Genes (Basel). 2022 Feb 10;13(2):330. doi: 10.3390/genes13020330.

ABSTRACT

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm derived from the balanced reciprocal translocation of chromosomes 9 and 22 t (9q34 and 22q11), which leads to the formation of the Philadelphia chromosome and fusion of the BCR-ABL genes. The first-line treatment for CML is imatinib, a tyrosine kinase inhibitor that acts on the BCR-ABL protein. However, even though it is a target-specific drug, about 25% of patients do not respond to this treatment. The resistance mechanisms involved in this process have been investigated and studies have shown that germinal alterations can influence this mechanism. The aim of this work was to investigate 32 polymorphisms in 24 genes of carcinogenic pathway to verify the influence of these genetic variants on the response to treatment with imatinib. Our results demonstrated that individuals with the recessive GG genotype for the rs2372536 variant in the ATIC gene are approximately three times more likely to experience treatment failure with imatinib (p = 0.045, HR = 2.726, 95% CI = 0.9986-7.441), as well as individuals with the TT genotype for the rs10821936 variant in the ARID5B gene, who also have a higher risk for treatment failure with imatinib over time (p = 0.02, HR = 0.4053, IC 95% = 0.1802-0.911). In conclusion, we show that variants in the ATIC and ARIDB5 gene, never screened in previous studies, could potentially influence the therapeutic response to imatinib in patients treated for CML.

PMID:35205374 | DOI:10.3390/genes13020330

Genes (Basel). 2022 Feb 7;13(2):311. doi: 10.3390/genes13020311.

ABSTRACT

Pharmacogenomics is based on the understanding of the individual differences in drug use, the response to drug therapy (efficacy and toxicity), and the mechanisms underlying variable drug responses. The identification of DNA variants which markedly contribute to inter-individual variations in drug responses would improve the efficacy of treatments and decrease the rate of the adverse side effects of drugs. This review focuses only on the impact of polymorphisms within drug-metabolizing enzymes on drug responses. Anticancer drugs usually have a very narrow therapeutic index; therefore, it is very important to use appropriate doses in order to achieve the maximum benefits without putting the patient at risk of life-threatening toxicities. However, the adjustment of the appropriate dose is not so easy, due to the inheritance of specific polymorphisms in the genes encoding the target proteins and drug-metabolizing enzymes. This review presents just a few examples of such polymorphisms and their impact on the response to therapy.

PMID:35205356 | DOI:10.3390/genes13020311

Genes (Basel). 2022 Jan 29;13(2):269. doi: 10.3390/genes13020269.

ABSTRACT

Pharmacists are considered among the most accessible healthcare workers in fundamental positions to implement new clinical initiatives, such as pharmacogenomics services. The scope of pharmacogenomics in improving health outcomes and the quality of health care is well-known. Implementation of such initiatives requires adequate knowledge, perception, and positive attitudes among pharmacists. A study was conducted on pharmacy students at King Saud University in Riyadh to analyze their attitudes, knowledge, and perceptions concerning pharmacogenomics to explore the feasibility of establishing full-time pharmacogenomics instruction and services. A cross-sectional study was carried out in one of the significant pharmacy schools of Saudi Arabia, using a simple questionnaire-based survey in pharmacy students pursuing Bpharm and PharmD courses to obtain preliminary information about pharmacogenomics among the surveyed population. The study's secondary objective was to determine the perceived belief about pharmacogenomics implementation in clinical practice. Out of the total of 552 participants, 41.8% correctly defined pharmacogenomics and 81.3% understood that genetic change could lead to adverse reactions. More than half of the participants agreed that the FDA recommends pharmacogenomics testing for certain drugs. The knowledge about a year of use of pharmacogenomics in clinical practice was found to be very low; only 15.2% could correctly answer. Only 60% of students agreed on pharmacogenomics testing for selecting the therapy with the most negligible adverse effects. Due to the limited knowledge about and understanding of pharmacogenomics, there is a lack of interest among pharmacy students in implementing pharmacogenomics testing in clinical practice. Our study highlights the need for improving pharmacy students' knowledge about pharmacogenomics and pharmacogenetics so that the implementation of pharmacogenomics testing in clinical practice will become easier. There is a need to introduce an up-to-date curriculum for pharmacy courses other pharmacogenomics-based health education programs in Saudi Arabia.

PMID:35205314 | DOI:10.3390/genes13020269

Biology (Basel). 2022 Jan 25;11(2):185. doi: 10.3390/biology11020185.

ABSTRACT

Alternative lengthening of telomeres-associated promyelocytic leukemia nuclear bodies (APBs) are a hallmark of telomere maintenance. In the last few years, APBs have been described as the main place where telomeric extension occurs in ALT-positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multiomics analyses to evaluate genomic, transcriptomic and proteomic alterations, and functional interactions of 71 APBs-related genes/proteins in 32 Pan-Cancer Atlas studies from The Cancer Genome Atlas Consortium (TCGA). As a result, we identified 13 key proteins which showed distinctive mutations, interactions, and functional enrichment patterns across all the cancer types and proposed this set of proteins as candidates for future ex vivo and in vivo analyses that will validate these proteins to improve the understanding of the ALT pathway, fill the current research gap about APBs function and their role in ALT, and be considered as potential therapeutic targets for the diagnosis and treatment of ALT-positive cancers in the future.

PMID:35205052 | DOI:10.3390/biology11020185

Biology (Basel). 2022 Jan 23;11(2):178. doi: 10.3390/biology11020178.

ABSTRACT

The rapid spread of COVID-19 outbreak lead to a global pandemic declared in March 2020. The common features of corona virus family helped to resolve structural characteristics and entry mechanism of SARS-CoV-2. However, rapid mutagenesis leads to the emergence of new strains that may have different reproduction rates or infectivity and may impact the course and severity of the disease. Host related factors may also play a role in the susceptibility for infection as well as the severity and outcomes of the COVID-19. We have performed a literature and database search to summarize potential viral and host-related genomic and epigenomic biomarkers, such as genetic variability, miRNA, and DNA methylation in the molecular pathway of SARS-CoV-2 entry into the host cell, that may be related to COVID-19 susceptibility and severity. Bioinformatics tools may help to predict the effect of mutations in the spike protein on the binding to the ACE2 receptor and the infectivity of the strain. SARS-CoV-2 may also target several transcription factors and tumour suppressor genes, thus influencing the expression of different host genes and affecting cell signalling. In addition, the virus may interfere with RNA expression in host cells by exploiting endogenous miRNA and its viral RNA. Our analysis showed that numerous human miRNA may form duplexes with different coding and non-coding regions of viral RNA. Polymorphisms in human genes responsible for viral entry and replication, as well as in molecular damage response and inflammatory pathways may also contribute to disease prognosis and outcome. Gene ontology analysis shows that proteins encoded by such polymorphic genes are highly interconnected in regulation of defense response. Thus, virus and host related genetic and epigenetic biomarkers may help to predict the course of the disease and the response to treatment.

PMID:35205046 | DOI:10.3390/biology11020178

Brain Sci. 2022 Jan 31;12(2):206. doi: 10.3390/brainsci12020206.

ABSTRACT

Understanding the role of the noradrenergic nucleus locus coeruleus (LC) in cognition and behavior is critical: It is involved in several key behavioral functions such as stress and vigilance, as well as in cognitive processes such as attention and decision making. In recent years, the development of viral tools has provided a clear insight into numerous aspects of brain functions in rodents. However, given the specificity of primate brains and the key benefit of monkey research for translational applications, developing viral tools to study the LC in monkeys is essential for understanding its function and exploring potential clinical strategies. Here, we describe a pharmacogenetics approach that allows to selectively and reversibly inactivate LC neurons using Designer Receptors Exclusively Activated by Designer Drugs (DREADD). We show that the expression of the hM4Di DREADD can be restricted to noradrenergic LC neurons and that the amount of LC inhibition can be adjusted by adapting the dose of the specific DREADD activator deschloroclozapine (DCZ). Indeed, even if high doses (>0.3 mg/kg) induce a massive inhibition of LC neurons and a clear decrease in vigilance, smaller doses (<0.3 mg/kg) induce a more moderate decrease in LC activity, but it does not affect vigilance, which is more compatible with an assessment of subtle cognitive functions such as decision making and attention.

PMID:35203969 | DOI:10.3390/brainsci12020206

Biomedicines. 2022 Feb 4;10(2):378. doi: 10.3390/biomedicines10020378.

ABSTRACT

Mesenchymal stem cells (MSCs) represent the basis of novel clinical concepts in cellular therapy and tissue regeneration. Therefore, the isolation of MSCs from various tissues has become an important endeavour for stem cell biobanking and the development of regenerative therapies. Paravertebral adipose tissue is readily exposed during spinal procedures in children and could be a viable source of stem cells for therapeutic applications. Here, we describe the first case of MSCs isolated from paravertebral adipose tissue (PV-ADMSCs), obtained during a routine spinal surgery on a child. Using quantitative real-time PCR and flow cytometry, we show that PV-ADMSCs have different levels of stem marker expression compared to the MSCs from other sources while having the highest proliferation rate. Furthermore, we evaluate the multipotency of PV-ADMSCs by the three-lineage (adipogenic, osteogenic and chondrogenic) differentiation and compare it to the multipotency of MSCs from other sources. It was found that the PV-ADMSCs have a strong osteogenic potential in particular. Taken together, our data indicate that PV-ADMSCs meet the criteria for successful cell therapy, defined by the International Society for Cellular Therapy (ISCT), and thus, could provide a source of MSCs that is relatively easy to isolate and expand in culture. Due to their strong osteogenic potential, these cells provide a promising basis, especially for orthopaedic applications.

PMID:35203587 | DOI:10.3390/biomedicines10020378

Biomedicines. 2022 Feb 3;10(2):370. doi: 10.3390/biomedicines10020370.

ABSTRACT

The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado-Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a Caenorhabditis elegans&nbsp;(C. elegans) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D2-like and serotonin 5-HT1A and 5-HT2A receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole's cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole.

PMID:35203579 | DOI:10.3390/biomedicines10020370

Biomedicines. 2022 Jan 23;10(2):240. doi: 10.3390/biomedicines10020240.

ABSTRACT

Gastric cancer (GC) is one of the major causes of cancer-related mortality worldwide. The vast majority of GC cases are adenocarcinomas including intestinal and diffuse GC. The incidence of diffuse GCs, often associated with poor overall survival, has constantly increased in USA and Europe The molecular basis of diffuse GC aggressivity remains unclear. Using mRNA from diffuse and intestinal GC tumor samples of a Western cohort, this study reports the expression level of the immunomodulatory aryl-hydrocarbon receptor (AhR), and genes involved in immune suppression (PD1, PD-L1, PD-L2) and the early steps of tryptophan metabolism (IDO1, IDO2, TDO2). Strongly increased expression of IDO1 (p < 0.001) and PD1 (p < 0.003) was observed in the intestinal sub-type. The highest expression of IDO1 and PDL1 correlated with early clinical stage and absence of lymphatic invasion (×25 p = 0.004, ×3 p = 0.04, respectively). Our results suggest that kynurenine, produced by tryptophan catabolism, and AhR activation play a central role in creating an immunosuppressive environment. Correspondingly, as compared to intestinal GCs, expression levels of IDO1-TDO2 and PD-L1 were less prominent in diffuse GCs which also had less infiltration of immune cells, suggesting an inactive immune response in the advanced diffuse GC. Confirmation of these patterns of gene expression will require a larger cohort of early and advanced stages of diffuse GC samples.

PMID:35203450 | DOI:10.3390/biomedicines10020240

Cells. 2022 Feb 17;11(4):702. doi: 10.3390/cells11040702.

ABSTRACT

The mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol-3 kinase (PI3K)/AKT pathways are dysregulated in various human cancers, including pancreatic ductal adenocarcinoma (PDAC), which has a very poor prognosis due to its lack of efficient therapies. We have previously identified ACAGT-007a (GT-7), an anti-cancer compound that kills ERK-active melanoma cells by inducing ERK-dependent apoptosis. Here, we investigated the apoptosis-inducing effect of GT-7 on three PDAC cell lines and its relevance with the MAPK/ERK and PI3K/AKT signaling pathways. GT-7 induced apoptosis in PDAC cells with different KRAS mutations (MIA-Pa-Ca-2 (KRAS G12C), T3M4 (KRAS Q61H), and PANC-1 (KRAS G12D)), being T3M4 most susceptible, followed by MIA-Pa-Ca-2, and PANC-1 was most resistant to apoptosis induction by GT-7. GT-7 stimulated ERK phosphorylation in the three PDAC cells, but only T3M4 displayed ERK-activation-dependent apoptosis. Furthermore, GT-7 induced a marked down-regulation of AKT phosphorylation after a transient peak in T3M4, whereas PANC-1 displayed the strongest and most sustained AKT activation, followed by MIA-Pa-Ca-2, suggesting that sustained AKT phosphorylation as a determinant for the resistance to GT-7-mediated apoptosis. Consistently, a PI3K inhibitor, Wortmannin, abolished AKT phosphorylation and enhanced GT-7-mediated apoptosis in T3M4 and MIA-Pa-Ca-2, but not in PANC-1, which showed residual AKT phosphorylation. This is the first report that ERK stimulation alone or in combination with AKT signaling inhibition can effectively induce apoptosis in PDAC and provides a rationale for a novel concurrent targeting of the PI3K/AKT and ERK pathways.

PMID:35203351 | DOI:10.3390/cells11040702

Cells. 2022 Feb 10;11(4):607. doi: 10.3390/cells11040607.

ABSTRACT

MicroRNAs (miRNAs) create systems networks and gene-expression circuits through molecular signaling and cell interactions that contribute to health imbalance and the emergence of cardiovascular disorders (CVDs). Because the clinical phenotypes of CVD patients present a diversity in their pathophysiology and heterogeneity at the molecular level, it is essential to establish genomic signatures to delineate multifactorial correlations, and to unveil the variability seen in therapeutic intervention outcomes. The clinically validated miRNA biomarkers, along with the relevant SNPs identified, have to be suitably implemented in the clinical setting in order to enhance patient stratification capacity, to contribute to a better understanding of the underlying pathophysiological mechanisms, to guide the selection of innovative therapeutic schemes, and to identify innovative drugs and delivery systems. In this article, the miRNA-gene networks and the genomic signatures resulting from the SNPs will be analyzed as a method of highlighting specific gene-signaling circuits as sources of molecular knowledge which is relevant to CVDs. In concordance with this concept, and as a case study, the design of the clinical trial GESS (NCT03150680) is referenced. The latter is presented in a manner to provide a direction for the improvement of the implementation of pharmacogenomics and precision cardiovascular medicine trials.

PMID:35203258 | DOI:10.3390/cells11040607

Clin Pharmacol Ther. 2022 Feb 24. doi: 10.1002/cpt.2563. Online ahead of print.

ABSTRACT

The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP3A5 gene. Genetic variation within the CYP3A5 gene locus impacts the metabolism of several clinically important drugs, including the immunosuppressants tacrolimus, sirolimus, cyclosporine, and the benzodiazepine midazolam. Variable CYP3A5 activity is of clinical importance regarding tacrolimus metabolism. This GeneFocus provides a CYP3A5 gene summary with a focus on aspects regarding standardized nomenclature. In addition, this review also summarizes recent changes and updates including the retirement of several allelic variants and provides an overview of how PharmVar CYP3A5 star allele nomenclature is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

PMID:35202484 | DOI:10.1002/cpt.2563

JCO Precis Oncol. 2022 Feb;6:e2100312. doi: 10.1200/PO.21.00312.

ABSTRACT

PURPOSE: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer.

METHODS: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes.

RESULTS: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme.

CONCLUSION: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.

PMID:35201852 | DOI:10.1200/PO.21.00312

Curr Res Microb Sci. 2022 Feb 10;3:100111. doi: 10.1016/j.crmicr.2022.100111. eCollection 2022.

ABSTRACT

Riboflavin, or more commonly known as vitamin B2, forms part of the component of vitamin B complex. Riboflavin consisting of two important cofactors, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are involved in multiple oxidative-reduction processes and energy metabolism. Besides maintaining human health, different sources reported that riboflavin can inhibit or inactivate the growth of different pathogens including bacteria, viruses, fungi and parasites, highlighting the possible role of riboflavin as an antimicrobial agent. Moreover, riboflavin and flavins could produce reactive oxygen species (ROS) when exposed to light, inducing oxidative damage in cells and tissues, and thus are excellent natural photosensitizers. Several studies have illustrated the therapeutic efficacy of photoactivated riboflavin against nosocomial infections and multidrug resistant bacterial infections as well as microbial associated biofilm infections, revealing the potential role of riboflavin as a promising antimicrobial candidate, which could serve as one of the alternatives in fighting the global crisis of the emergence of antimicrobial resistance seen in different pathogenic microbes. Riboflavin could also be involved in modulating host immune responses, which might increase the pathogen clearance from host cells and increase host defense against microbial infections. Thus, the dual effects of riboflavin on both pathogens and host immunity, reflected by its potent bactericidal effect and alleviation of inflammation in host cells further imply that riboflavin could be a potential candidate for therapeutic intervention in resolving microbial infections. Hence, this review aimed to provide some insights on the promising role of riboflavin as an antimicrobial candidate and also a host immune-modulator from a multi-perspective view as well as to discuss the application and challenges on using riboflavin in photodynamic therapy against various pathogens and microbial biofilm-associated infections.

PMID:35199072 | PMC:PMC8848291 | DOI:10.1016/j.crmicr.2022.100111

CJC Open. 2021 Sep 25;4(2):115-132. doi: 10.1016/j.cjco.2021.09.013. eCollection 2022 Feb.

ABSTRACT

Women have unique sex- and gender-related risk factors for cardiovascular disease (CVD) that can present or evolve over their lifespan. Pregnancy-associated conditions, polycystic ovarian syndrome, and menopause can increase a woman's risk of CVD. Women are at greater risk for autoimmune rheumatic disorders, which play a role in the predisposition and pathogenesis of CVD. The influence of traditional CVD risk factors (eg, smoking, hypertension, diabetes, obesity, physical inactivity, depression, anxiety, and family history) is greater in women than men. Finally, there are sex differences in the response to treatments for CVD risk and comorbid disease processes. In this Atlas chapter we review sex- and gender-unique CVD risk factors that can occur across a woman's lifespan, with the aim to reduce knowledge gaps and guide the development of optimal strategies for awareness and treatment.

PMID:35198930 | PMC:PMC8843896 | DOI:10.1016/j.cjco.2021.09.013

Oxid Med Cell Longev. 2022 Feb 14;2022:8214821. doi: 10.1155/2022/8214821. eCollection 2022.

ABSTRACT

Crocus species are mainly distributed in North Africa, Southern and Central Europe, and Western Asia, used in gardens and parks as ornamental plants, while Crocus sativus L. (saffron) is the only species that is cultivated for edible purpose. The use of saffron is very ancient; besides the use as a spice, saffron has long been known also for its medical and coloring qualities. Due to its distinctive flavor and color, it is used as a spice, which imparts food preservative activity owing to its antimicrobial and antioxidant activity. This updated review discusses the biological properties of Crocus sativus L. and its phytoconstituents, their pharmacological activities, signaling pathways, and molecular targets, therefore highlighting it as a potential herbal medicine. Clinical studies regarding its pharmacologic potential in clinical therapeutics and toxicity studies were also reviewed. For this updated review, a search was performed in the PubMed, Science, and Google Scholar databases using keywords related to Crocus sativus L. and the biological properties of its phytoconstituents. From this search, only the relevant works were selected. The phytochemistry of the most important bioactive compounds in Crocus sativus L. such as crocin, crocetin, picrocrocin, and safranal and also dozens of other compounds was studied and identified by various physicochemical methods. Isolated compounds and various extracts have proven their pharmacological efficacy at the molecular level and signaling pathways both in vitro and in vivo. In addition, toxicity studies and clinical trials were analyzed. The research results highlighted the various pharmacological potentials such as antimicrobial, antioxidant, cytotoxic, cardioprotective, neuroprotective, antidepressant, hypolipidemic, and antihyperglycemic properties and protector of retinal lesions. Due to its antioxidant and antimicrobial properties, saffron has proven effective as a natural food preservative. Starting from the traditional uses for the treatment of several diseases, the bioactive compounds of Crocus sativus L. have proven their effectiveness in modern pharmacological research. However, pharmacological studies are needed in the future to identify new mechanisms of action, pharmacokinetic studies, new pharmaceutical formulations for target transport, and possible interaction with allopathic drugs.

PMID:35198096 | PMC:PMC8860555 | DOI:10.1155/2022/8214821

Ann Appl Stat. 2021 Dec;15(4):1652-1672. doi: 10.1214/21-aoas1491. Epub 2021 Dec 21.

ABSTRACT

Single nucleotide polymorphism (SNP) set analysis aggregates both common and rare variants and tests for association between phenotype(s) of interest and a set. However, multiple SNP-sets, such as genes, pathways, or sliding windows are usually investigated across the whole genome in which all groups are tested separately, followed by multiple testing adjustments. We propose a novel method to prioritize SNP-sets in a joint multivariate variance component model. Each SNP-set corresponds to a variance component (or kernel), and model selection is achieved by incorporating either convex or nonconvex penalties. The uniqueness of this variance component selection framework, which we call VCSEL, is that it naturally encompasses multivariate traits (VCSEL-M) and SNP-set-treatment or -environment interactions (VCSEL-I). We devise an optimization algorithm scalable to many variance components, based on the majorization-minimization (MM) principle. Simulation studies demonstrate the superiority of our methods in model selection performance, as measured by the area under the precision-recall (PR) curve, compared to the commonly used marginal testing and group penalization methods. Finally, we apply our methods to a real pharmacogenomics study and a real whole exome sequencing study. Some top ranked genes by VCSEL are detected as insignificant by the marginal test methods which emphasizes formal inference of individual genes with a strict significance threshold. This provides alternative insights for biologists to prioritize follow-up studies and develop polygenic risk score models.

PMID:35198092 | PMC:PMC8863365 | DOI:10.1214/21-aoas1491

Pharmacogenomics J. 2022 Feb 23. doi: 10.1038/s41397-022-00270-y. Online ahead of print.

ABSTRACT

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

PMID:35197553 | DOI:10.1038/s41397-022-00270-y

Drug Metab Dispos. 2022 Feb 23:DMD-AR-2021-000624. doi: 10.1124/dmd.121.000624. Online ahead of print.

ABSTRACT

The major mode of metabolism of nicotine is via the formation of cotinine by the enzyme cytochrome P450 (CYP) 2A6. Cotinine undergoes further CYP2A6-mediated metabolism by hydroxylation to 3-hydroxycotinine and norcotinine but can also form cotinine-N-glucuronide and cotinine-N-oxide (COX). The goal of the present study was to investigate the enzymes that catalyze COX formation and determine whether genetic variation in these enzymes may affect this pathway. Specific inhibitors of major hepatic cytochrome P450 (CYP) enzymes were used in cotinine-N-oxidation reactions using pooled human liver microsomes (HLM). COX formation was monitored by ultra-high pressure liquid chromatography-mass spectrometry and enzyme kinetic analysis was performed using microsomes from CYP-overexpressing HEK293 cell lines. Genotype-phenotype analysis was performed in a panel of 113 human liver specimens. Inhibition of COX formation was only observed in HLM when using inhibitors of CYPs 2A6, 2B6, 2C19, 2E1, and 3A4. Microsomes from cells overexpressing CYPs 2A6 or 2C19 exhibited similar N-oxidation activity against cotinine, with Vmax/KM values of 4.4 and 4.2 nL/min/mg, respectively. CYP2B6-, CYP2E1-, and CYP3A4-overexpressing microsomes were also active in COX formation. Significant associations (p<0.05) were observed between COX formation and genetic variants in CYPs 2C19 (*2 and *17 alleles) in HLM. These results demonstrate that genetic variants in CYP2C19 are associated with decreased COX formation, potentially affecting the relative levels of cotinine in the plasma or urine of smokers and ultimately affecting recommended smoking cessation therapies. Significance Statement This study is the first to elucidate the enzymes responsible for cotinine-N-oxide formation and genetic variants that affect this biological pathway. Genetic variants in CYP2C19 have the potential to modify NMR in smokers and could affect pharmacotherapeutic decisions for smoking cessation treatments.

PMID:35197312 | DOI:10.1124/dmd.121.000624

Iran J Pharm Res. 2021 Fall;20(4):92-106. doi: 10.22037/ijpr.2021.114899.15091.

ABSTRACT

Having multiple dimensions, uncertainties and several stakeholders, the costly pharmacogenomics (PGx) is associated with dynamic implementation complexities. Identification of these challenges is critical to harness its full potential, especially in developing countries with fragile healthcare systems and scarce resources. This is the first study aimed to identify most salient challenges related to PGx implementation, with respect to the experiences of early-adopters and local experts' prospects, in the context of a developing country in the Middle East. To perform a comprehensive reconnaissance on PGx adoption challenges a scoping literature review was conducted based on national drug policy components: efficacy/safety, access, affordability and rational use of medicine (RUM). Strategic option development and analysis workshop method with cognitive mapping as the technique was used to evaluate challenges in the context of Iran. The cognitive maps were face-validated and analyzed via Decision Explorer XML. The findings indicated a complex network of issues relative to PGx adoption, categorized in national drug policy indicators. In the rational use of medicine category, ethics, education, bench -to- bedside strategies, guidelines, compliance, and health system issues were found. Clinical trial issues, test's utility, and biomarker validation were identified in the efficacy group. Affordability included pricing, reimbursement, and value assessment issues. Finally, access category included regulation, availability, and stakeholder management challenges. The current study identified the most significant challenges ahead of clinical implementation of PGx in a developing country. This could be the basis of a policy-note development in future work, which may consolidate vital communication among stakeholders and accelerate the efficient implementation in developing new-comer countries.

PMID:35194431 | PMC:PMC8842599 | DOI:10.22037/ijpr.2021.114899.15091