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Pharmacogenetics and Personalized Medicine

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

Deadline for manuscript submissions: closed (29 May 2015) | Viewed by 120941

Special Issue Editors

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, Collections and Topics in MDPI journals
Dr. Gloria Ravegnini

E-Mail Website
Guest Editor
Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48l, 40126 Bologna, Italy
Interests: pharmacogenetics; pharmacogenomics; epigenetics; miRNAs; liquid biopsy; circulating molecules; cancer
Special Issues, Collections and Topics 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 and select better treatments, and reduce possible drug adverse reactions. Despite personalized medicine being an attractive strategy in disease treatment (and 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 the Special Issue include, but are not limited to:

  • Genetic variability on drug toxicity and efficacy
  • Genomic and proteomic profiling
  • miRNA profiles to predict prognosis and outcome
  • Novel genomic targets for drug development
  • Stem cell as new therapeutic option for untreatable disease
  • Pharmacometabonomics a promising tool for monitoring therapy effectiveness on the basis of mathematical models of pre-dose metabolite profiles

Prof. Dr. Sabrina Angelini
Dr. Gloria Ravegnini
Guest Editors

 

Prof. Dr. Sabrina Angelini Dr. Gloria Ravegnini

Manuscript Submission Information

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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
  • pharmacogenomics
  • pharmacometabonomics
  • genetic variability
  • miRNA

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Published Papers (17 papers)

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Editorial

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160 KiB  
Editorial
Toward Precision Medicine: How Far Is the Goal?
by Gloria Ravegnini and Sabrina Angelini
Int. J. Mol. Sci. 2016, 17(2), 245; https://doi.org/10.3390/ijms17020245 - 17 Feb 2016
Cited by 5 | Viewed by 4436
Abstract
The accomplishment of the Human Genome Project, followed by the availability of high-throughput technologies, has led to an impressive change in biomedical research.[...] Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)

Research

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1147 KiB  
Article
Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation
by Jesus Ruiz, María José Herrero, Virginia Bosó, Juan Eduardo Megías, David Hervás, Jose Luis Poveda, Juan Escrivá, Amparo Pastor, Amparo Solé and Salvador Francisco Aliño
Int. J. Mol. Sci. 2015, 16(9), 20168-20182; https://doi.org/10.3390/ijms160920168 - 25 Aug 2015
Cited by 22 | Viewed by 5780
Abstract
Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 [...] Read more.
Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 and CYP3A5 genes with tacrolimus (Tac) and ABCC2, UGT1A9 and SLCO1B1 genes with mycophenolic acid (MPA), during the first six months after lung transplantation (51 patients). The genotype was correlated to the trough blood drug concentrations corrected for dose and body weight (C0/Dc). The ABCB1 variant in rs1045642 was associated with significantly higher Tac concentration, at six months post-transplantation (CT vs. CC). In the MPA analysis, CT patients in ABCC2 rs3740066 presented significantly lower blood concentrations than CC or TT, three months after transplantation. Other tendencies, confirming previously expected results, were found associated with the rest of studied SNPs. An interesting trend was recorded for the incidence of acute rejection according to NOD2/CARD15 rs2066844 (CT: 27.9%; CC: 12.5%). Relevant SNPs related to Tac and MPA in other solid organ transplants also seem to be related to the efficacy and safety of treatment in the complex setting of lung transplantation. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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705 KiB  
Article
Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration
by Francesco Parmeggiani, Ciro Costagliola, Francesco Semeraro, Mario R Romano, Michele Rinaldi, Carla Enrica Gallenga, Maria Luisa Serino, Carlo Incorvaia, Sergio D’Angelo, Katia De Nadai, Roberto Dell’Omo, Andrea Russo, Donato Gemmati and Paolo Perri
Int. J. Mol. Sci. 2015, 16(8), 19796-19811; https://doi.org/10.3390/ijms160819796 - 20 Aug 2015
Cited by 7 | Viewed by 5345
Abstract
Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic [...] Read more.
Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic therapy with verteporfin (PDT-V) is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985) has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1) total number of photodynamic treatments; and (2) change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype) received a higher number of photodynamic treatments than patients without it (GG wild-type genotype) (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively). Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively). The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of both anti-thrombophilic effects due to FXIII-A G185T variant and photo-thrombotic action of PDT-V toward CNV provides several clues about the rationale of this intriguing pharmacogenetic correlation. Further investigations are warranted to outline the appropriate paradigm for guiding PDT-V utilization in the course of the combined therapeutic protocol for neovascular macular degeneration. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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1946 KiB  
Article
MicroRNA Profiling of B Cell Subsets from Systemic Lupus Erythematosus Patients Reveals Promising Novel Biomarkers
by Isabelle Duroux-Richard, Jimena Cuenca, Clara Ponsolles, Alejandro Badilla Piñeiro, Fernando Gonzalez, Christine Roubert, Roser Areny, Rosa Chea, Jacqueline Pefaur, Yves-Marie Pers, Fernando E. Figueroa, Christian Jorgensen, Maroun Khoury and Florence Apparailly
Int. J. Mol. Sci. 2015, 16(8), 16953-16965; https://doi.org/10.3390/ijms160816953 - 27 Jul 2015
Cited by 34 | Viewed by 6717
Abstract
MicroRNAs control the differentiation and function of B cells, which are considered key elements in the pathogenesis of systemic lupus erythematosus (SLE). However, a common micro(mi)RNA signature has not emerged since published data includes patients of variable ethnic background, type of disease, and [...] Read more.
MicroRNAs control the differentiation and function of B cells, which are considered key elements in the pathogenesis of systemic lupus erythematosus (SLE). However, a common micro(mi)RNA signature has not emerged since published data includes patients of variable ethnic background, type of disease, and organ involvement, as well as heterogeneous cell populations. Here, we aimed at identifying a miRNA signature of purified B cells from renal and non-renal severe SLE patients of Latin American background, a population known to express severe disease. Genome-wide miRNA expression analyses were performed on naive and memory B cells and revealed two categories of miRNA signatures. The first signature represents B cell subset-specific miRNAs deregulated in SLE: 11 and six miRNAs discriminating naive and memory B cells of SLE patients from healthy controls (HC), respectively. Whether the miRNA was up or down-regulated in memory B cells as compared with naive B cells in HC, this difference was abolished in SLE patients, and vice versa. The second signature identifies six miRNAs associated with specific pathologic features affecting renal outcome, providing a further understanding for SLE pathogenesis. Overall, the present work provided promising biomarkers in molecular diagnostics for disease severity as well as potential new targets for therapeutic intervention in SLE. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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786 KiB  
Article
Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?
by Aurea Lima, Miguel Bernardes, Rita Azevedo, Rui Medeiros and Vítor Seabra
Int. J. Mol. Sci. 2015, 16(6), 13760-13780; https://doi.org/10.3390/ijms160613760 - 16 Jun 2015
Cited by 32 | Viewed by 7002
Abstract
Background: Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients’ therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins [...] Read more.
Background: Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients’ therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX. Methods: Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created. Results: Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1. Conclusions: This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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1460 KiB  
Article
Specific Colon Cancer Cell Cytotoxicity Induced by Bacteriophage E Gene Expression under Transcriptional Control of Carcinoembryonic Antigen Promoter
by Ana R. Rama, Rosa Hernandez, Gloria Perazzoli, Miguel Burgos, Consolación Melguizo, Celia Vélez and Jose Prados
Int. J. Mol. Sci. 2015, 16(6), 12601-12615; https://doi.org/10.3390/ijms160612601 - 04 Jun 2015
Cited by 14 | Viewed by 6726
Abstract
Colorectal cancer is one of the most prevalent cancers in the world. Patients in advanced stages often develop metastases that require chemotherapy and usually show a poor response, have a low survival rate and develop considerable toxicity with adverse symptoms. Gene therapy may [...] Read more.
Colorectal cancer is one of the most prevalent cancers in the world. Patients in advanced stages often develop metastases that require chemotherapy and usually show a poor response, have a low survival rate and develop considerable toxicity with adverse symptoms. Gene therapy may act as an adjuvant therapy in attempts to destroy the tumor without affecting normal host tissue. The bacteriophage E gene has demonstrated significant antitumor activity in several cancers, but without any tumor-specific activity. The use of tumor-specific promoters may help to direct the expression of therapeutic genes so they act against specific cancer cells. We used the carcinoembryonic antigen promoter (CEA) to direct E gene expression (pCEA-E) towards colon cancer cells. pCEA-E induced a high cell growth inhibition of human HTC-116 colon adenocarcinoma and mouse MC-38 colon cancer cells in comparison to normal human CCD18co colon cells, which have practically undetectable levels of CEA. In addition, in vivo analyses of mice bearing tumors induced using MC-38 cells showed a significant decrease in tumor volume after pCEA-E treatment and a low level of Ki-67 in relation to untreated tumors. These results suggest that the CEA promoter is an excellent candidate for directing E gene expression specifically toward colon cancer cells. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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4478 KiB  
Article
PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling
by Ming Li, Fenghe Niu, Xilin Zhu, Xiaopan Wu, Ning Shen, Xiaozhong Peng and Ying Liu
Int. J. Mol. Sci. 2015, 16(5), 9134-9151; https://doi.org/10.3390/ijms16059134 - 23 Apr 2015
Cited by 61 | Viewed by 8178
Abstract
Paroxysmal kinesigenic choreoathetosis (PKC) is an inherited disease of the nervous system. We previously identified PRRT2 as the causative gene of PKC. However, as little is known about the function of PRRT2, elucidating its function will benefit not only PKC studies, but also [...] Read more.
Paroxysmal kinesigenic choreoathetosis (PKC) is an inherited disease of the nervous system. We previously identified PRRT2 as the causative gene of PKC. However, as little is known about the function of PRRT2, elucidating its function will benefit not only PKC studies, but also many other related disorders. Here, we reveal higher levels of glutamate in the plasma of PKC patients and the culture medium of neurons following knock-out Prrt2 expression. Using double immunostaining assays we confirm Prrt2 is located at the glutamatergic neurons in accordance with its function. Our co-immunoprecipitation assays reveal mutant PRRT2 interferes with SNAP25 and GRIA1 interactions, respectively. Furthermore, using live-labeling techniques, we confirmed co-transfection with mutant PRRT2 caused an increase in GRIA1 distribution on the cell surface. Therefore, our results suggest that mutant PRRT2, probably through its weakened interaction with SNAP25, affects glutamate signaling and glutamate receptor activity, resulting in the increase of glutamate release and subsequent neuronal hyperexcitability. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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762 KiB  
Article
Genotyping Test with Clinical Factors: Better Management of Acute Postoperative Pain?
by Aline Hajj, Katell Peoc'h, Jean-Louis Laplanche, Hicham Jabbour, Nicole Naccache, Hicham Abou Zeid, Patricia Yazbeck and Lydia Rabbaa Khabbaz
Int. J. Mol. Sci. 2015, 16(3), 6298-6311; https://doi.org/10.3390/ijms16036298 - 19 Mar 2015
Cited by 12 | Viewed by 5867
Abstract
Individualization of acute postoperative pain treatment on an evidence-based decision process is a major health concern. The aim of this study is to investigate the influence of genetic and non-genetic factors on the variability of response to morphine in acute postoperative pain. A [...] Read more.
Individualization of acute postoperative pain treatment on an evidence-based decision process is a major health concern. The aim of this study is to investigate the influence of genetic and non-genetic factors on the variability of response to morphine in acute postoperative pain. A group of nighty-five patients undergoing major surgery were included prospectively. At 24 h, a logistic regression model was carried out to determine the factors associated with morphine doses given by a Patient Controlled Analgesia device. The dose of morphine was associated with age (p = 0.011), patient weight (p = 0.025) and the duration of operation (p = 0.030). This dose decreased with patient’s age and duration of operation and increased with patient’s weight. OPRM1 and ABCB1 polymorphisms were significantly associated with administered dose of morphine (p = 0.038 and 0.012 respectively). Patients with at least one G allele for c.118A>G OPRM1 polymorphism (AG/GG) needed 4 times the dose of morphine of AA patients. Additionally, patients with ABCB1 CT and CC genotypes for c.3435C>T polymorphism were 5.6 to 7.1 times more prone to receive higher dose of morphine than TT patients. Our preliminary results support the evidence that OPRM1/ABCB1 genotypes along with age, weight and duration of operation have an impact on morphine consumption for acute postoperative pain treatment. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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718 KiB  
Article
A Pharmacogenetics Study in Mozambican Patients Treated with Nevirapine: Full Resequencing of TRAF3IP2 Gene Shows a Novel Association with SJS/TEN Susceptibility
by Cinzia Ciccacci, Sara Rufini, Sandro Mancinelli, Ersilia Buonomo, Emiliano Giardina, Paola Scarcella, Maria C. Marazzi, Giuseppe Novelli, Leonardo Palombi and Paola Borgiani
Int. J. Mol. Sci. 2015, 16(3), 5830-5838; https://doi.org/10.3390/ijms16035830 - 12 Mar 2015
Cited by 8 | Viewed by 5248
Abstract
Steven–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe adverse drug reactions, characterized by extensive epidermal detachment and erosions of mucous membrane. SJS/TEN is one of the most serious adverse reactions to Nevirapine (NVP) treatment, commonly used in developing countries as first-line [...] Read more.
Steven–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe adverse drug reactions, characterized by extensive epidermal detachment and erosions of mucous membrane. SJS/TEN is one of the most serious adverse reactions to Nevirapine (NVP) treatment, commonly used in developing countries as first-line treatment of human immunodeficiency virus infection. In the last years TRAF3IP2 gene variants had been described as associated with susceptibility to several diseases such as psoriasis and psoriatic arthritis. We hypothesized that this gene, involved in immune response and in NF-κB activation, could also be implicated in the SJS/TEN susceptibility. We performed a full resequencing of TRAF3IP2 gene in a population of patients treated with NVP. Twenty-seven patients with NVP-induced SJS/TEN and 78 controls, all from Mozambique, were enrolled. We identified eight exonic and three intronic already described variants. The case/control association analysis highlighted an association between the rs76228616 SNP in exon 2 and the SJS/TEN susceptibility. In particular, the variant allele (C) resulted significantly associated with a higher risk to develop SJS/TEN (p = 0.012 and OR = 3.65 (95% CI 1.33–10.01)). A multivariate analysis by logistic regression confirmed its significant contribution (p = 0.027, OR = 4.39 (95% CI 1.19–16.23)). In conclusion, our study suggests that a variant in TRAF3IP2 gene could be involved in susceptibility to SJS/TEN. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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688 KiB  
Article
A Polymorphism at the Translation Start Site of the Vitamin D Receptor Gene Is Associated with the Response to Anti-Osteoporotic Therapy in Postmenopausal Women from Southern Italy
by Valeria Conti, Giusy Russomanno, Graziamaria Corbi, Giuseppe Toro, Vittorio Simeon, Walter Filippelli, Nicola Ferrara, Michela Grimaldi, Valeria D'Argenio, Nicola Maffulli and Amelia Filippelli
Int. J. Mol. Sci. 2015, 16(3), 5452-5466; https://doi.org/10.3390/ijms16035452 - 10 Mar 2015
Cited by 47 | Viewed by 6022
Abstract
The present study investigated the effect of two single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, rs1544410 A/G and rs2228570 C/T, in modulating bone mineral density (BMD) and the response to treatment with bisphosphonates or strontium ranelate in postmenopausal osteoporosis [...] Read more.
The present study investigated the effect of two single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, rs1544410 A/G and rs2228570 C/T, in modulating bone mineral density (BMD) and the response to treatment with bisphosphonates or strontium ranelate in postmenopausal osteoporosis (PMO). Four hundred eighteen postmenopausal women from Southern Italy treated with bisphosphonates or strontium ranelate for three years were enrolled and stratified according to their genotype. Changes in BMD were expressed as the delta t-score (Δt-score). Allelic frequencies for rs1544410 A/GSNP were 11.2% AA, 50.0% GA and 38.8% GG; for rs2228570 C/TSNP were 54.8% CC, 39.5% TC and 5.7% TT. TT carriers showed a lower t-score than TC and CC (both p < 0.02) genotypes and were more responsive to the therapy when compared to both TC (p < 0.02) and CC (p < 0.05) carriers. Specifically, TT carriers receiving alendronate demonstrated a significant improvement of the Δt-score compared to TC and CC (both p < 0.0001) carriers. After adjustment for confounders, the Δt-score showed evidence of a statistically significant positive association with TT in all treatments considered. Therapy response was independent of rs1544410 A/G SNP; instead, rs2228570 C/TSNP was associated with a better response to antiresorptive treatment, thus suggesting that the therapy for PMO should be personalized. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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Article
PRRT2 Mutations Are Related to Febrile Seizures in Epileptic Patients
by Zheng-Wen He, Jian Qu, Ying Zhang, Chen-Xue Mao, Zhi-Bin Wang, Xiao-Yuan Mao, Zhi-Yong Deng, Bo-Ting Zhou, Ji-Ye Yin, Hong-Yu Long, Bo Xiao, Yu Zhang, Hong-Hao Zhou and Zhao-Qian Liu
Int. J. Mol. Sci. 2014, 15(12), 23408-23417; https://doi.org/10.3390/ijms151223408 - 16 Dec 2014
Cited by 15 | Viewed by 6329
Abstract
Previous studies reported that the proline-rich transmembrane protein 2 (PRRT2) gene was identified to be related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with PKD, PKD with migraine and benign familial infantile epilepsy (BFIE). The present study explores whether the PRRT2 [...] Read more.
Previous studies reported that the proline-rich transmembrane protein 2 (PRRT2) gene was identified to be related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with PKD, PKD with migraine and benign familial infantile epilepsy (BFIE). The present study explores whether the PRRT2 mutation is a potential cause of febrile seizures, including febrile seizures plus (FS+), generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS); thus, it may provide a new drug target for personalized medicine for febrile seizure patients. We screened PRRT2 exons in a cohort of 136 epileptic patients with febrile seizures, including FS+, GEFS+ and DS. PRRT2 genetic mutations were identified in 25 out of 136 (18.4%) febrile seizures in epileptic patients. Five loss-of-function and coding missense mutations were identified: c.649delC (p.R217Efs*12), c.649_650insC (p.R217Pfs*8), c.412C>G (p.Pro138Ala), c.439G>C (p.Asp147His) and c.623C>A (p.Ser208Tyr). PRRT2 variants were probably involved in the etiology of febrile seizures in epileptic patients. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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Review

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4039 KiB  
Review
Epigenetics of Aging and Alzheimer’s Disease: Implications for Pharmacogenomics and Drug Response
by Ramón Cacabelos and Clara Torrellas
Int. J. Mol. Sci. 2015, 16(12), 30483-30543; https://doi.org/10.3390/ijms161226236 - 21 Dec 2015
Cited by 88 | Viewed by 12037
Abstract
Epigenetic variability (DNA methylation/demethylation, histone modifications, microRNA regulation) is common in physiological and pathological conditions. Epigenetic alterations are present in different tissues along the aging process and in neurodegenerative disorders, such as Alzheimer’s disease (AD). Epigenetics affect life span and longevity. AD-related genes [...] Read more.
Epigenetic variability (DNA methylation/demethylation, histone modifications, microRNA regulation) is common in physiological and pathological conditions. Epigenetic alterations are present in different tissues along the aging process and in neurodegenerative disorders, such as Alzheimer’s disease (AD). Epigenetics affect life span and longevity. AD-related genes exhibit epigenetic changes, indicating that epigenetics might exert a pathogenic role in dementia. Epigenetic modifications are reversible and can potentially be targeted by pharmacological intervention. Epigenetic drugs may be useful for the treatment of major problems of health (e.g., cancer, cardiovascular disorders, brain disorders). The efficacy and safety of these and other medications depend upon the efficiency of the pharmacogenetic process in which different clusters of genes (pathogenic, mechanistic, metabolic, transporter, pleiotropic) are involved. Most of these genes are also under the influence of the epigenetic machinery. The information available on the pharmacoepigenomics of most drugs is very limited; however, growing evidence indicates that epigenetic changes are determinant in the pathogenesis of many medical conditions and in drug response and drug resistance. Consequently, pharmacoepigenetic studies should be incorporated in drug development and personalized treatments. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
693 KiB  
Review
Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia
by Marialuisa Polillo, Sara Galimberti, Claudia Baratè, Mario Petrini, Romano Danesi and Antonello Di Paolo
Int. J. Mol. Sci. 2015, 16(9), 22811-22829; https://doi.org/10.3390/ijms160922811 - 21 Sep 2015
Cited by 32 | Viewed by 8055
Abstract
Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics [...] Read more.
Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics and pharmacodynamics of BCR-ABL1 tyrosine kinase activity inhibitors (TKIs). Transmembrane transporters seem to influence in a significant manner the disposition of TKIs, especially that of imatinib at both cellular and systemic levels. In particular, members of the ATP-binding cassette (ABC) family (namely ABCB1 and ABCG2) together with solute carrier (SLC) transporters (i.e., SLC22A1) are responsible for the differences in drug pharmacokinetics. In the case of the newer TKIs, such as nilotinib and dasatinib, the substrate affinity of these drugs for transporters is variable but lower than that measured for imatinib. In this scenario, the investigation of genetic variants as possible predictive markers has led to some discordant results. With the partial exception of imatinib, these discrepancies seem to limit the application of discovered biomarkers in the clinical settings. In order to overcome these issues, larger prospective confirmative trials are needed. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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777 KiB  
Review
Role of Pharmacogenetics in Hematopoietic Stem Cell Transplantation Outcome in Children
by Raffaella Franca, Gabriele Stocco, Diego Favretto, Nagua Giurici, Giuliana Decorti and Marco Rabusin
Int. J. Mol. Sci. 2015, 16(8), 18601-18627; https://doi.org/10.3390/ijms160818601 - 10 Aug 2015
Cited by 6 | Viewed by 5707
Abstract
Hematopoietic stem cell transplantation (HSCT) is an established therapeutic procedure for several congenital and acquired disorders, both malignant and nonmalignant. Despite the great improvements in HSCT clinical practices over the last few decades, complications, such as graft vs. host disease (GVHD) and sinusoidal [...] Read more.
Hematopoietic stem cell transplantation (HSCT) is an established therapeutic procedure for several congenital and acquired disorders, both malignant and nonmalignant. Despite the great improvements in HSCT clinical practices over the last few decades, complications, such as graft vs. host disease (GVHD) and sinusoidal obstructive syndrome (SOS), are still largely unpredictable and remain the major causes of morbidity and mortality. Both donor and patient genetic background might influence the success of bone marrow transplantation and could at least partially explain the inter-individual variability in HSCT outcome. This review summarizes some of the recent studies on candidate gene polymorphisms in HSCT, with particular reference to pediatric cohorts. The interest is especially focused on pharmacogenetic variants affecting myeloablative and immunosuppressive drugs, although genetic traits involved in SOS susceptibility and transplant-related mortality are also reviewed. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
1355 KiB  
Review
Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine
by Vittorio Simeon, Katia Todoerti, Francesco La Rocca, Antonella Caivano, Stefania Trino, Marta Lionetti, Luca Agnelli, Luciana De Luca, Ilaria Laurenzana, Antonino Neri and Pellegrino Musto
Int. J. Mol. Sci. 2015, 16(8), 17514-17534; https://doi.org/10.3390/ijms160817514 - 30 Jul 2015
Cited by 20 | Viewed by 7335
Abstract
Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last [...] Read more.
Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL). Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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847 KiB  
Review
Personalized Medicine in Gastrointestinal Stromal Tumor (GIST): Clinical Implications of the Somatic and Germline DNA Analysis
by Gloria Ravegnini, Margherita Nannini, Giulia Sammarini, Annalisa Astolfi, Guido Biasco, Maria A. Pantaleo, Patrizia Hrelia and Sabrina Angelini
Int. J. Mol. Sci. 2015, 16(7), 15592-15608; https://doi.org/10.3390/ijms160715592 - 09 Jul 2015
Cited by 31 | Viewed by 8557
Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. They are characterized by gain of function mutations in KIT or PDGFRA tyrosine kinase receptors, with their consequent constitutive activation. The gold standard therapy is imatinib that offers a [...] Read more.
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. They are characterized by gain of function mutations in KIT or PDGFRA tyrosine kinase receptors, with their consequent constitutive activation. The gold standard therapy is imatinib that offers a good and stable response for approximately 18–36 months. However, resistance is very common and it is vital to identify new biomarkers. Up until now, there have been two main approaches with focus to characterize novel targets. On the one hand, the focus is on the tumor genome, as the final clinical outcome depends mainly from the cancer specific mutations/alterations patterns. However, the germline DNA is important as well, and it is inconceivable to think the patients response to the drug is not related to it. Therefore the aim of this review is to outline the state of the art of the personalized medicine in GIST taking into account both the tumor DNA (somatic) and the patient DNA (germline). Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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Graphical abstract

1621 KiB  
Review
Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in “Omics” Medicine
by Gianluigi Zaza, Simona Granata, Paola Tomei, Alessandra Dalla Gassa and Antonio Lupo
Int. J. Mol. Sci. 2015, 16(2), 4281-4305; https://doi.org/10.3390/ijms16024281 - 17 Feb 2015
Cited by 28 | Viewed by 10420
Abstract
Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over [...] Read more.
Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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