mediate metformin transport in the liver and kidney, respectively. In this study, we investigated the association between the polymorphisms of OCT1 and OCT2 and the treatment effectiveness of metformin in PCOS patients. The single nucleotide polymorphisms (SNPs) of OCT1 (rs683369 and rs628031) and OCT2 (rs316019) were analyzed in 87 PCOS and 113 control women. Oral glucose tolerance tests (OGTTs), which represented metformin treatment response, were conducted at the start of treatment and after six-month treatment. The results demonstrated that the SNP frequencies of OCT1 and OCT2 were not associated with PCOS pathophysiology, and that the polymorphisms of OCT1 and OCT2 were not associated with the OGTT parameters at baseline. However, PCOS patients with the G allele of OCT1 rs683369 and/or with the A allele of OCT1 rs628031 had increased insulin sensitivity compared to those with wild-type genotype after receiving metformin treatment. Moreover, the interactions of metformin*SNP were significant in both OCT1 rs683369 (p < 0.001) and rs628031 (p = 0.001) during the treatment period. Taken together, genetic polymorphisms of OCT1 contributed to different metformin treatment responses, and further study is needed to establish personalized treatment programs using a pharmacogenomic algorithm approach in PCOS patients. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)

Review

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Open AccessReview
Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment against an Aggressive Tumor
Int. J. Mol. Sci. 2020, 21(6), 1991; https://doi.org/10.3390/ijms21061991 - 14 Mar 2020
Abstract
Serrated adenocarcinoma (SAC) is a tumor recognized by the WHO as a histological subtype accounting for around 9% of colorectal carcinomas. Compared to conventional carcinomas, SACs are characterized by a worse prognosis, weak development of the immune response, an active invasive front and [...] Read more.
Serrated adenocarcinoma (SAC) is a tumor recognized by the WHO as a histological subtype accounting for around 9% of colorectal carcinomas. Compared to conventional carcinomas, SACs are characterized by a worse prognosis, weak development of the immune response, an active invasive front and a frequent resistance to targeted therapy due to a high occurrence of KRAS or BRAF mutation. Nonetheless, several high-throughput studies have recently been carried out unveiling the biology of this cancer and identifying potential molecular targets, favoring a future histologically based treatment. This review revises the current evidence, aiming to propose potential molecular targets and specific treatments for this aggressive tumor. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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Open AccessReview
Circulating-Free DNA Analysis in Hepatocellular Carcinoma: A Promising Strategy to Improve Patients’ Management and Therapy Outcomes
Int. J. Mol. Sci. 2019, 20(21), 5498; https://doi.org/10.3390/ijms20215498 - 05 Nov 2019
Cited by 1
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, representing the third leading cause of cancer-related deaths. HCC genetic characterization at the tumor level has been recently completed, highlighting how a number of genes are frequently mutated in this pathology. Actionable somatic [...] Read more.
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, representing the third leading cause of cancer-related deaths. HCC genetic characterization at the tumor level has been recently completed, highlighting how a number of genes are frequently mutated in this pathology. Actionable somatic mutations found in a HCC tumor may represent targets for innovative drugs as well as prognostic/predictive markers. Nonetheless, surgical or bioptic tissue is hardly accessible in HCC and a single tumor sample is poorly representative of the tumor genetic heterogeneity. In this context, analyzing the circulating cell-free DNA (ccfDNA) and its tumor-derived fraction (ctDNA) could represent a promising strategy of liquid biopsy. Recent data suggested that the fluctuation of the ccfDNA quantity in the plasma of HCC patients could anticipate the detection of tumor progression. The presence of somatic mutations in p53 signaling, Wnt/β-catenin, chromatin remodeling, response to oxidative stress and telomerase maintenance pathways can also be studied in ccfDNA bypassing the need to perform a tumor biopsy. The profiling of ccfDNA fragmentation and the methylation pattern could further improve the clinical management of HCC patients. Performing a dynamic monitoring in the course of systemic treatment with sorafenib or regorafenib is a possible way to provide insights into the resistance mechanism, and to identify predictive and prognostic genetic alterations, helping the clinicians in terms of treatment decision making. This review will discuss the most recent literature data about the use of ccfDNA to monitor and improve the treatment of HCC. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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Open AccessReview
A Systems Biology Approach for Personalized Medicine in Refractory Epilepsy
Int. J. Mol. Sci. 2019, 20(15), 3717; https://doi.org/10.3390/ijms20153717 - 30 Jul 2019
Cited by 1
Abstract
Epilepsy refers to a common chronic neurological disorder that affects all age groups. Unfortunately, antiepileptic drugs are ineffective in about one-third of patients. The complex interindividual variability influences the response to drug treatment rendering the therapeutic failure one of the most relevant problems [...] Read more.
Epilepsy refers to a common chronic neurological disorder that affects all age groups. Unfortunately, antiepileptic drugs are ineffective in about one-third of patients. The complex interindividual variability influences the response to drug treatment rendering the therapeutic failure one of the most relevant problems in clinical practice also for increased hospitalizations and healthcare costs. Recent advances in the genetics and neurobiology of epilepsies are laying the groundwork for a new personalized medicine, focused on the reversal or avoidance of the pathophysiological effects of specific gene mutations. This could lead to a significant improvement in the efficacy and safety of treatments for epilepsy, targeting the biological mechanisms responsible for epilepsy in each individual. In this review article, we focus on the mechanism of the epilepsy pharmacoresistance and highlight the use of a systems biology approach for personalized medicine in refractory epilepsy. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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