Methods Mol Biol. 2022;2547:389-425. doi: 10.1007/978-1-0716-2573-6_14.

ABSTRACT

Antipsychotics are the mainstay treatment for schizophrenia. There is large variability between individuals in their response to antipsychotics, both in efficacy and adverse effects of treatment. While the source of interindividual variability in antipsychotic response is not completely understood, genetics is a major contributing factor. The identification of pharmacogenetic markers that predict antipsychotic efficacy and adverse reactions is a growing area of research and holds the potential to replace the current trial-and-error approach to treatment selection in schizophrenia with a personalized medicine approach.In this chapter, we provide an overview of the current state of pharmacogenetics in schizophrenia treatment. The most promising pharmacogenetic findings are presented for both antipsychotic response and commonly studied adverse reactions. The application of pharmacogenetics to schizophrenia treatment is discussed, with an emphasis on the clinical utility of pharmacogenetic testing and directions for future research.

PMID:36068471 | DOI:10.1007/978-1-0716-2573-6_14

Methods Mol Biol. 2022;2547:275-387. doi: 10.1007/978-1-0716-2573-6_13.

ABSTRACT

Alzheimer's disease (AD) is a priority health problem in developed countries with a high cost to society. Approximately 20% of direct costs are associated with pharmacological treatment. Over 90% of patients require multifactorial treatments, with risk of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) for the treatment of concomitant diseases such as hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60-90%), neuropsychiatric disorders (60-90%), and cancer (10%).For the past decades, pharmacological studies in search of potential treatments for AD focused on the following categories: neurotransmitter enhancers (11.38%), multitarget drugs (2.45%), anti-amyloid agents (13.30%), anti-tau agents (2.03%), natural products and derivatives (25.58%), novel synthetic drugs (8.13%), novel targets (5.66%), repository drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and other compounds (<1%).Pharmacogenetic studies have shown that the therapeutic response to drugs in AD is genotype-specific in close association with the gene clusters that constitute the pharmacogenetic machinery (pathogenic, mechanistic, metabolic, transporter, pleiotropic genes) under the regulatory control of epigenetic mechanisms (DNA methylation, histone/chromatin remodeling, microRNA regulation). Most AD patients (>60%) are carriers of over ten pathogenic genes. The genes that most frequently (>50%) accumulate pathogenic variants in the same AD case are A2M (54.38%), ACE (78.94%), BIN1 (57.89%), CLU (63.15%), CPZ (63.15%), LHFPL6 (52.63%), MS4A4E (50.87%), MS4A6A (63.15%), PICALM (54.38%), PRNP (80.7059), and PSEN1 (77.19%). There is also an accumulation of 15 to 26 defective pharmagenes in approximately 85% of AD patients. About 50% of AD patients are carriers of at least 20 mutant pharmagenes, and over 80% are deficient metabolizers for the most common drugs, which are metabolized via the CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 enzymes.The implementation of pharmacogenetics can help optimize drug development and the limited therapeutic resources available to treat AD, and personalize the use of anti-dementia drugs in combination with other medications for the treatment of concomitant disorders.

PMID:36068470 | DOI:10.1007/978-1-0716-2573-6_13

Methods Mol Biol. 2022;2547:255-266. doi: 10.1007/978-1-0716-2573-6_11.

ABSTRACT

Studies of genetic variants and systems biology have indicated that Yin-Yang dynamics are especially meaningful for cardiovascular pharmacogenomics and personalized therapeutic strategies. The comprehensive concepts of Yin-Yang can be used to characterize the dynamical factors in the adaptive microenvironments of the complex cardiovascular systems. The Yin-Yang imbalances in the complex adaptive systems (CAS) at different levels and stages are essential for cardiovascular diseases (CVDs), including atherosclerosis, hypertension, and heart failure (HF). At the molecular and cellular levels, Yin-Yang interconnections have been considered critical for genetic variants and various pathways, mitophagy, cell death, and cholesterol homeostasis. The significance of the adaptive and spatiotemporal factors in the nonlinear Yin-Yang interactions has been identified in different pathophysiological processes such as fibrosis. The Yin-Yang dynamical balances between proinflammatory and anti-inflammatory cytokines have vital roles in the complex reactions to stress and impairments to the heart. Procoagulant and anticoagulant lipids and lipoproteins in plasma have the Yin-Yang roles that increase or decrease thrombin productions and thrombosis. At the systems level, the Yin-Yang type of relationships has been suggested between atrial fibrillation (AF), diastolic dysfunction (DD), and HF. Based on such perceptions, systemic and personalized cardiovascular profiles can be constructed by embracing the features of CAS, especially the microenvironments and the adaptative pathophysiological stages. These features can be integrated into the comprehensive Yin-Yang dynamics framework to identify more accurate biomarkers for better prevention and treatments. The goal of reestablishing ubiquitous Yin-Yang dynamical balances may become the central theme for personalized and systems medicine for cardiovascular diseases.

PMID:36068468 | DOI:10.1007/978-1-0716-2573-6_11

Methods Mol Biol. 2022;2547:241-253. doi: 10.1007/978-1-0716-2573-6_10.

ABSTRACT

Calcium imaging is an invaluable technique to detect and characterize calcium flux in cells. The use of calcium dye provides information on the concentration and spatial distribution of calcium. Calcium imaging is a well-established technique to assess the calcium-induced calcium release mechanism in cardiomyocytes. It can also be used to characterize mutations in genes crucial for this mechanism that frequently causes arrhythmia. Here we describe a high-throughput methodology of calcium imaging that records individual calcium transients in more than 10,000 human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in less than 30 min.

PMID:36068467 | DOI:10.1007/978-1-0716-2573-6_10

Methods Mol Biol. 2022;2547:201-240. doi: 10.1007/978-1-0716-2573-6_9.

ABSTRACT

Precision medicine exemplifies the emergence of personalized treatment options which may benefit specific patient populations based upon their genetic makeup. Application of pharmacogenomics requires an understanding of how genetic variations impact pharmacokinetic and pharmacodynamic properties. This particular approach in pharmacotherapy is helpful because it can assist in and improve clinical decisions. Application of pharmacogenomics to cardiovascular pharmacotherapy provides for the ability of the medical provider to gain critical knowledge on a patient's response to various treatment options and risk of side effects.

PMID:36068466 | DOI:10.1007/978-1-0716-2573-6_9

Methods Mol Biol. 2022;2547:187-199. doi: 10.1007/978-1-0716-2573-6_8.

ABSTRACT

The SARS-CoV-2 virus has been the subject of intense pharmacological research. Various pharmacotherapeutic approaches including antiviral and immunotherapy are being explored. A pandemic, however, cannot depend on the development of new drugs; the time required for conventional drug discovery and development is far too lengthy. As such, repurposing drugs is being used as a viable approach for identifying pharmacological agents for COVID-19 infections. Evaluation of repurposed drug candidates with pharmacogenomic analysis is being used to identify near-term pharmacological remedies for COVID-19.

PMID:36068465 | DOI:10.1007/978-1-0716-2573-6_8

Methods Mol Biol. 2022;2547:165-185. doi: 10.1007/978-1-0716-2573-6_7.

ABSTRACT

The good clinical results of immune checkpoint inhibitors (ICIs) in recent cancer therapy and the success of RNA vaccines against SARS-nCoV2 have provided important lessons to the scientific community. On the one hand, the efficacy of ICI depends on the number and immunogenicity of tumor neoantigens (TNAs) which unfortunately are not abundantly expressed in many cancer subtypes. On the other hand, novel RNA vaccines have significantly improved both the stability and immunogenicity of mRNA and its efficient delivery, this way overcoming past technique limitations and also allowing a quick vaccine development at the same time. These two facts together have triggered a resurgence of therapeutic cancer vaccines which can be designed to include individual TNAs and be synthesized in a timeframe short enough to be suitable for the tailored treatment of a given cancer patient.In this chapter, we explain the pipeline for the synthesis of TNA-carrying RNA vaccines which encompasses several steps such as individual tumor next-generation sequencing (NGS), selection of immunogenic TNAs, nucleic acid synthesis, drug delivery systems, and immunogenicity assessment, all of each step comprising different alternatives and variations which will be discussed.

PMID:36068464 | DOI:10.1007/978-1-0716-2573-6_7

Methods Mol Biol. 2022;2547:141-163. doi: 10.1007/978-1-0716-2573-6_6.

ABSTRACT

The enormous heterogeneity of cancer systems has made it very challenging to overcome drug resistance and adverse reactions to achieve personalized therapies. Recent developments in systems biology, especially the perception of cancer as the complex adaptive system (CAS), may help meet the challenges by deciphering the interactions at various levels from the molecular, cellular, tissue-organ, to the whole organism. The ubiquitous Yin-Yang interactions among the coevolving components, including the genes and proteins, decide their spatiotemporal features at various stages from cancer initiation to metastasis. The Yin-Yang imbalances across different systems levels, from genetic mutations to tumor cells adaptation, have been related to the intra- and inter-tumoral heterogeneity in the micro- and macro-environments. At the molecular and cellular levels, dysfunctional Yin-Yang dynamics in the cytokine networks, mitochondrial activities, redox systems, apoptosis, and metabolism can contribute to tumor cell growth and escape of immune surveillance. Up to the organism and system levels, the Yin-Yang imbalances in the cancer microenvironments can lead to different phenotypes from breast cancer to leukemia. These factors may be considered the systems-based biomarkers and treatment targets. The features of adaptation and nonlinearity in Yin-Yang dynamical interactions should be addressed by individualized drug combinations, dosages, intensities, timing, and frequencies at different cancer stages. The comprehensive "Yin-Yang dynamics" framework would enable powerful approaches for personalized and systems medicine strategies.

PMID:36068463 | DOI:10.1007/978-1-0716-2573-6_6

Methods Mol Biol. 2022;2547:95-140. doi: 10.1007/978-1-0716-2573-6_5.

ABSTRACT

Pharmacogenomics is a powerful tool to predict individual response to treatment, in order to personalize therapy, and it has been explored extensively in oncology practice. Not only efficacy on the malignant disease has been investigated but also the possibility to predict adverse effects due to drug administration. Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of those. This potentially severe and long-lasting/permanent side effect of commonly administered anticancer drugs can severely impair quality of life (QoL) in a large cohort of long survival patients. So far, a pharmacogenomics-based approach in CIPN regard has been quite delusive, making a methodological improvement warranted in this field of interest: even the most refined genetic analysis cannot be effective if not applied correctly. Here we try to devise why it is so, suggesting how THE "bench-side" (pharmacogenomics) might benefit from and should cooperate with THE "bed-side" (clinimetrics), in order to make genetic profiling effective if applied to CIPN.

PMID:36068462 | DOI:10.1007/978-1-0716-2573-6_5

Methods Mol Biol. 2022;2547:63-94. doi: 10.1007/978-1-0716-2573-6_4.

ABSTRACT

Pharmacogenetic testing in patients with cancer requiring cytotoxic chemotherapy offers the potential to predict, prevent, and mitigate chemotherapy-related toxicities. While multiple drug-gene pairs have been identified and studied, few drug-gene pairs are currently used routinely in the clinical status. Here we review what is known, theorized, and unknown regarding the use of pharmacogenetic testing in cancer.

PMID:36068461 | DOI:10.1007/978-1-0716-2573-6_4

Methods Mol Biol. 2022;2547:47-61. doi: 10.1007/978-1-0716-2573-6_3.

ABSTRACT

Targeted therapies have significantly altered the landscape of available cancer therapies across all diagnoses and patient populations, and supportive care therapies have steadily improved throughout the years to make therapy more tolerable for patients. Even so, these therapies have varied efficacy and toxicity among patients with cancer, and pharmacogenomics presents an opportunity to identify which patients are most at risk of toxicities and most likely to benefit from them. While the field of pharmacogenomics in targeted cancer therapy is still growing, we review current knowledge, hypotheses, and clinical practices in this chapter, along with a brief review of pharmacogenomics in supportive therapies in cancer treatment.

PMID:36068460 | DOI:10.1007/978-1-0716-2573-6_3

Methods Mol Biol. 2022;2547:21-45. doi: 10.1007/978-1-0716-2573-6_2.

ABSTRACT

The genetic region on the short arm of chromosome 6 where the human leukocyte antigen (HLA) genes are located is the major histocompatibility complex. The genes in this region are highly polymorphic, and some loci have a high degree of homology with other genes and pseudogenes. Histocompatibility testing has traditionally been performed in the setting of transplantation and involves determining which specific alleles are present. Several HLA alleles have been associated with disease risk or increased risk of adverse drug reaction (ADR) when treated with certain medications. Testing for these applications differs from traditional histocompatibility in that the desired result is simply presence or absence of the allele of interest, rather than determining which allele is present. At present, the majority of HLA typing is done by molecular methods using commercially available kits. A subset of pharmacogenomics laboratories has developed their own methods, and in some cases, query single nucleotide variants associated with certain HLA alleles rather than directly testing for the allele. In this chapter, a brief introduction to the HLA system is provided, followed by an overview of a variety of testing technologies including those specifically used in pharmacogenomics, and the chapter concludes with details regarding specific HLA alleles associated with ADR.

PMID:36068459 | DOI:10.1007/978-1-0716-2573-6_2

Pharmacogenomics J. 2022 Sep 6. doi: 10.1038/s41397-022-00288-2. Online ahead of print.

ABSTRACT

Genes encoding cytochrome P450 enzymes (CYPs) are extremely polymorphic and multiple CYP variants constitute clinically relevant biomarkers for the guidance of drug selection and dosing. We previously reported the distribution of the most relevant CYP alleles using population-scale sequencing data. Here, we update these findings by making use of the increasing wealth of data, incorporating whole exome and whole genome sequencing data from 141,614 unrelated individuals across 12 human populations. We furthermore extend our previous studies by systematically considering also uncharacterized rare alleles and reveal that they contribute between 1.5% and 17.5% to the overall genetically encoded functional variability. By using established guidelines, we aggregate and translate the available sequencing data into population-specific patterns of metabolizer phenotypes. Combined, the presented data refine the worldwide landscape of ethnogeographic variability in CYP genes and aspire to provide a relevant resource for the optimization of population-specific genotyping strategies and precision public health.

PMID:36068297 | DOI:10.1038/s41397-022-00288-2

Metabolism. 2022 Sep 3:155309. doi: 10.1016/j.metabol.2022.155309. Online ahead of print.

NO ABSTRACT

PMID:36067806 | DOI:10.1016/j.metabol.2022.155309

Ugeskr Laeger. 2022 Aug 22;184(34):V05220300.

ABSTRACT

Use of predictive biomarkers plays a promising role in stratifying patients to a more effective medical treatment with less side effects. This review provides a brief overview in a Danish context of the potential of applying pharmacogenomics (PGx) including companion diagnostics (CDx) in daily clinical practice based on the current knowledge and regulation from the FDA and EMA, Summary of Product Characteristics (SPC), PharmGKB (pharmacogenomics knowledge resource providing clinical dosing guidelines) and partly promedicin.dk. Also, the barriers to more widespread use are being addressed.

PMID:36065863

Expert Rev Clin Pharmacol. 2022 Sep 5:1-11. doi: 10.1080/17512433.2022.2118714. Online ahead of print.

ABSTRACT

INTRODUCTION: Metformin has been recognized as the first-choice drug for type 2 diabetes mellitus (T2DM). The potency of metformin in the treatment of type 2 diabetes has always been in the spotlight and shown significant individual differences. Based on previous studies, the efficacy of metformin is related to the single-nucleotide polymorphisms of transporter genes carried by patients, amongst which a variety of gene polymorphisms of transporter and target protein genes affect the effectiveness and adverse repercussion of metformin.

AREAS COVERED: Here, we reviewed the current knowledge about gene polymorphisms impacting metformin efficacy based on transporter and drug target proteins.

EXPERT OPINION: The reason for the difference in clinical drug potency of metformin can be attributed to the gene polymorphism of drug transporters and drug target proteins in the human body. Substantial evidence shows that genetic polymorphisms in transporters such as organic cation transporter 1 (OCT1) and organic cation transporter 2 (OCT2) affect the glucose-lowering effectiveness of metformin. However, optimization of individualized dosing regimens of metformin is necessary to clarify the role of several polymorphisms.

PMID:36065506 | DOI:10.1080/17512433.2022.2118714

Life Sci. 2022 Sep 2:120929. doi: 10.1016/j.lfs.2022.120929. Online ahead of print.

ABSTRACT

AIMS: Although impaired insulin signaling at a post-receptor level was a well-established key driver of insulin resistance, the role of surface abnormal insulin receptor (INSR) location in insulin resistance pathogenesis tended to be ignored and its molecular mechanisms remained obscure. Herein, this study aimed to investigate hepatic apolipoprotein E (APOE) impaired cellular insulin action via reducing cell surface INSR, especially in caveolae.

KEY FINDINGS: Downregulation of APOE enhanced the caveolae translocation of INSR and glucose transporter 2 (GLUT2), and improved hepatic cells' sensitivity to insulin. Consistently, mice with selective suppression of liver tissue APOE showed lower fasting insulin and fasting glucose levels, better homeostatic model assessment (HOMA) index (HOMA-IS, HOMA-IR, HOMA-β) and quantitative insulin sensitivity check index (QUICKI). Furthermore, the co-localization of INSR and CAV1 in the liver of these mice were more substantial than controls.

SIGNIFICANCE: APOE might adversely set the basal gain of INSR signaling implied that APOE could be a new endogenous INSR regulator.

PMID:36063979 | DOI:10.1016/j.lfs.2022.120929

Eur J Haematol. 2022 Sep 5. doi: 10.1111/ejh.13862. Online ahead of print.

ABSTRACT

Acute myeloid leukemia (AML) is a complex disease, and its treatment needs to be adjusted to the risk, which is conferred by cytogenetics and molecular markers. Cytarabine is the main drug to treat AML, and it has been suggested that the genotype of cytarabine metabolizing enzymes may have a prognostic relevance in AML. Here we report the association between the 5'-nucleotidase, cytosolic II (NT5C2) rs10883841, cytidine deaminase (CDA) rs2072671 and rs532545 genotypes and the clinical outcome of 477 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients younger than 50 years old with the NT5C2 rs10883841 AA genotype had lower overall survival (OS) (p: 0.003; HR 2.16, 95%CI 1.29 - 3.61) and lower disease-free survival (DFS) (p: 0.002; HR 2.45, 95%CI 1.41 - 4.27), associated to a higher relapse incidence (p: 0.010; HR 2.23, 95%CI 1.21 - 4.12). Interestingly, subgroup analysis showed that the negative effect of the NT5C2 rs10883841 AA genotype was detected in all subgroups except in patients with nucleophosmin mutation without high ratio FLT-3 internal tandem duplication. CDA polymorphisms were associated with the complete remission rate after induction chemotherapy, without influencing OS. Further studies are warranted to determine whether this pharmacogenomic approach may be helpful to individualize AML treatment.

PMID:36063368 | DOI:10.1111/ejh.13862

Cardiovasc Res. 2022 Sep 5:cvac150. doi: 10.1093/cvr/cvac150. Online ahead of print.

NO ABSTRACT

PMID:36063101 | DOI:10.1093/cvr/cvac150

Front Pharmacol. 2022 Aug 17;13:943538. doi: 10.3389/fphar.2022.943538. eCollection 2022.

ABSTRACT

Cytochrome P450 (CYP) drug metabolizing enzymes are responsible for the metabolism of over 70% of currently used medications with the CYP3A family being the most important CYP enzymes in the liver. Large inter-person variability in expression/activity of the CYP3As greatly affects drug exposure and treatment outcomes, yet the cause of such variability remains elusive. Micro-RNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression and are involved in diverse cellular processes including metabolism of xenobiotics and therapeutic outcomes. Target prediction and in vitro functional assays have linked several miRNAs to the control of CYP3A4 expression. Yet, their co-expression with CYP3As in the liver remain unclear. In this study, we used genome-wide miRNA profiling in liver samples to identify miRNAs associated with the expression of the CYP3As. We identified and validated both miR-107 and miR-1260 as strongly associated with the expression of CYP3A4, CYP3A5, and CYP3A43. Moreover, we found associations between miR-107 and nine transcription factors (TFs) that regulate CYP3A expression, with estrogen receptor alpha (ESR1) having the largest effect size. Including ESR1 and the other TFs in the regression model either diminished or abolished the associations between miR-107 and the CYP3As, indicating that the role of miR-107 in CYP3A expression may be indirect and occur through these key TFs. Indeed, testing the other nine CYPs previously shown to be regulated by ESR1 identified similar miR-107 associations that were dependent on the exclusion of ESR1 and other key TFs in the regression model. In addition, we found significant differences in miRNA expression profiles in liver samples between race and sex. Together, our results identify miR-107 as a potential epigenetic regulator that is strongly associated with the expression of many CYPs, likely via impacting the CYP regulatory network controlled by ESR1 and other key TFs. Therefore, both genetic and epigenetic factors that alter the expression of miR-107 may have a broad influence on drug metabolism.

PMID:36059981 | PMC:PMC9428441 | DOI:10.3389/fphar.2022.943538