Andrology. 2021 Jun 11. doi: 10.1111/andr.13068. Online ahead of print.

ABSTRACT

BACKGROUND: Semen quality impairment is a serious consequence of testicular torsion-detorsion (TD). Adequate germ-cell mitochondrial oxidative phosphorylation (OXPHOS) plays a crucial role in male fertility. Changes in cellular OXPHOS in testicular tissues after testicular TD remain unclear.

OBJECTIVES: This study investigated whether testicular TD induces alternations of mitochondrial OXPHOS in testicular tissues.

MATERIALS AND METHODS: BALB/c male mice were divided into a Sham group and a testicular TD group. At the end of the procedure, the mice were euthanized, and their bilateral testicles were removed. Mitochondria morphology was evaluated through transmission electron microscopy. The cellular respiratory functions of germ cells were evaluated using a Seahorse analyzer assay. The proteome profiles in testicular tissues were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The differences in the expression levels of each component in the OXPHOS were revealed using Ingenuity Pathways Analysis (IPA).

RESULTS: Inner mitochondrial membrane disruption was found in ipsilateral twisted testicular mitochondria in the TD group but not in contralateral untwisted testes. The cellular respiratory function in germ cells were significantly decreased after testicular TD in ipsilateral twisted testes but not in contralateral untwisted testes. LC-MS/MS analysis of ipsilateral twisted testicular tissue revealed that mitochondrial proteins were differentially expressed after testicular TD. Testicular TD induced downregulation of OXPHOS and revealed alternations of specific proteins in the OXPHOS complexes.

DISCUSSION AND CONCLUSION: Testicular TD produced mitochondria injury and dysregulation of mitochondrial OXPHOS in ipsilateral twisted testes. Different protein expressions were identified in the mitochondrial OXPHOS complexes with testicular TD; new therapeutic targets may be identified to restore the OXPHOS function of germ cells. This article is protected by copyright. All rights reserved.

PMID:34115449 | DOI:10.1111/andr.13068

Pharmacogenomics. 2021 Jun 11. doi: 10.2217/pgs-2021-0017. Online ahead of print.

ABSTRACT

Given the expansion of genetics in medicine, there is a growing need to develop approaches to engage patients in understanding how genetics affects their health. Various qualitative methods have been applied to gain a deeper understanding of patient perspectives in topics related to genetics. Community dialogues (CD) are a bi-directional research method that invites community members to discuss a pertinent, challenging topic over the course of a multi-week period and the community members openly discuss their positions on the topic. Authors discuss the first application of the CD method to the topic of pharmacogenetics testing. Additional CD are needed to engage diverse participant populations on this topic to improve genetics literacy, enhance physician engagement and drive policy change.

PMID:34114883 | DOI:10.2217/pgs-2021-0017

Clin Pharmacol Ther. 2021 Jun 11. doi: 10.1002/cpt.2334. Online ahead of print.

ABSTRACT

Approximately twenty drugs have been shown to be effective for the treatment of colorectal cancer (CRC). These drugs are from several classes of agents and include cytotoxic drugs, therapeutics that target cell signaling pathways at the extracellular and/or intracellular levels, and combination therapies that contain multiple targeted agents and/or cytotoxic compounds. Targeted therapeutics can include monoclonal antibodies, fusion proteins, and small molecule drugs. 5-Fluorouracil (5-FU) was first introduced into clinical use in the late 1950s and remains the foundation for most CRC treatments in both adjuvant therapy and in advanced (metastatic) treatment regimens. As with other cancers, the consideration of biomarkers has the potential to improve CRC therapy through patient stratification. The biomarkers can include germline genetic markers, tumor-specific genetic markers, immune markers, and other biomarkers that can predict antitumor efficacy or the likelihood of toxicity prior to administration of a specific drug. Consistent with the benefit of considering biomarkers in treatment, many newer targeted therapies are developed and approved simultaneously with a companion diagnostic test to determine efficacy. This review will focus on biomarkers that have demonstrated clinical utility in CRC treatment; however, it is noted that many additional biomarkers have been theorized to contribute to drug response and/or toxicity based on known biological pathways but thus far have not attained widespread use in the clinic. The importance of pre-treatment biomarker testing is expected to increase as future drug development will likely continue to focus on the concurrent development of companion diagnostics.

PMID:34114648 | DOI:10.1002/cpt.2334

Cancer Chemother Pharmacol. 2021 Jun 10. doi: 10.1007/s00280-021-04307-0. Online ahead of print.

ABSTRACT

PURPOSE: Genetic variation in the activation of the prodrug cyclophosphamide (CP) by cytochrome P450 (CYP) enzymes has been shown to influence outcomes. However, CYP are also subject to phenoconversion due to either the effects of comedications or cancer associated down-regulation of expression. The aim of this study was to assess the relationship between CP bioactivation with CYP2B6 and CYP2C19 genotype, as well as CYP2C19 phenotype, in breast cancer patients.

METHODS: CP and the active metabolite levels were assessed in breast cancer patients (n = 34) at cycle 1 and cycle 3 of treatment. Patients were genotyped for a series of SNP known to affect CYP2B6 and CYP2C19 function. The activity of CYP2C19 was also assessed using a probe drug.

RESULTS: We found a significant linear gene-dose relationship with CYP2B6 coding SNP and formation of 4-hydroxycyclophosphamide. A possible association with CYP2C19 null genotype at cycle 1 was obscured at cycle 3 due to the substantial intra-individual change in CP bioactivation on subsequent dosing.

CONCLUSION: Comedications may be the cause for this inter-occasion variation in bioactivation of cyclophosphamide and the ensuing phenoconversion may account for the conflicting reports in the literature about the relationship between CYP2C19 genotype and CP bioactivation pharmacokinetics. Trial registration ANZCTR363222 (6/11/2012, retrospectively registered).

PMID:34114066 | DOI:10.1007/s00280-021-04307-0

Front Psychiatry. 2021 May 25;12:623143. doi: 10.3389/fpsyt.2021.623143. eCollection 2021.

ABSTRACT

Background: Patients with schizophrenia are at high risk of pre-mature mortality due to cardiovascular disease (CVD). Our group has completed studies in pharmacogenomics and metabolomics that have independently identified perturbations in one-carbon metabolism as associated with risk factors for CVD in this patient population. Therefore, this study aimed to use genetic and metabolomic data to determine the relationship between folate pharmacogenomics, one-carbon metabolites, and insulin resistance as measured using the homeostatic model assessment for insulin resistance (HOMA-IR) as a marker of CVD. Methods: Participants in this pilot analysis were on a stable atypical antipsychotic regimen for at least 6 months, with no diabetes diagnosis or use of antidiabetic medications. Participant samples were genotyped for MTHFR variants rs1801131 (MTHFR A1298C) and rs1801133 (MTHFR C677T). Serum metabolite concentrations were obtained with NMR. A least squares regression model was used to predict log(HOMA-IR) values based on the following independent variables: serum glutamate, glycine, betaine, serine, and threonine concentrations, and carrier status of the variant alleles for the selected genotypes. Results: A total of 67 participants were included, with a median age of 47 years old (IQR 42-52), 39% were female, and the median BMI was 30.3 (IQR 26.3-37.1). Overall, the model demonstrated an ability to predict log(HOMA-IR) values with an adjusted R 2 of 0.44 and a p-value of < 0.001. Glutamate, threonine, and carrier status of the MTHFR 1298 C or MTHFR 677 T allele were positively correlated with log(HOMA-IR), whereas glycine, serine, and betaine concentrations trended inversely with log(HOMA-IR). All factors included in this final model were considered as having a possible effect on predicting log(HOMA-IR) as measured with a p-value < 0.1. Conclusions: Presence of pharmacogenomic variants that decrease the functional capacity of the MTHFR enzyme are associated with increased risk for cardiovascular disease, as measured in this instance by log(HOMA-IR). Furthermore, serine, glycine, and betaine concentrations trended inversely with HOMA-IR, suggesting that increased presence of methyl-donating groups is associated with lower measures of insulin resistance. Ultimately, these results will need to be replicated in a significantly larger population.

PMID:34113268 | PMC:PMC8185170 | DOI:10.3389/fpsyt.2021.623143

Biomed Pharmacother. 2021 Jun 8:111652. doi: 10.1016/j.biopha.2021.111652. Online ahead of print.

ABSTRACT

Chemotherapy resistance remains to be the primary barrier to acute myeloid leukemia (AML) treatment failure. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been well established as a truly pleiotropic transcription factor. Inhibition of Nrf2 function increases the sensitivity of various chemotherapeutics and overcomes chemoresistance effectively. Brusatol (Bru) has been reported to decrease Nrf2 protein expression specifically by ubiquitin degradation of Nrf2. However, it remains elusive whether combination of Brusatol and Cytarabine (Ara-C) elicits a synergistic antitumor effect in AML. Our results demonstrated that combination of Ara-C and Brusatol synergistically exerted remarkable pro-apoptosis effect in HL-60 and THP-1 cells. Mechanistically, synergistic anti-tumor effect of Ara-C/Brusatol in AML cells is mediated by attenuating Nrf2 expression. To our surprise, Nrf2 inhibition by Brusatol causes downregulation of the expression of glycolysis-related proteins and decreased glucose consumption and lactate production, whereas the level of ROS production was unaffected. The activation of Nrf2 by Sulforaphane (SFP) could reverse the chemotherapeutic effect and changes of glycolysis of concomitant of Ara-C with Brusatol in AML cell lines. Additionally, Ara-C/Brusatol co-treatment decreased Glucose-6-phosphate dehydrogenase (G6PD) protein expression and increased the sensitivity of Ara-C. Moreover, the mouse xenograft in vivo experiment confirmed that combining Ara-C with Brusatol exerted stronger antileukemia than Ara-C alone. The efficacy, together with the mechanistic observations, reveals the potential of simultaneously giving these two drugs and provides a rational basis for targeting glucose catabolism in future clinical therapeutic approach.

PMID:34112534 | DOI:10.1016/j.biopha.2021.111652

BMC Med Genomics. 2021 Jun 9;14(1):153. doi: 10.1186/s12920-021-01005-x.

ABSTRACT

BACKGROUND: Refractive eye development is regulated by optical defocus in a process of emmetropization. Excessive exposure to negative optical defocus often leads to the development of myopia. However, it is still largely unknown how optical defocus is detected by the retina.

METHODS: Here, we used genome-wide RNA-sequencing to conduct analysis of the retinal gene expression network underlying contrast perception and refractive eye development.

RESULTS: We report that the genetic network subserving contrast perception plays an important role in optical defocus detection and emmetropization. Our results demonstrate an interaction between contrast perception, the retinal circadian clock pathway and the signaling pathway underlying optical defocus detection. We also observe that the relative majority of genes causing human myopia are involved in the processing of optical defocus.

CONCLUSIONS: Together, our results support the hypothesis that optical defocus is perceived by the retina using contrast as a proxy and provide new insights into molecular signaling underlying refractive eye development.

PMID:34107987 | PMC:PMC8190860 | DOI:10.1186/s12920-021-01005-x

FASEB J. 2021 Jul;35(7):e21730. doi: 10.1096/fj.202100157RR.

ABSTRACT

Adipose tissue macrophages (ATMs) represent the most abundant leukocytes in adipose tissue (AT). An increase in number and a phenotypical switch of ATMs during the development of obesity contribute to chronic inflammation and metabolic disorders, which have been regarded as potential therapeutic targets to restore AT homeostasis. Emodin has been shown to exert strong anti-inflammatory property via acting on macrophages in a range of disease models. However, whether emodin exerts a beneficial effect on obesity via modulating ATMs has not been reported. In high-fat diet (HFD)-induced obese mice, emodin significantly inhibited the increase of body weight and lipid accumulation in ATs. Emodin apparently reduced glucose and insulin levels and ameliorated serum lipid profiles in HFD-fed mice. Moreover, the local and systemic inflammation was dramatically alleviated by emodin. We next discovered that M2 macrophage percentage was greatly increased by emodin although total ATMs was not altered, which resulted in a net increase of M2 macrophages in AT. In vitro studies confirmed that emodin promoted the polarization of macrophages towards M2. Gene ontology (GO) analysis showed that myeloid leukocyte differentiation and activation were among the most significant biological processes in emodin-treated ATMs. We further identified that TREM2 was the most dramatically upregulated molecule by emodin and emodin-induced M2 macrophage polarization was dependent on TREM2. Furthermore, silencing TREM2 apparently abrogated the effect of emodin on AT inflammation and adipogenesis. We, for the first time, disclosed that emodin inhibited obesity by promoting M2 macrophage polarization via TREM2, suggesting that emodin may be explored as a clinical and translational candidate in preventing obesity and its related metabolic diseases.

PMID:34110631 | DOI:10.1096/fj.202100157RR

Clin Pharmacol Ther. 2021 Jun 10. doi: 10.1002/cpt.2333. Online ahead of print.

ABSTRACT

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C9 gene. Genetic variation within the CYP2C9 gene locus impacts the metabolism or bioactivation of many clinically important drugs including NSAIDs, phenytoin, anti-diabetic agents and angiotensin receptor blocker. Variable CYP2C9 activity is of particular importance regarding efficacy and safety of warfarin and siponimod as indicated in their package inserts. This GeneFocus provides a comprehensive overview and summary of CYP2C9 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

PMID:34109627 | DOI:10.1002/cpt.2333

Sci Rep. 2021 Jun 9;11(1):12568. doi: 10.1038/s41598-021-92113-2.

NO ABSTRACT

PMID:34108605 | DOI:10.1038/s41598-021-92113-2

Nat Commun. 2021 Jun 9;12(1):3505. doi: 10.1038/s41467-021-23556-4.

ABSTRACT

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

PMID:34108472 | DOI:10.1038/s41467-021-23556-4

Med Res Rev. 2021 Jun 9. doi: 10.1002/med.21838. Online ahead of print.

ABSTRACT

Atremorine is a novel bioproduct obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba. Atremorine is a potent dopamine (DA) enhancer with powerful effects on the neuronal dopaminergic system, acting as a neuroprotective agent in Parkinson's disease (PD). Over 97% of PD patients respond to a single dose of Atremorine (5 g, p.o.) 1 h after administration. This response is gender-, time-, dose-, and genotype-dependent, with optimal doses ranging from 5 to 20 g/day, depending upon disease severity and concomitant medication. Drug-free patients show an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ml; and patients chronically treated with anti-PD drugs show an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effects of conventional anti-PD drugs. Atremorine also influences the levels of other neurotransmitters (adrenaline, noradrenaline) and hormones which are regulated by DA (e.g., prolactin, PRL), with no effect on serotonin or histamine. The variability in Atremorine-induced DA response is highly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic (SNCA, NUCKS1, ITGA8, GPNMB, GCH1, BCKDK, APOE, LRRK2, ACMSD), mechanistic (DRD2), metabolic (CYP2D6, CYP2C9, CYP2C19, CYP3A4/5, NAT2), transporter (ABCB1, SLC6A2, SLC6A3, SLC6A4) and pleiotropic genes (APOE) influence the DA response to Atremorine and its psychomotor and brain effects. Atremorine enhances DNA methylation and displays epigenetic activity via modulation of the pharmacoepigenetic network. Atremorine is a novel neuroprotective agent for dopaminergic neurons with potential prophylactic and therapeutic activity in PD.

PMID:34106485 | DOI:10.1002/med.21838

Pharmacol Rep. 2021 Jun 9. doi: 10.1007/s43440-021-00297-1. Online ahead of print.

ABSTRACT

BACKGROUND: Several studies optimized the warfarin dose based on CYP2C9*2, CYP2C9*3, VKORC1 -1639 G > A, CYP4F2 V433M. But, the information on the rare variants is lacking. In this study, we have explored the prevalence of common and rare pharmacogenetic determinants of warfarin and determined their damaging nature.

METHODS: We have analyzed 2000 healthy adults using the Infinium global screening array (GSA) for 15 pharmacogenetic determinants of warfarin. In addition, we have elucidated the impact of these variants on protein function, stability, dynamics, evolutionary preservation, and ligand binding propensity.

RESULTS: The GSA Analysis has revealed that CYP4F2 V433M (MAF: 39.425%), VKORC1 -1639 G > A (MAF: 20.5%), CYP2C9*3 (MAF:9.925%), and CYP2C9*2 (MAF:4.575%) are common, while CYP2C9*14 (MAF: 1.475%), CYP2C9*4 (0.175%), CYP2C9*5 (0.125%), and CYP2C9*11 (0.125%) are rare. Position-specific evolutionary preservation (PSEP) analysis has revealed that CYP2C9*4 is possibly damaging, while CYP2C9*5, CYP2C9*11, and CYP2C9*14 are probably damaging. CYP2C9*4 has high thermolability (-10.14 kcal/mol). Among the rare CYP2C9 variants, CYP2C9*4 and CYP2C9*11 exert destabilizing effects and may have increased molecular flexibility, while CYP2C9*5 and CYP2C9*14 exert stabilizing effects and may have decreased molecular flexibility. DNase I footprint analysis has revealed the loss of the E-box consensus sequence due to VKORC1 -1639 G > A polymorphism.

CONCLUSION: CYP2C9*2, CYP2C9*3, VKORC1 -1639 G > A and CYP4F2 V433M are common; CYP2C9*4, CYP2C9*5, CYP2C9*11, and CYP2C9*14 variants are rare in Indian subjects. All the CYP2C9 variants are found to be damaging. DNase I footprint analysis provided the mechanistic rationale for the association of VKORC1 -1639 G > A with warfarin sensitivity.

PMID:34106453 | DOI:10.1007/s43440-021-00297-1

Clin Pharmacokinet. 2021 Jun 9. doi: 10.1007/s40262-021-01037-7. Online ahead of print.

ABSTRACT

BACKGROUND: Mycophenolic acid (MPA) is among the most commonly prescribed medications for immunosuppression following organ transplantation. Highly variable MPA exposure and drug response are observed among individuals receiving the same dosage of the drug. Identification of candidate genes whose polymorphisms could be used to predict MPA exposure and clinical outcome is of clinical value.

OBJECTIVES: This study aimed to determine the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of MPA in humans by means of a systematic review and meta-analysis.

METHODS: A systematic search was conducted on PubMed, EMBASE, Web of Sciences, Scopus, and the Cochrane Library databases. A meta-analysis was conducted to determine any associations between genetic polymorphisms and pharmacokinetic or pharmacodynamic parameters of MPA. Pooled-effect estimates were calculated by means of the random-effects model.

RESULTS: A total of 37 studies involving 3844 individuals were included in the meta-analysis. Heterozygous carriers of the UGT1A9 -275T>A polymorphism were observed to have a significantly lower MPA exposure than wild-type individuals. Four single nucleotide polymorphisms (SNPs), namely UGT1A9 -2152C>T, UGT1A8 518C>G, UGT2B7 211G>T, and SLCO1B1 521T>C, were also significantly associated with altered MPA pharmacokinetics. However, none of the investigated SNPs, including SNPs in the IMPDH gene, were found to be associated with the clinical efficacy of MPA. The only SNP that was associated with adverse outcomes was SLCO1B3 344T>G.

CONCLUSIONS: The present systematic review and meta-analysis identified six SNPs that were significantly associated with pharmacokinetic variability or adverse effects of MPA. Our findings represent the basis for future research and clinical implications with regard to the role of pharmacogenetics in MPA pharmacokinetics and drug response.

PMID:34105062 | DOI:10.1007/s40262-021-01037-7

Pharmgenomics Pers Med. 2021 Jun 1;14:655-665. doi: 10.2147/PGPM.S307694. eCollection 2021.

ABSTRACT

INTRODUCTION: Pharmacogenetic testing (PGx) is a diagnostic technique used by physicians to determine the possible reactions of patients to drug treatment on the basis of their genetic makeup. The aim of this study was to determine the impact of physicians' awareness, attitudes, and sociodemographics on the adoption of point-of-care (POC) PGx testing as a diagnostic method, as well as the impact of their knowledge, attitudes, and sociodemographics on its adoption.

METHODS: A cross-sectional survey of 200 physicians and medical trainees working at the Clinics of King Abdullah University Hospital in Jordan was performed. Data on sociodemographics, knowledge and attitudes concerning PGx testing, genetic information sources, and barriers to POC-PGx testing adoption were gathered.

RESULTS: Participants' perceived knowledge of the role of PGx testing in therapeutic decision-making was rated as "Excellent" (1.9%), "Very Good" (19.4%), "Good" (34.4%), "Fair" (32.5%), and "Poor" (11.9%). Physicians' actual knowledge of PGx testing was adequate (mean=3.56 out of 7, SD=1.2), but their attitudes were generally favorable (mean=3.64 out of 5.00, SD=0.52). According to Rogers' theory, many variables (eg, perceived need, relative advantage, compatibility) had a significant impact on physicians' willingness to endorse POC-PGx testing.

DISCUSSION: The majority of physicians stated that they were unaware of PGx testing. Physicians' perceived knowledge of POC-PGx testing, however, was higher than those who participated in other studies. Participants were optimistic about the future benefits of PGx testing in prescribing effective medications and reducing potential side effects, which were consistent with previous studies. Physicians' willingness to accept and implement POC-PGx testing was hampered by a lack of PGx expertise, as well as concerns about patient confidentiality, employability, and insurability. More training and genetic courses are needed, according to the majority of participants.

PMID:34103970 | PMC:PMC8179816 | DOI:10.2147/PGPM.S307694

Drug Des Devel Ther. 2021 Jun 1;15:2375-2384. doi: 10.2147/DDDT.S309763. eCollection 2021.

ABSTRACT

PURPOSE: DA-8031 is a novel selective serotonin reuptake inhibitor for the treatment of premature ejaculation. This study investigated the pharmacokinetics, safety and tolerability of multiple oral doses of DA-8031. In addition, a genetic analysis was explored to evaluate the effect of genetic polymorphisms on the pharmacokinetics of DA-8031.

SUBJECTS AND METHODS: A dose block-randomized, double-blind, placebo-controlled study was conducted in 3 dose groups with 20, 30 and 40 mg of DA-8031. Healthy male subjects were randomized to DA-8031 or placebo at a 4:1 ratio in each dose group of 10 subjects by oral administration once daily for 7 consecutive days. Serial blood and urine samples were collected for the pharmacokinetic evaluation, and the pharmacokinetic-related genes were analyzed by DMETTM plus. A safety evaluation was conducted including adverse events (AEs) monitoring and 12-lead electrocardiogram (ECG).

RESULTS: The plasma DA-8031 concentration reached the maximum concentration (Cmax) in 2.2 to 3.0 h and was eliminated with a mean half-life of 25.5 to 26.7 h at steady state. The accumulation index of DA-8031 ranged 2.3 to 2.8. The systemic exposure of DA-8031 of the CYP2D6 intermediate metabolizer (IM) was significantly higher compared to the CYP2D6 poor metabolizer (PM). There were no clinically significant QTc interval changes, and all the adverse events were mild.

CONCLUSION: After multiple oral doses of DA-8031 20, 30, and 40 mg in this study, the systemic exposure of DA-8031 increased in a more than dose-proportional manner with the increasing doses, and DA-8031 was generally well tolerated. In addition, the genetic polymorphisms of CYP2D6 have an impact on the pharmacokinetics of DA-8031.

PMID:34103898 | PMC:PMC8179755 | DOI:10.2147/DDDT.S309763

Transl Psychiatry. 2021 Jun 8;11(1):351. doi: 10.1038/s41398-021-01471-y.

ABSTRACT

Tardive dyskinesia (TD) is a severe condition characterized by repetitive involuntary movement of orofacial regions and extremities. Patients treated with antipsychotics typically present with TD symptomatology. Here, we conducted the largest GWAS of TD to date, by meta-analyzing samples of East-Asian, European, and African American ancestry, followed by analyses of biological pathways and polygenic risk with related phenotypes. We identified a novel locus and three suggestive loci, implicating immune-related pathways. Through integrating trans-ethnic fine mapping, we identified putative credible causal variants for three of the loci. Post-hoc analysis revealed that SNPs harbored in TNFRSF1B and CALCOCO1 independently conferred three-fold increase in TD risk, beyond clinical risk factors like Age of onset and Duration of illness to schizophrenia. Further work is necessary to replicate loci that are reported in the study and evaluate the polygenic architecture underlying TD.

PMID:34103471 | DOI:10.1038/s41398-021-01471-y

BMC Cardiovasc Disord. 2021 Jun 8;21(1):284. doi: 10.1186/s12872-021-02092-5.

ABSTRACT

BACKGROUND: Coronary artery disease (CAD) remains one of the leading causes of mortality worldwide and is associated with multiple inherited and environmental risk factors. This study is designed to identify, design, and develop a panel of genetic markers that combined with clinical and angiographic information, will facilitate the creation of a personalized risk prediction algorithm (GEnetic Syntax Score-GESS). GESS score could be a reliable tool for predicting cardiovascular risk for future adverse events and for guiding therapeutic strategies.

METHODS: GESS (ClinicalTrials.gov Identifier: NCT03150680) is a prospective, non-interventional clinical study designed to enroll 1080 consecutive patients with no prior history of coronary revascularization procedure, who undergo scheduled or emergency coronary angiography in AHEPA, University General Hospital of Thessaloniki. Next generation sequencing (NGS) technology will be used to genotype specific single-nucleotide polymorphisms (SNPs) across the genome of study participants, which were identified as clinically relevant to CAD after extensive bioinformatic analysis of literature-based SNPs. Enrichment analyses of Gene Ontology-Molecular Function, Reactome Pathways and Disease Ontology terms were also performed to identify the top 15 statistically significant terms and pathways. Furthermore, the SYNTAX score will be calculated for the assessment of CAD severity of all patients based on their angiographic findings. All patients will be followed-up for one-year, in order to record any major adverse cardiovascular events.

DISCUSSION: A group of 228 SNPs was identified through bioinformatic and pharmacogenomic analysis to be involved in CAD through a wide range of pathways and was correlated with various laboratory and clinical parameters, along with the patients' response to clopidogrel and statin therapy. The annotation of these SNPs revealed 127 genes being affected by the presence of one or more SNPs. The first patient was enrolled in the study in February 2019 and enrollment is expected to be completed until June 2021. Hence, GESS is the first trial to date aspiring to develop a novel risk prediction algorithm, the GEnetic Syntax Score, able to identify patients at high risk for complex CAD based on their molecular signature profile and ultimately promote pharmacogenomics and precision medicine in routine clinical settings. Trial registration GESS trial registration: ClinicalTrials.gov Number: NCT03150680. Registered 12 May 2017- Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT03150680 .

PMID:34103005 | DOI:10.1186/s12872-021-02092-5

Clin Pharmacol Ther. 2021 Jun 8. doi: 10.1002/cpt.2327. Online ahead of print.

ABSTRACT

The evidence for pharmacogenetics has grown rapidly in recent decades. However, the strength of evidence required for the clinical implementation of pharmacogenetics is highly debated. Therefore, the purpose of this review is to summarize different perspectives on the evidence required for the clinical implementation of pharmacogenetics. First, we present two patient cases that demonstrate how knowledge of pharmacogenetic evidence affected their care. Then we summarize resources that curate pharmacogenetic evidence, types of evidence (with an emphasis on randomized controlled trials [RCT]) and their limitations, and different perspectives from implementers, clinicians, and patients. We compare pharmacogenetics to a historical example (i.e., the evidence required for the clinical implementation of pharmacokinetics/therapeutic drug monitoring), and we provide future perspectives on the evidence for pharmacogenetic panels and the need for more education in addition to evidence. While there are differences in the interpretation of pharmacogenetic evidence across resources, efforts for standardization are underway. Survey data illustrate the value of pharmacogenetic testing from the patient perspective, with their providers seen as key to ensuring maximum benefit from test results. However, clinicians and practice guidelines from medical societies often rely on RCT data to guide treatment decisions, which are not always feasible or ethical in pharmacogenetics. Thus, recognition of other types of evidence to support pharmacogenetic implementation is needed. Among pharmacogenetic implementers, consistent evidence of pharmacogenetic associations is deemed most critical. Ultimately, moving pharmacogenetics into practice will require consideration of multiple stakeholder perspectives, keeping particularly attuned to the voice of the ultimate stakeholder - the patient.

PMID:34101169 | DOI:10.1002/cpt.2327

Food Funct. 2021 Jun 7;12(11):4972-4982. doi: 10.1039/d0fo02865g. Epub 2021 Apr 15.

ABSTRACT

The non-dialyzable material (NDM) of polyphenol-rich cranberry extract (CRE) powder (NDM-CRE) was studied for its effect of inducing body weight (BW) loss in 13 different mouse lines with well-defined genetically diverse backgrounds, named the collaborative cross (CC). From the age of 8 weeks, the mice were maintained on a high-fat diet (HFD) for 18 weeks, to induce obesity, and BW was measured biweekly. From week 12, CRE was injected intraperitoneally (IP) (50 mg kg-1) 3 times a week per mouse for a 6 week period. Statistical analysis results have shown a significant increase in body weight between week 0 and week 12; the increase in BW of 13 lines of mice on HFD was in the range of 10.41% to 68.65% for males and 9.78% to 64.74% for females. After injecting NDM-CRE extract, our analysis has shown an induced change in BW between week 12 and week 18. In males, NDM-CRE caused a significant decrease in BW of 5 out of the 13 lines in the range of -5.68% to -16.69% and a significant increase of 8.31% in BW of one male line, whereas in seven lines there was no significant decrease (-2.14% to -4.09%). In females, NDM-CRE caused a significant decrease in BW of 5 out of the 13 lines in the range of -3.90% to -11.83%, whereas in eight lines there were no significant changes in BW and it ranged between -1.50% and 4.90%. The broad-sense heritability (H2) and genetic coefficient of variation (CVg) were estimated and found to be between 0.71 and 0.81 for H2, and 0.18 and 0.24 for CVg of females and males, respectively, with respect to the efficacy of NDM-CRE on body weight reduction. Our results have shown that hosts with different genetic backgrounds respond differently to body weight increase, as well as to NDM-CRE treatment for body weight reduction. These results provide a platform for assessing more CC lines and mapping genes underlying the efficacy of the NDM-CRE treatment as a way of understanding pharmacogenomics.

PMID:34100468 | DOI:10.1039/d0fo02865g