Research

17 pages, 854 KiB

Open AccessArticle

The MAOA rs979605 Genetic Polymorphism Is Differentially Associated with Clinical Improvement Following Antidepressant Treatment between Male and Female Depressed Patients

by Kenneth Chappell, Romain Colle, Jérôme Bouligand, Séverine Trabado, Bruno Fève, Laurent Becquemont, Emmanuelle Corruble and Céline Verstuyft

Int. J. Mol. Sci. 2023, 24(1), 497; https://doi.org/10.3390/ijms24010497 - 28 Dec 2022

Cited by 3 | Viewed by 1960

Abstract

Major depressive disorder (MDD) is the leading cause of disability worldwide. Treatment with antidepressant drugs (ATD), which target monoamine neurotransmitters including serotonin (5HT), are only modestly effective. Monoamine oxidase (MAO) metabolizes 5HT to 5-hydroxy indoleacetic acid (5HIAA). Genetic variants in the X-chromosome-linked MAO-encoding [...] Read more.

Major depressive disorder (MDD) is the leading cause of disability worldwide. Treatment with antidepressant drugs (ATD), which target monoamine neurotransmitters including serotonin (5HT), are only modestly effective. Monoamine oxidase (MAO) metabolizes 5HT to 5-hydroxy indoleacetic acid (5HIAA). Genetic variants in the X-chromosome-linked MAO-encoding genes, MAOA and MAOB, have been associated with clinical improvement following ATD treatment in depressed patients. Our aim was to analyze the association of MAOA and MAOB genetic variants with (1) clinical improvement and (2) the plasma 5HIAA/5HT ratio in 6-month ATD-treated depressed individuals. Clinical (n = 378) and metabolite (n = 148) data were obtained at baseline and up to 6 months after beginning ATD treatment (M6) in patients of METADAP. Mixed-effects models were used to assess the association of variants with the Hamilton Depression Rating Scale (HDRS) score, response and remission rates, and the plasma 5HIAA/5HT ratio. Variant × sex interactions and dominance terms were included to control for X-chromosome-linked factors. The MAOA rs979605 and MAOB rs1799836 polymorphisms were analyzed. The sex × rs979605 interaction was significantly associated with the HDRS score (p = 0.012). At M6, A allele-carrying males had a lower HDRS score (n = 24, 10.9 ± 1.61) compared to AA homozygous females (n = 14, 18.1 ± 1.87; p = 0.0067). The rs1799836 polymorphism was significantly associated with the plasma 5HIAA/5HT ratio (p = 0.018). Overall, CC/C females/males had a lower ratio (n = 44, 2.18 ± 0.28) compared to TT/T females/males (n = 60, 2.79 ± 0.27; p = 0.047). The MAOA rs979605 polymorphism, associated with the HDRS score in a sex-dependent manner, could be a useful biomarker for the response to ATD treatment. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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12 pages, 1337 KiB

Open AccessArticle

Predicting Dihydropyrimidine Dehydrogenase Deficiency and Related 5-Fluorouracil Toxicity: Opportunities and Challenges of DPYD Exon Sequencing and the Role of Phenotyping Assays

by Ottavia De Luca, Gerardo Salerno, Donatella De Bernardini, Maria Simona Torre, Maurizio Simmaco, Luana Lionetto, Giovanna Gentile and Marina Borro

Int. J. Mol. Sci. 2022, 23(22), 13923; https://doi.org/10.3390/ijms232213923 - 11 Nov 2022

Cited by 7 | Viewed by 1926

Abstract

Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of [...] Read more.

Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype–phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A>G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype–phenotype association data is needed to enable the clinical use of sequencing data. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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10 pages, 686 KiB

Open AccessArticle

GSTT1/GSTM1 Genotype and Anti-Tuberculosis Drug-Induced Hepatotoxicity in Peruvian Patients

by Luis Jaramillo-Valverde, Kelly S. Levano, David D. Tarazona, Andres Vasquez-Dominguez, Anel Toledo-Nauto, Silvia Capristano, Cesar Sanchez, Eduardo Tarazona-Santos, Cesar Ugarte-Gil and Heinner Guio

Int. J. Mol. Sci. 2022, 23(19), 11028; https://doi.org/10.3390/ijms231911028 - 20 Sep 2022

Cited by 1 | Viewed by 1912

Abstract

In Peru, 24,581 people were diagnosed with tuberculosis (TB) in 2020. Although TB treatments are effective, 3.4–13% are associated with significant adverse drug reactions (ADRs), with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid (INH) is the [...] Read more.

In Peru, 24,581 people were diagnosed with tuberculosis (TB) in 2020. Although TB treatments are effective, 3.4–13% are associated with significant adverse drug reactions (ADRs), with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid (INH) is the main drug responsible for the appearance of DILI. In the liver, INH is metabolized by the enzymes N-acetyltransferase-2 (NAT2), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase (GST) with two isoforms, GSTT1 and GSTM1. Based on previous studies, we hypothesized that interactions between the GSTT1 and GSTM1 null genotypes induce DILI in TB patients. In this cross-sectional study of 377 participants who completed their anti-TB treatment, we genotyped by revealing the presence or absence of 215- and 480-bp bands of GSTM1 and GSTT1, respectively. We found that the prevalence of the GSTM1 genotype was 52.79% and 47.21% for presence and null, respectively, and for GSTT1 it was 69.76% and 30.24% for presence and null, respectively. Neither genotype was prevalent in the patients who developed DILI (n = 16). We did not confirm our hypothesis; however, we found that the combination of GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype had a significant risk for the development of ADR (OR 11; p = 0.017; 95% CI: (0.54–186.35)). We propose that the presence of the GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype in the Peruvian population could be considered a risk factor for the development of ADR due to therapeutic drug intake. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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18 pages, 502 KiB

Open AccessArticle

Genetic Variation among Pharmacogenes in the Sardinian Population

by Maria Laura Idda, Magdalena Zoledziewska, Silvana Anna Maria Urru, Gregory McInnes, Alice Bilotta, Viola Nuvoli, Valeria Lodde, Sandro Orrù, David Schlessinger, Francesco Cucca and Matteo Floris

Int. J. Mol. Sci. 2022, 23(17), 10058; https://doi.org/10.3390/ijms231710058 - 02 Sep 2022

Cited by 1 | Viewed by 2007

Abstract

Pharmacogenetics (PGx) aims to identify the genetic factors that determine inter-individual differences in response to drug treatment maximizing efficacy while decreasing the risk of adverse events. Estimating the prevalence of PGx variants involved in drug response, is a critical preparatory step for large-scale [...] Read more.

Pharmacogenetics (PGx) aims to identify the genetic factors that determine inter-individual differences in response to drug treatment maximizing efficacy while decreasing the risk of adverse events. Estimating the prevalence of PGx variants involved in drug response, is a critical preparatory step for large-scale implementation of a personalized medicine program in a target population. Here, we profiled pharmacogenetic variation in fourteen clinically relevant genes in a representative sample set of 1577 unrelated sequenced Sardinians, an ancient island population that accounts for genetic variation in Europe as a whole, and, at the same time is enriched in genetic variants that are very rare elsewhere. To this end, we used PGxPOP, a PGx allele caller based on the guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC), to identify the main phenotypes associated with the PGx alleles most represented in Sardinians. We estimated that 99.43% of Sardinian individuals might potentially respond atypically to at least one drug, that on average each individual is expected to have an abnormal response to about 17 drugs, and that for 27 drugs the fraction of the population at risk of atypical responses to therapy is more than 40%. Finally, we identified 174 pharmacogenetic variants for which the minor allele frequency was at least 10% higher among Sardinians as compared to other European populations, a fact that may contribute to substantial interpopulation variability in drug response phenotypes. This study provides baseline information for further large-scale pharmacogenomic investigations in the Sardinian population and underlines the importance of PGx characterization of diverse European populations, such as Sardinians. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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10 pages, 1476 KiB

Open AccessArticle

Inferred Ancestral Origin of Cancer Cell Lines Associates with Differential Drug Response

by Phong B. H. Nguyen, Alexander J. Ohnmacht, Samir Sharifli, Mathew J. Garnett and Michael P. Menden

Int. J. Mol. Sci. 2021, 22(18), 10135; https://doi.org/10.3390/ijms221810135 - 20 Sep 2021

Cited by 1 | Viewed by 3523

Abstract

Disparities between risk, treatment outcomes and survival rates in cancer patients across the world may be attributed to socioeconomic factors. In addition, the role of ancestry is frequently discussed. In preclinical studies, high-throughput drug screens in cancer cell lines have empowered the identification [...] Read more.

Disparities between risk, treatment outcomes and survival rates in cancer patients across the world may be attributed to socioeconomic factors. In addition, the role of ancestry is frequently discussed. In preclinical studies, high-throughput drug screens in cancer cell lines have empowered the identification of clinically relevant molecular biomarkers of drug sensitivity; however, the genetic ancestry from tissue donors has been largely neglected in this setting. In order to address this, here, we show that the inferred ancestry of cancer cell lines is conserved and may impact drug response in patients as a predictive covariate in high-throughput drug screens. We found that there are differential drug responses between European and East Asian ancestries, especially when treated with PI3K/mTOR inhibitors. Our finding emphasizes a new angle in precision medicine, as cancer intervention strategies should consider the germline landscape, thereby reducing the failure rate of clinical trials. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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12 pages, 3984 KiB

Open AccessArticle

Performance Comparisons of AlexNet and GoogLeNet in Cell Growth Inhibition IC50 Prediction

by Yeeun Lee and Seungyoon Nam

Int. J. Mol. Sci. 2021, 22(14), 7721; https://doi.org/10.3390/ijms22147721 - 19 Jul 2021

Cited by 11 | Viewed by 3315

Abstract

Drug responses in cancer are diverse due to heterogenous genomic profiles. Drug responsiveness prediction is important in clinical response to specific cancer treatments. Recently, multi-class drug responsiveness models based on deep learning (DL) models using molecular fingerprints and mutation statuses have emerged. However, [...] Read more.

Drug responses in cancer are diverse due to heterogenous genomic profiles. Drug responsiveness prediction is important in clinical response to specific cancer treatments. Recently, multi-class drug responsiveness models based on deep learning (DL) models using molecular fingerprints and mutation statuses have emerged. However, for multi-class models for drug responsiveness prediction, comparisons between convolution neural network (CNN) models (e.g., AlexNet and GoogLeNet) have not been performed. Therefore, in this study, we compared the two CNN models, GoogLeNet and AlexNet, along with the least absolute shrinkage and selection operator (LASSO) model as a baseline model. We constructed the models by taking drug molecular fingerprints of drugs and cell line mutation statuses, as input, to predict high-, intermediate-, and low-class for half-maximal inhibitory concentration (IC50) values of the drugs in the cancer cell lines. Additionally, we compared the models in breast cancer patients as well as in an independent gastric cancer cell line drug responsiveness data. We measured the model performance based on the area under receiver operating characteristic (ROC) curves (AUROC) value. In this study, we compared CNN models for multi-class drug responsiveness prediction. The AlexNet and GoogLeNet showed better performances in comparison to LASSO. Thus, DL models will be useful tools for precision oncology in terms of drug responsiveness prediction. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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16 pages, 3805 KiB

Open AccessArticle

In Silico Inference of Synthetic Cytotoxic Interactions from Paclitaxel Responses

by Jeong Hoon Lee, Kye Hwa Lee and Ju Han Kim

Int. J. Mol. Sci. 2021, 22(3), 1097; https://doi.org/10.3390/ijms22031097 - 22 Jan 2021

Viewed by 2071

Abstract

To exploit negatively interacting pairs of cancer somatic mutations in chemotherapy responses or synthetic cytotoxicity (SC), we systematically determined mutational pairs that had significantly lower paclitaxel half maximal inhibitory concentration (IC₅₀) values. We evaluated 407 cell lines with somatic mutation profiles [...] Read more.

To exploit negatively interacting pairs of cancer somatic mutations in chemotherapy responses or synthetic cytotoxicity (SC), we systematically determined mutational pairs that had significantly lower paclitaxel half maximal inhibitory concentration (IC₅₀) values. We evaluated 407 cell lines with somatic mutation profiles and estimated their copy number and drug-inhibitory concentrations in Genomics of Drug Sensitivity in Cancer (GDSC) database. The SC effect of 142 mutated gene pairs on response to paclitaxel was successfully cross-validated using human cancer datasets for urogenital cancers available in The Cancer Genome Atlas (TCGA) database. We further analyzed the cumulative effect of increasing SC pair numbers on the TP53 tumor suppressor gene. Patients with TCGA bladder and urogenital cancer exhibited improved cancer survival rates as the number of disrupted SC partners (i.e., SYNE2, SON, and/or PRY) of TP53 increased. The prognostic effect of SC burden on response to paclitaxel treatment could be differentiated from response to other cytotoxic drugs. Thus, the concept of pairwise SC may aid the identification of novel therapeutic and prognostic targets. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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Review

Jump to: Research, Other

20 pages, 893 KiB

Open AccessReview

Pharmacokinetic Markers of Clinical Outcomes in Severe Mental Illness: A Systematic Review

by Pasquale Paribello, Mirko Manchia, Federica Pinna, Ulker Isayeva, Alessio Squassina, Claudia Pisanu, Lorenzo Balderi, Martina Contu, Marco Pinna and Bernardo Carpiniello

Int. J. Mol. Sci. 2023, 24(5), 4776; https://doi.org/10.3390/ijms24054776 - 01 Mar 2023

Cited by 1 | Viewed by 1552

Abstract

The term severe mental illness (SMI) encompasses those psychiatric disorders exerting the highest clinical burden and socio-economic impact on the affected individuals and their communities. Pharmacogenomic (PGx) approaches hold great promise in personalizing treatment selection and clinical outcomes, possibly reducing the burden of [...] Read more.

The term severe mental illness (SMI) encompasses those psychiatric disorders exerting the highest clinical burden and socio-economic impact on the affected individuals and their communities. Pharmacogenomic (PGx) approaches hold great promise in personalizing treatment selection and clinical outcomes, possibly reducing the burden of SMI. Here, we sought to review the literature in the field, focusing on PGx testing and particularly on pharmacokinetic markers. We performed a systematic review on PUBMED/Medline, Web of Science, and Scopus. The last search was performed on the 17 September 2022, and further augmented with a comprehensive pearl-growing strategy. In total, 1979 records were screened, and after duplicate removal, 587 unique records were screened by at least 2 independent reviewers. Ultimately, forty-two articles were included in the qualitative analysis, eleven randomized controlled trials and thirty-one nonrandomized studies. The observed lack of standardization in PGx tests, population selection, and tested outcomes limit the overall interpretation of the available evidence. A growing body of evidence suggests that PGx testing might be cost-effective in specific settings and may modestly improve clinical outcomes. More efforts need to be directed toward improving PGx standardization, knowledge for all stakeholders, and clinical practice guidelines for screening recommendations. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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29 pages, 2763 KiB

Open AccessReview

Human Cytochrome P450 1, 2, 3 Families as Pharmacogenes with Emphases on Their Antimalarial and Antituberculosis Drugs and Prevalent African Alleles

by Chiratidzo R. Chamboko, Wayde Veldman, Rolland Bantar Tata, Birgit Schoeberl and Özlem Tastan Bishop

Int. J. Mol. Sci. 2023, 24(4), 3383; https://doi.org/10.3390/ijms24043383 - 08 Feb 2023

Cited by 4 | Viewed by 3307

Abstract

Precision medicine gives individuals tailored medical treatment, with the genotype determining the therapeutic strategy, the appropriate dosage, and the likelihood of benefit or toxicity. Cytochrome P450 (CYP) enzyme families 1, 2, and 3 play a pivotal role in eliminating most drugs. Factors that [...] Read more.

Precision medicine gives individuals tailored medical treatment, with the genotype determining the therapeutic strategy, the appropriate dosage, and the likelihood of benefit or toxicity. Cytochrome P450 (CYP) enzyme families 1, 2, and 3 play a pivotal role in eliminating most drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes. Therefore, polymorphisms of these enzymes result in alleles with diverse enzymatic activity and drug metabolism phenotypes. Africa has the highest CYP genetic diversity and also the highest burden of malaria and tuberculosis, and this review presents current general information on CYP enzymes together with variation data concerning antimalarial and antituberculosis drugs, while focusing on the first three CYP families. Afrocentric alleles such as CYP2A6*17, CYP2A6*23, CYP2A6*25, CYP2A6*28, CYP2B6*6, CYP2B6*18, CYP2C8*2, CYP2C9*5, CYP2C9*8, CYP2C9*9, CYP2C19*9, CYP2C19*13, CYP2C19*15, CYP2D6*2, CYP2D6*17, CYP2D6*29, and CYP3A4*15 are implicated in diverse metabolic phenotypes of different antimalarials such as artesunate, mefloquine, quinine, primaquine, and chloroquine. Moreover, CYP3A4, CYP1A1, CYP2C8, CYP2C18, CYP2C19, CYP2J2, and CYP1B1 are implicated in the metabolism of some second-line antituberculosis drugs such as bedaquiline and linezolid. Drug–drug interactions, induction/inhibition, and enzyme polymorphisms that influence the metabolism of antituberculosis, antimalarial, and other drugs, are explored. Moreover, a mapping of Afrocentric missense mutations to CYP structures and a documentation of their known effects provided structural insights, as understanding the mechanism of action of these enzymes and how the different alleles influence enzyme function is invaluable to the advancement of precision medicine. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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24 pages, 1634 KiB

Open AccessReview

Pharmacogenomics in Psychiatry Practice: The Value and the Challenges

by Aminah Alchakee, Munazza Ahmed, Leen Eldohaji, Hamid Alhaj and Maha Saber-Ayad

Int. J. Mol. Sci. 2022, 23(21), 13485; https://doi.org/10.3390/ijms232113485 - 03 Nov 2022

Cited by 5 | Viewed by 3757

Abstract

The activity of cytochrome P450 enzymes is influenced by genetic and nongenetic factors; hence, the metabolism of exogenous psychotropic medications and potentially some endogenous neuropeptides is variably affected among different ethnic groups of psychiatric patients. The aim of this review is to highlight [...] Read more.

The activity of cytochrome P450 enzymes is influenced by genetic and nongenetic factors; hence, the metabolism of exogenous psychotropic medications and potentially some endogenous neuropeptides is variably affected among different ethnic groups of psychiatric patients. The aim of this review is to highlight the most common cytochrome P450 isoenzymes associated with the metabolism of psychotropic medications (antidepressants, antipsychotics, and mood stabilizers), their variations among different populations, their impact on endogenous neurotransmitters (dopamine and serotonin), and the effect of nongenetic factors, particularly smoking, age, and pregnancy, on their metabolic activity. Furthermore, the adverse effects of psychiatric medications may be associated with certain human leukocytic antigen (HLA) genotypes. We also highlight the gene variants that may potentially increase susceptibility to obesity and metabolic syndrome, as the adverse effects of some psychiatry medications. Collectively, the literature revealed that variation of CYP450 activity is mostly investigated in relation to genetic polymorphism, and is directly correlated with individualized clinical outcomes; whereas adverse effects are associated with HLA variants, projecting the value of pharmacogenetics implementation in psychiatry clinics. Only a few previous studies have discussed the impact of such genetic variations on the metabolism of endogenous neuropeptides. In this review, we also report on the prevalence of key variants in different ethnicities, by demonstrating publicly available data from the 1000 Genomes Project and others. Finally, we highlight the future direction of further investigations to enhance the predictability of the individual gene variants to achieve precision therapies for psychiatric patients. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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74 pages, 22168 KiB

Open AccessReview

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

by Ramón Cacabelos, Vinogran Naidoo, Lola Corzo, Natalia Cacabelos and Juan C. Carril

Int. J. Mol. Sci. 2021, 22(24), 13302; https://doi.org/10.3390/ijms222413302 - 10 Dec 2021

Cited by 26 | Viewed by 6541

Abstract

Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug–drug interactions. Pharmacogenomics (PGx) provides the [...] Read more.

Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug–drug interactions. Pharmacogenomics (PGx) provides the physician effective clues for optimizing drug efficacy and safety in major problems of health such as cardiovascular disease and associated disorders, cancer and brain disorders. Important aspects to be considered are also the impact of immunopharmacogenomics in cutaneous ADRs as well as the influence of genomic factors associated with COVID-19 and vaccination strategies. Major limitations for the routine use of PGx procedures for ADRs prevention are the lack of education and training in physicians and pharmacists, poor characterization of drug-related PGx, unspecific biomarkers of drug efficacy and toxicity, cost-effectiveness, administrative problems in health organizations, and insufficient regulation for the generalized use of PGx in the clinical setting. The implementation of PGx requires: (i) education of physicians and all other parties involved in the use and benefits of PGx; (ii) prospective studies to demonstrate the benefits of PGx genotyping; (iii) standardization of PGx procedures and development of clinical guidelines; (iv) NGS and microarrays to cover genes with high PGx potential; and (v) new regulations for PGx-related drug development and PGx drug labelling. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

24 pages, 616 KiB

Open AccessReview

A Systematic Review of Parkinson’s Disease Pharmacogenomics: Is There Time for Translation into the Clinics?

by Vladimira Vuletić, Valentino Rački, Eliša Papić and Borut Peterlin

Int. J. Mol. Sci. 2021, 22(13), 7213; https://doi.org/10.3390/ijms22137213 - 05 Jul 2021

Cited by 6 | Viewed by 3633

Abstract

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects [...] Read more.

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson’s disease. Methods: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson’s disease treatment, along with a manual search, and finally included a total of 116 publications in the review. Results: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. Conclusions: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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9 pages, 447 KiB

Open AccessCase Report

Severe Adverse Drug Reactions to Quetiapine in Two Patients Carrying CYP2D6*4 Variants: A Case Report

by Céline K. Stäuble, Markus L. Lampert, Thorsten Mikoteit, Martin Hatzinger, Kurt E. Hersberger and Henriette E. Meyer zu Schwabedissen

Int. J. Mol. Sci. 2021, 22(12), 6480; https://doi.org/10.3390/ijms22126480 - 17 Jun 2021

Cited by 9 | Viewed by 3969

Abstract

We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to [...] Read more.

We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient’s pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine. Full article

(This article belongs to the Special Issue Pharmacogenomics 2.0)

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