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Pharmacogenetics and Personalized Medicine 3.0

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: 20 May 2024 | Viewed by 10091

Special Issue Editors


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Guest Editor
Department of Internal Medicine, Hospital Universitario Marqués de Valdecilla-IDIVAL, University of Cantabria, CEBERER, 39008 Santander, Spain
Interests: genomics and epigenomics of skeletal and metabolic disorders

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 emergence 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 adverse drug 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, the following:

  • 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

Prof. Dr. José A. Riancho
Dr. Gloria Ravegnini
Guest Editors

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.

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Keywords

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

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Published Papers (34 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 4440
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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16 pages, 2021 KiB  
Article
Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide
by Paula Soria-Chacartegui, Pablo Zubiaur, Dolores Ochoa, Marcos Navares-Gómez, Houwaida Abbes, Gonzalo Villapalos-García, Alejandro de Miguel, Eva González-Iglesias, Andrea Rodríguez-Lopez, Gina Mejía-Abril, Samuel Martín-Vilchez, Sergio Luquero-Bueno, Manuel Román and Francisco Abad-Santos
Int. J. Mol. Sci. 2023, 24(20), 15265; https://doi.org/10.3390/ijms242015265 - 17 Oct 2023
Cited by 1 | Viewed by 1149
Abstract
Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was [...] Read more.
Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters’ genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, β = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, β = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 3.0)
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11 pages, 11609 KiB  
Article
RAD51D Secondary Mutation-Mediated Resistance to PARP-Inhibitor-Based Therapy in HGSOC
by Jing Xu, Yilin Dai, Yi Gao, Ranran Chai, Chong Lu, Bing Yu, Yu Kang and Congjian Xu
Int. J. Mol. Sci. 2023, 24(19), 14476; https://doi.org/10.3390/ijms241914476 - 23 Sep 2023
Cited by 2 | Viewed by 1218
Abstract
Ovarian cancer is the leading cause of gynecologic cancer-related death, and PARP inhibitors (PARPis) are becoming a promising treatment option, as demonstrated by recent clinical trials. After PARPi exposure, somatic reversion mutations in the homologous recombination genes may be a mechanism of PARPi [...] Read more.
Ovarian cancer is the leading cause of gynecologic cancer-related death, and PARP inhibitors (PARPis) are becoming a promising treatment option, as demonstrated by recent clinical trials. After PARPi exposure, somatic reversion mutations in the homologous recombination genes may be a mechanism of PARPi resistance in ovarian carcinoma. We present an ovarian cancer case of a 61-year-old woman, who underwent routine tumor reduction surgery followed by platinum and PARPis. She demonstrated a good response to PARPis for 15 months before recurrence and secondary tumor reduction surgery. However, post-surgery platinum and PARPi treatment only kept the disease stable for 5 months. A potential molecular mechanism for PARPi resistance was investigated using next-generation sequencing, immunohistochemical (IHC) staining, and other functional assays. A germline RAD51D loss-of-function mutation was found in the reported case (LRG_516t1:c.270_271dup p1:p.(Lys91fs*13)). Subsequently, a secondary mutation (LRG_516t1:c.271_282 del) was identified in the same locus of the germline duplication in the post-progression biopsies and ctDNA. The IHC staining supported low expression of RAD51D in the initial tumor tissue, but the expression was restored after the correction of the open reading frame by the secondary mutation. The in vitro results supported that the loss-of-function mutation of RAD51D was the basis for the initial response to the platinum and PARPi therapy, while the newly acquired reversion mutation could be attributed to the observed PARPi resistance. An acquired mutation can reverse a loss-of-function change in RAD51D and can result in PARPi resistance in a hereditary ovarian cancer patient. Liquid biopsy could be considered for longitudinal monitoring in ovarian patients under PARPi-based therapy, which can identify acquired resistant mutations earlier and facilitate precision management. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 3.0)
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15 pages, 1351 KiB  
Article
Pharmacogenetic Guided Opioid Therapy Improves Chronic Pain Outcomes and Comorbid Mental Health: A Randomized, Double-Blind, Controlled Study
by Laura Agulló, Isidro Aguado, Javier Muriel, César Margarit, Alba Gómez, Mónica Escorial, Astrid Sánchez, Alicia Fernández and Ana M. Peiró
Int. J. Mol. Sci. 2023, 24(13), 10754; https://doi.org/10.3390/ijms241310754 - 28 Jun 2023
Cited by 3 | Viewed by 1656
Abstract
Interindividual variability in analgesic response is at least partly due to well-characterized polymorphisms that are associated with opioid dosing and adverse outcomes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has put forward recommendations for the CYP2D6 phenotype, but the list of studied drug-gene pairs [...] Read more.
Interindividual variability in analgesic response is at least partly due to well-characterized polymorphisms that are associated with opioid dosing and adverse outcomes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has put forward recommendations for the CYP2D6 phenotype, but the list of studied drug-gene pairs continues to grow. This clinical trial randomized chronic pain patients (n = 60), referred from primary care to pain unit care into two opioid prescribing arms, one guided by CYP2D6, μ-opioid receptor (OPRM1), and catechol-O-methyl transferase (COMT) genotypes vs. one with clinical routine. The genotype-guided treatment reduced pain intensity (76 vs. 59 mm, p < 0.01) by improving pain relief (28 vs. 48 mm, p < 0.05), increased quality of life (43 vs. 56 mm p < 0.001), and lowered the incidence of clinically relevant adverse events (3 [1–5] vs. 1 [0–2], p < 0.01) and 42% opioid dose (35 [22–61] vs. 60 [40–80] mg/day, p < 0.05) as opposed to usual prescribing arm. The final health utility score was significantly higher (0.71 [0.58–0.82] vs. 0.51 [0.13–0.67] controls, p < 0.05) by improving sleepiness and depression comorbidity, with a significant reduction of 30–34% for headache, dry mouth, nervousness, and constipation. A large-scale implementation analysis could help clinical translation, together with a pharmaco-economic evaluation. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 3.0)
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11 pages, 488 KiB  
Article
A Longitudinal Study of the Association between the LEPR Polymorphism and Treatment Response in Patients with Bipolar Disorder
by Hui Hua Chang, Yuan-Shuo Hsueh, Yung Wen Cheng and Huai-Hsuan Tseng
Int. J. Mol. Sci. 2022, 23(17), 9635; https://doi.org/10.3390/ijms23179635 - 25 Aug 2022
Viewed by 1274
Abstract
Patients with bipolar disorder (BD) exhibit individual variability in the treatment outcome, and genetic background could contribute to BD itself and the treatment outcome. Leptin levels significantly change in BD patients treated with valproate (VPA), but whether LEPR polymorphisms are associated with treatment [...] Read more.
Patients with bipolar disorder (BD) exhibit individual variability in the treatment outcome, and genetic background could contribute to BD itself and the treatment outcome. Leptin levels significantly change in BD patients treated with valproate (VPA), but whether LEPR polymorphisms are associated with treatment response is still unknown. This longitudinal study aimed to investigate the associations between LEPR polymorphisms and VPA treatment response in BD patients who were drug naïve at their first diagnosis of BD. The single-nucleotide polymorphisms (SNPs) of LEPR (rs1137101, rs1137100, rs8179183, and rs12145690) were assayed, and the LEPR polymorphism frequencies of alleles and genotypes were not significantly different between the controls (n = 77) and BD patients (n = 130). In addition, after the 12-week course of VPA treatment in BD patients, the LEPR polymorphisms showed significant effects on changes in disease severity. Moreover, considering the effect of the LEPR haplotype, the frequency of the CAGG haplotype in BD patients was higher than that in the controls (9.3 vs. 2.9%, p = 0.016), and the LEPR CAGG haplotype was associated with a better treatment response than the other haplotypes in BD patients receiving VPA treatment. Therefore, LEPR polymorphisms might serve as mediators involved in the therapeutic action of VPA treatment. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 3.0)
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14 pages, 336 KiB  
Article
Paradoxical Psoriasis Induced by Anti-TNFα Treatment: Evaluation of Disease-Specific Clinical and Genetic Markers
by Agostino Bucalo, Federica Rega, Arianna Zangrilli, Valentina Silvestri, Virginia Valentini, Giorgia Scafetta, Federica Marraffa, Sara Grassi, Elena Rogante, Arianna Piccolo, Salvatore Cucchiara, Franca Viola, Luca Bianchi, Laura Ottini and Antonio Richetta
Int. J. Mol. Sci. 2020, 21(21), 7873; https://doi.org/10.3390/ijms21217873 - 23 Oct 2020
Cited by 19 | Viewed by 3127
Abstract
Paradoxical psoriasis (PP) may occur during treatment with anti-tumor necrosis factor-alpha (TNF-α) drugs in various chronic immune-mediated diseases, mainly inflammatory bowel diseases (IBD) and psoriasis. In this study, clinical and genetic characteristics of PP arising in IBD and psoriatic patients were investigated to [...] Read more.
Paradoxical psoriasis (PP) may occur during treatment with anti-tumor necrosis factor-alpha (TNF-α) drugs in various chronic immune-mediated diseases, mainly inflammatory bowel diseases (IBD) and psoriasis. In this study, clinical and genetic characteristics of PP arising in IBD and psoriatic patients were investigated to identify disease-specific markers of the paradoxical effect. A total of 161 IBD and psoriatic patients treated with anti-TNF-α drugs were included in the study. Of these patients, 39 developed PP. All patients were characterized for the main clinical–pathologic characteristics and genotyped for six candidate single nucleotide polymorphisms (SNPs) selected for their possible role in PP susceptibility. In IBD patients, the onset of PP was associated with female sex, presence of comorbidities, and use of adalimumab. IBD patients with PP had a higher frequency of the TNF-α rs1799964 rare allele (p = 0.006) compared with cases without the paradoxical effect, and a lower frequency of the human leucocyte antigen (HLA)-Cw06 rs10484554 rare allele (p = 0.03) compared with psoriatic patients with PP. Overall, these findings point to specific clinical and genetic characteristics of IBD patients with PP and provide data showing that genetic variability may be related to the paradoxical effect of anti-TNF-α drugs with possible implications into clinical practice. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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18 pages, 2589 KiB  
Article
MTHFR and VDR Polymorphisms Improve the Prognostic Value of MYCN Status on Overall Survival in Neuroblastoma Patients
by Gladys G. Olivera, Yania Yáñez, Pablo Gargallo, Luis Sendra, Salvador F. Aliño, Vanessa Segura, Miguel Ángel Sanz, Adela Cañete, Victoria Castel, Jaime Font De Mora, David Hervás, Pablo Berlanga and María José Herrero
Int. J. Mol. Sci. 2020, 21(8), 2714; https://doi.org/10.3390/ijms21082714 - 14 Apr 2020
Cited by 9 | Viewed by 2283
Abstract
Single nucleotide polymorphisms (SNPs) in Pharmacogenetics can play an important role in the outcomes of the chemotherapy treatment in Neuroblastoma, helping doctors maximize efficacy and minimize toxicity. Employing AgenaBioscience MassArray, 96 SNPs were genotyped in 95 patients looking for associations of SNP with [...] Read more.
Single nucleotide polymorphisms (SNPs) in Pharmacogenetics can play an important role in the outcomes of the chemotherapy treatment in Neuroblastoma, helping doctors maximize efficacy and minimize toxicity. Employing AgenaBioscience MassArray, 96 SNPs were genotyped in 95 patients looking for associations of SNP with response to induction therapy (RIT) and grade 3–4 toxicities, in High Risk patients. Associations of SNPs with overall (OS) and event-free (EFS) survival in the whole cohort were also explored. Cox and logistic regression models with Elastic net penalty were employed. Association with grade 3–4 gastrointestinal and infectious toxicities was found for 8 different SNPs. Better RIT was correlated with rs726501 AG, rs3740066 GG, rs2010963 GG and rs1143684 TT (OR = 2.87, 1.79, 1.23, 1.14, respectively). EFS was affected by rs2032582, rs4880, rs3814058, rs45511401, rs1544410 and rs6539870. OS was influenced by rs 1801133, rs7186128 and rs1544410. Remarkably, rs1801133 in MTHFR (p = 0.02) and rs1544410 in VDR (p = 0.006) also added an important predictive value for OS to the MYCN status, with a more accurate substratification of the patients. Although validation studies in independent cohorts will be required, the data obtained supports the utility of Pharmacogenetics for predicting Neuroblastoma treatment outcomes. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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15 pages, 4216 KiB  
Article
Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
by Sylvan M. Caspar, Timo Schneider, Janine Meienberg and Gabor Matyas
Int. J. Mol. Sci. 2020, 21(7), 2308; https://doi.org/10.3390/ijms21072308 - 26 Mar 2020
Cited by 24 | Viewed by 5019
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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21 pages, 1195 KiB  
Article
Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients
by Jing Zhu, Tejendra Patel, Jordan A. Miller, Chad D. Torrice, Mehak Aggarwal, Margaret R. Sketch, Maurice D. Alexander, Paul M. Armistead, James M. Coghill, Tatjana Grgic, Katarzyna J. Jamieson, Jonathan R. Ptachcinski, Marcie L. Riches, Jonathan S. Serody, John L. Schmitz, J. Ryan Shaw, Thomas C. Shea, Oscar Suzuki, Benjamin G. Vincent, William A. Wood, Kamakshi V. Rao, Tim Wiltshire, Eric T. Weimer and Daniel J. Cronaadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2020, 21(3), 858; https://doi.org/10.3390/ijms21030858 - 29 Jan 2020
Cited by 16 | Viewed by 4397
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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17 pages, 279 KiB  
Article
Clinical and Genetic Factors Associated with Resistance to Treatment in Patients with Schizophrenia: A Case-Control Study
by Aline Hajj, Sahar Obeid, Saria Sahyoun, Chadia Haddad, Jocelyne Azar, Lydia Rabbaa Khabbaz and Souheil Hallit
Int. J. Mol. Sci. 2019, 20(19), 4753; https://doi.org/10.3390/ijms20194753 - 25 Sep 2019
Cited by 14 | Viewed by 3296
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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10 pages, 225 KiB  
Article
Association between Polymorphisms of OCT1 and Metabolic Response to Metformin in Women with Polycystic Ovary Syndrome
by Hui Hua Chang, Yuan-Shuo Hsueh, Yung Wen Cheng, Huang-Tz Ou and Meng-Hsing Wu
Int. J. Mol. Sci. 2019, 20(7), 1720; https://doi.org/10.3390/ijms20071720 - 07 Apr 2019
Cited by 14 | Viewed by 3082
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)
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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 5788
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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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 5348
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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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 6746
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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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 7015
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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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 6733
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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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 8183
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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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 5873
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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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 5252
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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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 6091
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 6336
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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18 pages, 1182 KiB  
Review
Genetic Variants Associated with Biological Treatment Response in Inflammatory Bowel Disease: A Systematic Review
by Javier Plaza, Alejandro Mínguez, Guillermo Bastida, Remedios Marqués, Pilar Nos, Jose Luis Poveda and Inés Moret-Tatay
Int. J. Mol. Sci. 2024, 25(7), 3717; https://doi.org/10.3390/ijms25073717 - 27 Mar 2024
Viewed by 858
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn’s disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening [...] Read more.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn’s disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening complications, involving possible malignancy and surgery. The available therapies aim to achieve long-term remission and prevent disease progression. Biologics are bioengineered therapeutic drugs that mainly target proteins. Although they have revolutionized the treatment of IBD, their potential therapeutic benefits are limited due to large interindividual variability in clinical response in terms of efficacy and toxicity, resulting in high rates of long-term therapeutic failure. It is therefore important to find biomarkers that provide tailor-made treatment strategies that allow for patient stratification to maximize treatment benefits and minimize adverse events. Pharmacogenetics has the potential to optimize biologics selection in IBD by identifying genetic variants, specifically single nucleotide polymorphisms (SNPs), which are the underlying factors associated with an individual’s drug response. This review analyzes the current knowledge of genetic variants associated with biological agent response (infliximab, adalimumab, ustekinumab, and vedolizumab) in IBD. An online literature search in various databases was conducted. After applying the inclusion and exclusion criteria, 28 reports from the 1685 results were employed for the review. The most significant SNPs potentially useful as predictive biomarkers of treatment response are linked to immunity, cytokine production, and immunorecognition. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 3.0)
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24 pages, 1380 KiB  
Review
Modulation of the Gut Microbiota by Nutrition and Its Relationship to Epigenetics
by Katarzyna Ferenc, Aneta Sokal-Dembowska, Kacper Helma, Elżbieta Motyka, Sara Jarmakiewicz-Czaja and Rafał Filip
Int. J. Mol. Sci. 2024, 25(2), 1228; https://doi.org/10.3390/ijms25021228 - 19 Jan 2024
Cited by 1 | Viewed by 1615
Abstract
The intestinal microbiota is a community of microorganisms inhabiting the human intestines, potentially influencing both physiological and pathophysiological processes in the human body. Existing evidence suggests that nutrients can influence the modulation of the gut microbiota. However, there is still limited evidence regarding [...] Read more.
The intestinal microbiota is a community of microorganisms inhabiting the human intestines, potentially influencing both physiological and pathophysiological processes in the human body. Existing evidence suggests that nutrients can influence the modulation of the gut microbiota. However, there is still limited evidence regarding the effects of vitamin and mineral supplementation on the human gut microbiota through epigenetic modification. It is plausible that maintaining an adequate dietary intake of vitamin D, iron, fibre, zinc and magnesium may have a beneficial effect on alleviating inflammation in the body, reducing oxidative stress, and improving the condition of the intestinal microbiota through various epigenetic mechanisms. Moreover, epigenetics involves alterations in the phenotype of a cell without changing its fundamental DNA sequence. It appears that the modulation of the microbiota by various nutrients may lead to epigenetic regulation. The correlations between microbiota and epigenetics are potentially interdependent. Therefore, the primary objective of this review is to identify the complex relationships between diet, gut microbiota, and epigenetic regulation. These interactions could play a crucial role in systemic health. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 3.0)
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48 pages, 2077 KiB  
Review
Genetic Landscape of Common Epilepsies: Advancing towards Precision in Treatment
by Sarita Thakran, Debleena Guin, Pooja Singh, Priyanka Singh, Samiksha Kukal, Chitra Rawat, Saroj Yadav, Suman S. Kushwaha, Achal K. Srivastava, Yasha Hasija, Luciano Saso, Srinivasan Ramachandran and Ritushree Kukreti
Int. J. Mol. Sci. 2020, 21(20), 7784; https://doi.org/10.3390/ijms21207784 - 21 Oct 2020
Cited by 53 | Viewed by 10025
Abstract
Epilepsy, a neurological disease characterized by recurrent seizures, is highly heterogeneous in nature. Based on the prevalence, epilepsy is classified into two types: common and rare epilepsies. Common epilepsies affecting nearly 95% people with epilepsy, comprise generalized epilepsy which encompass idiopathic generalized epilepsy [...] Read more.
Epilepsy, a neurological disease characterized by recurrent seizures, is highly heterogeneous in nature. Based on the prevalence, epilepsy is classified into two types: common and rare epilepsies. Common epilepsies affecting nearly 95% people with epilepsy, comprise generalized epilepsy which encompass idiopathic generalized epilepsy like childhood absence epilepsy, juvenile myoclonic epilepsy, juvenile absence epilepsy and epilepsy with generalized tonic-clonic seizure on awakening and focal epilepsy like temporal lobe epilepsy and cryptogenic focal epilepsy. In 70% of the epilepsy cases, genetic factors are responsible either as single genetic variant in rare epilepsies or multiple genetic variants acting along with different environmental factors as in common epilepsies. Genetic testing and precision treatment have been developed for a few rare epilepsies and is lacking for common epilepsies due to their complex nature of inheritance. Precision medicine for common epilepsies require a panoramic approach that incorporates polygenic background and other non-genetic factors like microbiome, diet, age at disease onset, optimal time for treatment and other lifestyle factors which influence seizure threshold. This review aims to comprehensively present a state-of-art review of all the genes and their genetic variants that are associated with all common epilepsy subtypes. It also encompasses the basis of these genes in the epileptogenesis. Here, we discussed the current status of the common epilepsy genetics and address the clinical application so far on evidence-based markers in prognosis, diagnosis, and treatment management. In addition, we assessed the diagnostic predictability of a few genetic markers used for disease risk prediction in individuals. A combination of deeper endo-phenotyping including pharmaco-response data, electro-clinical imaging, and other clinical measurements along with genetics may be used to diagnose common epilepsies and this marks a step ahead in precision medicine in common epilepsies management. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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19 pages, 1929 KiB  
Review
Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment against an Aggressive Tumor
by Begoña Alburquerque-González, Fernando F. López-Calderón, María Dolores López-Abellán, Ángel Esteban-Gil, José García-Solano and Pablo Conesa-Zamora
Int. J. Mol. Sci. 2020, 21(6), 1991; https://doi.org/10.3390/ijms21061991 - 14 Mar 2020
Cited by 6 | Viewed by 2951
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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22 pages, 634 KiB  
Review
Circulating-Free DNA Analysis in Hepatocellular Carcinoma: A Promising Strategy to Improve Patients’ Management and Therapy Outcomes
by Silvia Mezzalira, Elena De Mattia, Michela Guardascione, Chiara Dalle Fratte, Erika Cecchin and Giuseppe Toffoli
Int. J. Mol. Sci. 2019, 20(21), 5498; https://doi.org/10.3390/ijms20215498 - 05 Nov 2019
Cited by 23 | Viewed by 5602
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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15 pages, 859 KiB  
Review
A Systems Biology Approach for Personalized Medicine in Refractory Epilepsy
by Giuseppina Daniela Naimo, Maria Guarnaccia, Teresa Sprovieri, Carmine Ungaro, Francesca Luisa Conforti, Sebastiano Andò and Sebastiano Cavallaro
Int. J. Mol. Sci. 2019, 20(15), 3717; https://doi.org/10.3390/ijms20153717 - 30 Jul 2019
Cited by 23 | Viewed by 5318
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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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 12057
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)
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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 8067
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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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 5715
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)
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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 7342
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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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 8565
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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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 10426
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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10 pages, 1531 KiB  
Case Report
Erdheim–Chester Disease Due to a Novel Internal Duplication of NRAS: Response to Targeted Therapy with Cobimetinib
by José A. Riancho, José L. Hernández, Carmen González-Vela, Ana E. López-Sundh, Marcos A. González-Lopez, Francisco Gomez de la Fuente, Remedios Quirce and Eli L. Diamond
Int. J. Mol. Sci. 2023, 24(20), 15467; https://doi.org/10.3390/ijms242015467 - 23 Oct 2023
Viewed by 782
Abstract
Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim–Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been [...] Read more.
Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim–Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been challenging. However, recent breakthroughs in our understanding, particularly the discovery of somatic mutations in the RAS-MAPK pathway, have opened new opportunities for targeted therapy in a significant subset of patients with ECD and other histiocytoses. In this report, we present the case of a patient with ECD harboring a previously unidentified microduplication in the NRAS gene in a small fraction of skin cells. This discovery played a pivotal role in tailoring an effective therapeutic approach involving kinase inhibitors downstream of NRAS. This case underscores the crucial role of deep sequencing of tissue samples in ECD, enabling the delivery of personalized targeted therapy to patients. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 3.0)
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