Technologies for Pharmacogenomics: A Review.

Genes (Basel). 2020 Dec 04;11(12):

Authors: van der Lee M, Kriek M, Guchelaar HJ, Swen JJ

Abstract
The continuous development of new genotyping technologies requires awareness of their potential advantages and limitations concerning utility for pharmacogenomics (PGx). In this review, we provide an overview of technologies that can be applied in PGx research and clinical practice. Most commonly used are single nucleotide variant (SNV) panels which contain a pre-selected panel of genetic variants. SNV panels offer a short turnaround time and straightforward interpretation, making them suitable for clinical practice. However, they are limited in their ability to assess rare and structural variants. Next-generation sequencing (NGS) and long-read sequencing are promising technologies for the field of PGx research. Both NGS and long-read sequencing often provide more data and more options with regard to deciphering structural and rare variants compared to SNV panels-in particular, in regard to the number of variants that can be identified, as well as the option for haplotype phasing. Nonetheless, while useful for research, not all sequencing data can be applied to clinical practice yet. Ultimately, selecting the right technology is not a matter of fact but a matter of choosing the right technique for the right problem.

PMID: 33291630 [PubMed - in process]

Advances in biological therapies for dyslipidemias and atherosclerosis.

Metabolism. 2020 Dec 05;:154461

Authors: Valanti EK, Dalakoura-Karagkouni K, Siasos G, Kardassis D, Eliopoulos AG, Sanoudou D

Abstract
Atherosclerosis is a multifactorial disease influenced by genetics, lifestyle and environmental factors. Despite therapeutic advances that reduce the risk of cardiovascular events, atherosclerosis-related diseases remain the leading cause of mortality worldwide. Precise targeting of genes involved in lipoprotein metabolism is an emergent approach for atherosclerosis prevention and treatment. This article focuses on the latest developments, clinical potential and current challenges of monoclonal antibodies, vaccines and genome/transcriptome modification strategies, including antisense oligonucleotides, genome/base editing and gene therapy. Multiple lipid lowering biological therapies have already been approved by the FDA with impressive results to date, while many more promising targets are being pursued in clinical trials or pre-clinical animal models.

PMID: 33290761 [PubMed - as supplied by publisher]

Genetic variants associated with therapy-related cardiomyopathy among childhood cancer survivors of African ancestry.

Cancer Res. 2020 Dec 07;:

Authors: Sapkota Y, Qin N, Ehrhardt MJ, Wang Z, Chen Y, Wilson CL, Estepp J, Rai P, Hankins JS, Burridge PW, Jefferies JL, Zhang J, Hudson MM, Robison LL, Armstrong GT, Mulrooney DA, Yasui Y

Abstract
Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiation) (n=246) were compared to cardiotoxic-exposed survivors of European ancestry (n=1645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2-4 and grade 3-4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF [rs6689879*C: EF reduction=4.2%; P=2.8×10-8] in 246 survivors of African ancestry, which was successfully replicated in 1645 survivors of European ancestry but with attenuated magnitude (EF reduction=0.4%; P=0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2-4 cardiomyopathy, the PHTF1 promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2-4 cardiomyopathy. PHTF1 was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry.

PMID: 33288658 [PubMed - as supplied by publisher]

Is there a place for genetics in the management of PONV?

Best Pract Res Clin Anaesthesiol. 2020 Dec;34(4):713-720

Authors: Candiotti K, Shrestha C, Silva Ceschim MR

Abstract
Antiemetic prophylaxis for postoperative nausea and vomiting (PONV) - a frequent complication in the postoperative period - is routinely given to high-risk patients. However, standard PONV risk models do not account for genetic factors, which have been shown to have a significant influence on PONV incidence and drug response. In this review, we describe the polymorphisms of various genes (serotonin, dopamine, cholinergic, etc.) and how pharmacogenomics is involved in the pathophysiology of PONV. This review also addresses how genetics is involved in today's clinical practice related to PONV and how it will change in the upcoming years as personalized medicine advances.

PMID: 33288121 [PubMed - in process]

New insights into the pathophysiology and risk factors for PONV.

Best Pract Res Clin Anaesthesiol. 2020 Dec;34(4):667-679

Authors: Stoops S, Kovac A

Abstract
Postoperative nausea and vomiting (PONV) affects patient outcomes and satisfaction. New research has centered on evaluation of post-discharge and opioid-related nausea and vomiting. Mechanical and drug effects stimulate the release of central nervous system neurotransmitters acting at receptors in the vomiting center, area postrema, and nucleus of the solitary tract. Brain surgery has allowed insight into specific central emetogenic areas. Stimuli from peripheral organs act through afferent vagus neurons and a parasympathetic response causing nausea and vomiting. Opioids stimulate mu receptors in the chemoreceptor trigger zone and cholinergic receptors in the vestibular system. Opioids also affect gastrointestinal (GI) tract mechanics by decreasing gastric emptying, intestinal motility, GI peristalsis, and secretions. Regional blocks and non-opioid multimodal analgesia help to decrease nausea and vomiting. Patient, surgery, and anesthesia factors contribute to risk and degree of PONV experienced. Pharmacogenetics plays a role in gene typing as antiemetic medication metabolism results in varying drug effectiveness. Risk scoring systems are available. Individualized multimodal plans can be designed as part of an enhanced recovery after surgery protocol.

PMID: 33288117 [PubMed - in process]

Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer.

Cancer Res Treat. 2020 Dec 02;:

Authors: Dong SQ, Wang TM, Zhang JB, He YQ, Xue WQ, Wu ZY, Yang DW, Cao LJ, Huang JW, Li XZ, Zhang PF, Zheng XH, Jia WH

Abstract
Purpose: Capecitabine is an extensively used oral prodrug of 5-fluorouracil in treatment of colon cancer and is known to cause hand-foot syndrome (HFS). As the target enzyme for capecitabine, thymidylate synthase (TYMS) plays a key role for 5-fluorouracil metabolism and has been associated with some side effects caused by capecitabine. The aim of our study is to identify the possible genetic predictors of capecitabine-induced HFS (CAP-HFS) in Chinese colorectal cancer patients.
Materials and Methods: Whole exons of TYMS were sequenced for 288 extreme phenotype HFS patients, including 144 severe or early-onset (first 2 cycles) moderate HFS extreme cases and 144 extreme controls with no reported HFS. The associations between polymorphisms and CAP-HFS were analyzed using logistic regression under an additive model.
Results: We identified a novel risk mutation (c.1A>G, chr18:657743), was associated with severe HFS in an Ex-case who was affected during the first cycle of treatment. Moreover, we identified three new variants, rs3786362, rs699517, rs2790, and two previously reported variants, 5'VNTR 2R/3R and 3'-untranslated region 6 bp ins-del, which were significantly associated with CAP-HFS (p < 0.05). In silico bioinformatics analysis revealed that the effect of these polymorphisms in the TYMS region on the development of HFS might not be restricted solely to the regulation of TYMS expression, but also the TYMS catalytic activity through the indirect effect on ENOSF1 expression.
Conclusion: This study identified new polymorphisms in TYMS gene significantly associated with CAP-HFS, which may serve as useful genetic predictors for CAP-HFS and help to elucidate the underlying mechanism of HFS.

PMID: 33285053 [PubMed - as supplied by publisher]

Association of RANK and RANKL gene polymorphism with survival and calcium levels in multiple myeloma.

Mol Carcinog. 2020 Dec 07;:

Authors: Łacina P, Butrym A, Humiński M, Dratwa M, Frontkiewicz D, Mazur G, Bogunia-Kubik K

Abstract
Multiple myeloma (MM) is a heterogeneous bone marrow cancer characterized by proliferation of malignant plasma cells in the bone marrow. One of its major symptoms are hypercalcaemia and bone lesions, which may result in pathologic bone fractures. Receptor activator for nuclear factor κB (RANK) and its ligand, RANKL, are part of an activation pathway for osteoclasts and are thus responsible for bone resorption. Furthermore, RANKL expression is increased in multiple myeloma. In the present study, we investigated the role of single nucleotide polymorphisms (SNPs) in the genes coding for RANK (rs1805034, rs8086340), RANKL (rs7325635, rs7988338), and TACI (rs34562254), a receptor for osteoclast-derived pro-survival factors. The study involved 222 patients and 222 healthy individuals, and the analysis included disease susceptibility, survival, bone lesions, calcium levels, and vascular endothelial growth factor levels. Patients with allele RANK rs1805034 C had higher survival (p = .003). This relationship was especially evident in women (p = .006). Furthermore, allele rs1805034 C was associated with slightly lower median age at diagnosis (64.0 vs. 65.5, p = .008). Allele RANKL rs7325635 A correlated with lower progression-free survival (p = .027), and with lack of early progression (p = .023). Additionally, women with allele rs7325635 G were found to have higher calcium blood concentration (p = .040). Allele TACI rs34562254 A was more common in MM patients in more advanced stages (II and III stage International Staging System) at diagnosis (p = .017), and the SNP showed a slight trend towards association in a multivariate analysis (p = .084). Taken together, our results suggest that RANK rs1805034 and RANKL rs7325635 may have a role in MM development and progression.

PMID: 33283899 [PubMed - as supplied by publisher]

Genetic factors influencing the development of vincristine-induced neurotoxicity.

Expert Opin Drug Metab Toxicol. 2020 Dec 06;:1-12

Authors: Pozzi E, Fumagalli G, Chiorazzi A, Canta A, Cavaletti G

Abstract
Introduction: One of the most common side effects during vincristine (VCR) use is the establishment of VCR-induced peripheral neuropathy (VIPN). Among several risk factors that can influence the development of VIPN, such as cumulative dose and patient's age, sex, ethnicity, and genetic variants, this review is focused on the genetic variability. Areas covered: A literature research was performed firstly using the following PubMed search string ((((CIPN OR (vincristine AND neurotoxicity OR (vincristine AND neuropathy))) AND (polymorphisms OR (genetic variants OR (genetic factors OR (genetic profile OR (pharmacogenetics OR (genome-wide OR (genetic risk OR (expression genotype))))))))))) but also other relevant papers cited by the selected articles were included. Based on the obtained results, we identified two main categories of genes: genes involved in pharmacokinetics (genes related to metabolism and transport) or pharmacodynamics (genes related to mechanism of action) of VCR. Expert opinion: Despite several clinical retrospective studies investigating the possible correlations between patient genotype and VIPN onset, contrasting and inconsistent results are reported. In conclusion, given the clinical relevance of VIPN, further and more focused research would be fundamental in order to identify genetic variants able to predict its development and to allow a safer management of treated patients.

PMID: 33283553 [PubMed - as supplied by publisher]

Breaking the Intracellular Redox Balance with Diselenium Nanoparticles for Maximizing Chemotherapy Efficacy on Patient-Derived Xenograft Models.

ACS Nano. 2020 Dec 07;:

Authors: Wei D, Yu Y, Zhang X, Wang Y, Chen H, Zhao Y, Wang F, Rong G, Wang W, Kang X, Cai J, Wang Z, Yin JY, Hanif M, Sun Y, Zha G, Li L, Nie G, Xiao H

Abstract
Excessive oxidative stress in cancer cells can induce cancer cell death. Anticancer activity and drug resistance of chemotherapy are closely related to the redox state of tumor cells. Herein, five lipophilic Pt(IV) prodrugs were synthesized on the basis of the most widely used anticancer drug cisplatin, whose anticancer efficacy and drug resistance are closely related to the intracellular redox state. Subsequently, a series of cisplatin-sensitive and drug-resistant cell lines as well as three patient-derived primary ovarian cancer cells have been selected to screen those prodrugs. To verify if the disruption of redox balance can be combined with these Pt(IV) prodrugs, we then synthesized a polymer with a diselenium bond in the main chain for encapsulating the most effective prodrug to form nanoparticles (NP(Se)s). NP(Se)s can efficiently break the redox balance via simultaneously depleting GSH and augmenting ROS, thereby achieving a synergistic effect with cisplatin. In addition, genome-wide analysis via RNA-seq was employed to provide a comprehensive understanding of the changes in transcriptome and the alterations in redox-related pathways in cells treated with NP(Se)s and cisplatin. Thereafter, patient-derived xenograft models of hepatic carcinoma (PDXHCC) and multidrug-resistant lung cancer (PDXMDR) were established to evaluate the therapeutic effect of NP(Se)s, and a significant antitumor effect was achieved on both models with NP(Se)s. Overall, this study provides a promising strategy to break the redox balance for maximizing the efficacy of platinum-based cancer therapy.

PMID: 33283501 [PubMed - as supplied by publisher]

Role of biomarkers in evaluation, treatment and clinical studies of pulmonary arterial hypertension.

Pulm Circ. 2020 Oct-Dec;10(4):2045894020957234

Authors: Hemnes A, Rothman AMK, Swift AJ, Zisman LS

Abstract
Pulmonary arterial hypertension is a complex disease resulting from the interplay of myriad biological and environmental processes that lead to remodeling of the pulmonary vasculature with consequent pulmonary hypertension. Despite currently available therapies, there remains significant morbidity and mortality in this disease. There is great interest in identifying and applying biomarkers to help diagnose patients with pulmonary arterial hypertension, inform prognosis, guide therapy, and serve as surrogate endpoints. An extensive literature on potential biomarker candidates is available, but barriers to the implementation of biomarkers for clinical use in pulmonary arterial hypertension are substantial. Various omic strategies have been undertaken to identify key pathways regulated in pulmonary arterial hypertension that could serve as biomarkers including genomic, transcriptomic, proteomic, and metabolomic approaches. Other biologically relevant components such as circulating cells, microRNAs, exosomes, and cell-free DNA have recently been gaining attention. Because of the size of the datasets generated by these omic approaches and their complexity, artificial intelligence methods are being increasingly applied to decipher their meaning. There is growing interest in imaging the lung with various modalities to understand and visualize processes in the lung that lead to pulmonary vascular remodeling including high resolution computed tomography, Xenon magnetic resonance imaging, and positron emission tomography. Such imaging modalities have the potential to demonstrate disease modification resulting from therapeutic interventions. Because right ventricular function is a major determinant of prognosis, imaging of the right ventricle with echocardiography or cardiac magnetic resonance imaging plays an important role in the evaluation of patients and may also be useful in clinical studies of pulmonary arterial hypertension.

PMID: 33282185 [PubMed]

DRIM: A Web-Based System for Investigating Drug Response at the Molecular Level by Condition-Specific Multi-Omics Data Integration.

Front Genet. 2020;11:564792

Authors: Oh M, Park S, Lee S, Lee D, Lim S, Jeong D, Jo K, Jung I, Kim S

Abstract
Pharmacogenomics is the study of how genes affect a person's response to drugs. Thus, understanding the effect of drug at the molecular level can be helpful in both drug discovery and personalized medicine. Over the years, transcriptome data upon drug treatment has been collected and several databases compiled before drug treatment cancer cell multi-omics data with drug sensitivity (IC 50, AUC) or time-series transcriptomic data after drug treatment. However, analyzing transcriptome data upon drug treatment is challenging since more than 20,000 genes interact in complex ways. In addition, due to the difficulty of both time-series analysis and multi-omics integration, current methods can hardly perform analysis of databases with different data characteristics. One effective way is to interpret transcriptome data in terms of well-characterized biological pathways. Another way is to leverage state-of-the-art methods for multi-omics data integration. In this paper, we developed Drug Response analysis Integrating Multi-omics and time-series data (DRIM), an integrative multi-omics and time-series data analysis framework that identifies perturbed sub-pathways and regulation mechanisms upon drug treatment. The system takes drug name and cell line identification numbers or user's drug control/treat time-series gene expression data as input. Then, analysis of multi-omics data upon drug treatment is performed in two perspectives. For the multi-omics perspective analysis, IC 50-related multi-omics potential mediator genes are determined by embedding multi-omics data to gene-centric vector space using a tensor decomposition method and an autoencoder deep learning model. Then, perturbed pathway analysis of potential mediator genes is performed. For the time-series perspective analysis, time-varying perturbed sub-pathways upon drug treatment are constructed. Additionally, a network involving transcription factors (TFs), multi-omics potential mediator genes, and perturbed sub-pathways is constructed, and paths to perturbed pathways from TFs are determined by an influence maximization method. To demonstrate the utility of our system, we provide analysis results of sub-pathway regulatory mechanisms in breast cancer cell lines of different drug sensitivity. DRIM is available at: http://biohealth.snu.ac.kr/software/DRIM/.

PMID: 33281870 [PubMed]

Developing and validating a clinical warfarin dose-initiation model for Black-African patients in South Africa and Uganda.

Clin Pharmacol Ther. 2020 Dec 06;:

Authors: Asiimwe IG, Waitt C, Sekaggya-Wiltshire C, Hutchinson C, Okello E, Zhang EJ, Semakula JR, Mouton JP, Cohen K, Blockman M, Lamorde M, Jorgensen AL, Pirmohamed M

Abstract
Warfarin remains the oral anticoagulant of choice in sub-Saharan Africa. However, dosing is challenging due to a highly variable clinical response for a given dose. This study aimed to develop and validate a clinical warfarin dose-initiation model in sub-Saharan Black-African patients. For the development cohort, we used data from 364 patients who were recruited from 8 outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was undertaken using the International Warfarin Pharmacogenetics Consortium (IWPC) dataset (690 Black patients). Four predictors (age, weight, target International Normalized Ratio range and HIV status) were included in the final model which achieved mean absolute errors (MAEs, mean of absolute differences between true dose and dose predicted by the model) of 11.6 (95% CI 10.4 to 12.8) and 12.5 (11.6 to 13.4) mg/week in the development and validation cohorts respectively. Two other clinical models, IWPC and Gage, respectively obtained MAEs of 12.5 (11.3 to 13.7) and 12.7 (11.5 to 13.8) mg/week in the development cohort, and 12.1 (11.2 to 13.0) and 12.2 (11.4 to 13.1) mg/week in the validation cohort. Compared to fixed dose-initiation, our model decreased the percentage of patients at high risk of suboptimal anticoagulation by 7.5% (1.5% to 13.7%) and 11.9% (7.1% to 16.8%) in the development and validation cohorts, respectively. The clinical utility of this model will be tested in a prospective study.

PMID: 33280090 [PubMed - as supplied by publisher]

Pitfalls and challenges associated with phenoconversion in forensic toxcicology.

Forensic Sci Int Genet. 2020 Nov 28;51:102433

Authors: Drevin G, Picard N, Jousset N, Briet M, Abbara C

Abstract
PURPOSE: In recent years, several publications have demonstrated the interest and the usefulness of pharmacogenetics in forensic toxicology. However, this approach remains namely focused on DNA-based phenotype, which may potentially lead to misinterpretation. Other determinants such as co-medication or physiological parameters may also impact the phenotype. This article aims to highlight the importance of considering such determinants in forensic toxicology, through the original case of a heroin-related fatality.
METHOD: Ethanol concentration determination and toxicological screening were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection and gas chromatography with mass spectrometry detection. CYP2C19 and CYP2D6 genotypes were determined by Taqman® real-time PCR analyses.
RESULTS: Femoral blood analyses revealed the presence of ethanol, morphine, codeine, venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV), paroxetine, and risperidone. 6-acetylmorphine was also identified in urine. VEN, paroxetine and risperidone were quantified at supra-therapeutic or toxic blood concentrations. NDV was not quantified. The metabolic ratio of VEN (ODV to VEN) was exceptionally low (about 0.7). Pharmacogenetics testing showed that the patient was heterozygous for the CYP2C19*2 loss-of-function allele, which predict an intermediate metabolism for CYP2C19. None of the deficient CYP2D6 alleles investigated were identified. Those results suggest an extensive CYP2D6-metabolism phenotype.
CONCLUSION: A discrepancy was seen between the results of the genomic evaluation and the observed metabolic ratio of VEN. This tends to exclude a genetic origin and lead us to formulate other hypotheses, such as phenoconversion that may have been induced by drug interaction involving patients' regular medications. Phenoconversion is as a complex phenomenon that leads to genotype-phenotype mismatch without any genetic abnormality particularly described for cytochromes P450 2D6 and 2C19. Although transient, phenoconversion can have a significant impact on the analysis and interpretation of genotype-focused clinical outcomes correlation and in forensic toxicology conclusions.

PMID: 33278816 [PubMed - as supplied by publisher]

Implications of Polymorphisms in the BCKDK and GATA-4 Gene Regions on Stable Warfarin Dose in African Americans.

Clin Transl Sci. 2020 Dec 05;:

Authors: Bargal SA, Kight JN, de Oliveira FA, Shahin MH, Langaee T, Gong Y, Hamadeh IS, Cooper-DeHoff RM, Cavallari LH

Abstract
VKORC1 and CYP2C9 genotypes explain less variability in warfarin dose requirements in African Americans (AAs) compared to Europeans. Variants in BCKDK and GATA-4 gene regions, purported to regulate VKORC1 and CYP2C9 expression, have been shown to play an important role in warfarin dose requirements in Europeans and Asians, respectively. We sought to determine whether rs56314408 near BCKDK or GATA-4 rs2645400 influence warfarin dose requirements in 200 AAs. Unlike the strong linkage disequilibrium (LD) between rs56314408 and VKORC1 rs9923231 in Europeans, they were not in LD in AAs. No associations were found on univariate analysis. On multivariable analysis, rs56314408 was associated (p=0.027) with dose in a regression model excluding VKORC1 rs9923231, and GATA-4 rs2645400 was associated (p=0.032) with dose in a model excluding CYP2C variants (CYP2C9*2, *3, *5, *6, *8, *11, CYP2C rs12777823). Neither variant contributed to dose in the model including both VKORC1 rs9923231 and CYP2C variants. Our results do not support contributions of the studied variants to warfarin dose requirements in AAs. However, they illustrate the value of studies in African descent populations, who have low LD in their genome, in teasing out genetic variation underlying drug response associations. They also emphasize the importance of confirming associations in persons of African ancestry.

PMID: 33278335 [PubMed - as supplied by publisher]

Metabolic Effects of Aripiprazole and Olanzapine Multiple-Dose Treatment in a Randomised Crossover Clinical Trial in Healthy Volunteers: Association with Pharmacogenetics.

Adv Ther. 2020 Dec 05;:

Authors: Koller D, Almenara S, Mejía G, Saiz-Rodríguez M, Zubiaur P, Román M, Ochoa D, Navares-Gómez M, Santos-Molina E, Pintos-Sánchez E, Abad-Santos F

Abstract
INTRODUCTION: Aripiprazole and olanzapine are atypical antipsychotics. Both drugs can induce metabolic changes; however, the metabolic side effects produced by aripiprazole are more benign. The aim of the study was to evaluate if aripiprazole and olanzapine alter prolactin levels, lipid and glucose metabolism and hepatic, haematological, thyroid and renal function.
METHODS: Twenty-four healthy volunteers received a daily oral dose of 10 mg aripiprazole and 5 mg olanzapine tablets for 5 days in a crossover randomised clinical trial and were genotyped for 51 polymorphisms in 18 genes by qPCR. Drug plasma concentrations were measured by LC-MS. The biochemical and haematological analyses were performed by enzymatic methods.
RESULTS: Olanzapine induced hyperprolactinaemia but aripiprazole did not. Dopamine D3 receptor (DRD3) Ser/Gly and ATP binding cassette subfamily B member 1 (ABCB1) rs10280101, rs12720067 and rs11983225 polymorphisms and cytochrome P450 3A (CYP3A) phenotype had an impact on plasma prolactin levels. C-peptide concentrations were higher after aripiprazole administration and were influenced by catechol-O-methyltransferase (COMT) rs4680 and rs13306278 polymorphisms. Olanzapine and the UDP glucuronosyltransferase family 1 member A1 (UGT1A1) rs887829 polymorphism were associated with elevated glucose levels. CYP3A poor metabolizers had increased insulin levels. Volunteers' weight decreased significantly during aripiprazole treatment and a tendency for weight gain was observed during olanzapine treatment. Triglyceride concentrations decreased as a result of olanzapine and aripiprazole treatment, and varied on the basis of CYP3A phenotypes and the apolipoprotein C-III (APOC3) rs4520 genotype. Cholesterol levels were also decreased and depended on 5-hydroxytryptamine receptor 2A (HTR2A) rs6314 polymorphism. All hepatic enzymes, platelet and albumin levels, and prothrombin time were altered during both treatments. Additionally, olanzapine reduced the leucocyte count, aripiprazole increased free T4 and both decreased uric acid concentrations.
CONCLUSIONS: Short-term treatment with aripiprazole and olanzapine had a significant influence on the metabolic parameters. However, it seems that aripiprazole provokes less severe metabolic changes.
TRIAL REGISTRATION: Clinical trial registration number (EUDRA-CT): 2018-000744-26.

PMID: 33278020 [PubMed - as supplied by publisher]

Statin-induced rhabdomyolysis from azithromycin interaction in a patient with heterozygous SLCO1B1 polymorphism.

J Clin Pharm Ther. 2020 Dec 05;:

Authors: Burns H, Russell L, Cox ZL

Abstract
WHAT IS KNOWN AND OBJECTIVE: Unlike other macrolide antibiotics, azithromycin is considered safe to co-prescribe with simvastatin. We aim to elucidate the mechanism of a rare azithromycin-simvastatin interaction.
CASE DESCRIPTION: We report a case of simvastatin-induced rhabdomyolysis caused by an azithromycin drug interaction in a patient with heterozygous SLCO1B1 loss-of-function polymorphism. We propose a dual-hit mechanism for this drug-drug-genome interaction. Azithromycin mildly inhibits simvastatin's CYP 3A4 hepatic metabolism, and the SLCO1B1 polymorphism reduces simvastatin hepatic uptake. The combination increases simvastatin serum concentrations significantly, inducing rhabdomyolysis.
WHAT IS NEW AND CONCLUSION: Patients with statin-induced myopathy associated with non-classic CYP inhibitors should be considered for genetic testing and alternative statins with less risk of future interactions.

PMID: 33277702 [PubMed - as supplied by publisher]

Variation in 100 relevant pharmacogenes among emiratis with insights from understudied populations.

Sci Rep. 2020 Dec 04;10(1):21310

Authors: Al-Mahayri ZN, Patrinos GP, Wattanapokayakit S, Iemwimangsa N, Fukunaga K, Mushiroda T, Chantratita W, Ali BR

Abstract
Genetic variations have an established impact on the pharmacological response. Investigating this variation resulted in a compilation of variants in "pharmacogenes". The emergence of next-generation sequencing facilitated large-scale pharmacogenomic studies and exhibited the extensive variability of pharmacogenes. Some rare and population-specific variants proved to be actionable, suggesting the significance of population pharmacogenomic research. A profound gap exists in the knowledge of pharmacogenomic variants enriched in some populations, including the United Arab Emirates (UAE). The current study aims to explore the landscape of variations in relevant pharmacogenes among healthy Emiratis. Through the resequencing of 100 pharmacogenes for 100 healthy Emiratis, we identified 1243 variants, of which 63% are rare (minor allele frequency ≤ 0.01), and 30% were unique. Filtering the variants according to Pharmacogenomics Knowledge Base (PharmGKB) annotations identified 27 diplotypes and 26 variants with an evident clinical relevance. Comparison with global data illustrated a significant deviation of allele frequencies in the UAE population. Understudied populations display a distinct allelic architecture and various rare and unique variants. We underscored pharmacogenes with the highest variation frequencies and provided investigators with a list of candidate genes for future studies. Population pharmacogenomic studies are imperative during the pursuit of global pharmacogenomics implementation.

PMID: 33277594 [PubMed - as supplied by publisher]

Targeting aurora kinases as a potential prognostic and therapeutical biomarkers in pediatric acute lymphoblastic leukaemia.

Sci Rep. 2020 Dec 04;10(1):21272

Authors: Moreira-Nunes CA, Mesquita FP, Portilho AJS, Mello Júnior FAR, Maués JHDS, Pantoja LDC, Wanderley AV, Khayat AS, Zuercher WJ, Montenegro RC, de Moraes-Filho MO, de Moraes MEA

Abstract
Aurora kinases (AURKA and AURKB) are mitotic kinases with an important role in the regulation of several mitotic events, and in hematological malignancies, AURKA and AURKB hyperexpression are found in patients with cytogenetic abnormalities presenting a unfavorable prognosis. The aim of this study was evaluated the mRNA expression profile of pediatric Acute Lymphoblastic Leukaemia (ALL) patients and the efficacy of two AURKA and AURKB designed inhibitors (GW809897X and GW806742X) in a leukemia cell line as a potential novel therapy for ALL patients. Cellular experiments demonstrated that both inhibitors induced cell death with caspase activation and cell cycle arrest, however only the GW806742X inhibitor decreased with more efficacy AURKA and AURKB expression in K-562 leukemia cells. In ALL patients both AURKA and AURKB showed a significant overexpression, when compared to health controls. Moreover, AURKB expression level was significant higher than AURKA in patients, and predicted a poorer prognosis with significantly lower survival rates. No differences were found in AURKA and AURKB expression between gene fusions, immunophenotypic groups, white blood cells count, gender or age. In summary, the results in this study indicates that the AURKA and AURKB overexpression are important findings in pediatric ALL, and designed inhibitor, GW806742X tested in vitro were able to effectively inhibit the gene expression of both aurora kinases and induce apoptosis in K-562 cells, however our data clearly shown that AURKB proves to be a singular finding and potential prognostic biomarker that may be used as a promising therapeutic target to those patients.

PMID: 33277547 [PubMed - as supplied by publisher]

Stress granules as a feedback mechanism of MAPK signaling by sequestering PKC/Pck2.

J Cell Sci. 2020 Dec 04;:

Authors: Kanda Y, Satoh R, Takasaki T, Tomimoto N, Tsuchiya K, Tsai CA, Tanaka T, Kyomoto S, Hamada K, Fujiwara T, Sugiura R

Abstract
The PKC signaling is a highly conserved signaling module, which plays a central role in a myriad of physiological processes, ranging from cell proliferation to cell death via various signaling pathways, including MAPK. Stress granules (SGs) are non-membranous cytoplasmic foci that aggregate in cells exposed to environmental stresses. Here we explored the role of SGs in PKC/MAPK signaling activation in fission yeast. High heat-stress (HHS) induced Pmk1 MAPK activation and Pck2/PKC translocation from the cell tips into poly(A)-binding protein (Pabp)-positive SGs. Pck2 dispersal from the cell tips required Pck2 kinase activity and the constitutively active Pck2 promotes its translocation to SGs. Importantly, Pmk1 deletion impaired Pck2 recruitment into SGs, indicating that MAPK activation stimulates Pck2 SG translocation. Consistently, HHS-induced SGs delayed Pck2 relocalization at the cell tips, thereby blocking subsequent Pmk1 reactivation after recovery from HHS. HHS partitioned Pck2 into the Pabp-positive SG-containing fraction, which resulted in the reduced Pck2 abundance and kinase activity in the soluble fraction. Collectively, MAPK-dependent Pck2 SG recruitment serves as a feedback mechanism to intercept PKC/MAPK activation induced by HHS, which might underlie PKC-related diseases.

PMID: 33277379 [PubMed - as supplied by publisher]

Osteonecrosis of the Jaw Risk Factors in Bisphosphonate Treated Patients with Metastatic Cancer.

Oral Dis. 2020 Dec 04;:

Authors: Van Poznak C, Reynolds EL, Estilo CL, Hu M, Schneider BP, Hertz DL, Gersch C, Thibert J, Thomas D, Banerjee M, Rae JM, Hayes DF

Abstract
BACKGROUND: A case control study was performed to define clinical and genetic risk factors associated with osteonecrosis of the jaw in patients with metastatic cancer treated with bisphosphonates.
METHODS: Clinical data and tissues were collected from patients treated with bisphosphonates for metastatic bone disease who were diagnosed with osteonecrosis of the jaw (cases) and matched controls. Clinical data included patient, behavioral, disease, and treatment information. Genetic polymorphisms in CYP2C8 (rs1934951) and other candidate genes were genotyped. Odds ratios from conditional logistic regression models were examined to identify clinical and genetic characteristics associated with case or control status.
RESULTS: The study population consisted of 76 cases and 126 controls. In the final multivariable clinical model, patients with osteonecrosis of the jaw were less likely to have received pamidronate than zoledronic acid (odds ratio=0.18, 95% Confidence interval: 0.03-0.97, p=0.047) and more likely to have been exposed to bevacizumab (OR=5.15, 95% CI: 1.67-15.95, p=0.005). The exploratory genetic analyses suggested a protective effect for VEGFC rs2333496 and risk effects for VEGFC rs7664413 and PPARG rs1152003.
CONCLUSIONS: We observed patients with ONJ were more likely to have been exposed to bevacizumab and zoledronic and identified potential genetic predictors that require validation prior to clinical translation.

PMID: 33274559 [PubMed - as supplied by publisher]