To the Editor.

Ethn Dis. 2020;30(4):701-702

Authors: Raj GM, Mathaiyan J

PMID: 32989371 [PubMed - in process]

Association of ANRIL Polymorphism With Overall Survival in Adult Patients With Hematologic Malignancies After Allogeneic Hematopoietic Stem Cell Transplantation.

Anticancer Res. 2020 Oct;40(10):5707-5713

Authors: Li J, Seligson N, Zhang X, Johnson J, Vangundy Z, Wang D, Phelps M, Hofmeister C, Sadee W, Poi MJ

Abstract
BACKGROUND/AIM: Genetic variations of the non-coding RNA gene, ANRIL, have been associated with human diseases including cancer, type-2 diabetes, and atherosclerosis. In the present study, we investigated the potential associations of select ANRIL single nucleotide polymorphisms (SNPs) with overall survival and other clinical outcomes in adult patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
PATIENTS AND METHODS: Genomic DNA was extracted from whole blood samples from 103 adult patients with hematologic malignancies who had received allo-HSCT followed by oral tacrolimus therapy. The genotypes of four select ANRIL SNPs, rs564398, rs1063192, rs2151280, and rs2157719 were determined using qRT-PCR-based genotyping assays.
RESULTS: rs2151280 (C->T) in ANRIL was associated with worse overall survival in these patients (CT/CC vs. TT). Contrarily, rs2151280 and the other select ANRIL SNPs were not associated with death at Day-100 after transplantation, the incidence of graft-versus-host disease (GVHD), acute kidney injury (AKI), and neurotoxicity in the study cohort.
CONCLUSION: rs2151280 represents a potential prognostic biomarker for overall survival in adult patients with hematologic malignancies after allo-HSCT.

PMID: 32988896 [PubMed - in process]

Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19.

J Antimicrob Chemother. 2020 10 01;75(10):2977-2980

Authors: Tempestilli M, Caputi P, Avataneo V, Notari S, Forini O, Scorzolini L, Marchioni L, Ascoli Bartoli T, Castilletti C, Lalle E, Capobianchi MR, Nicastri E, D'Avolio A, Ippolito G, Agrati C, COVID 19 INMI Study Group

Abstract
BACKGROUND: Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients.
OBJECTIVES: To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients.
METHODS: Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method.
RESULTS: We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure.
CONCLUSIONS: We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.

PMID: 32607555 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis.

Redox Biol. 2020 Sep 12;37:101719

Authors: Kwon OS, Kwon EJ, Kong HJ, Choi JY, Kim YJ, Lee EW, Kim W, Lee H, Cha HJ

Abstract
Erastin, a synthetic lethal compound against cancer expressing an oncogenic RAS, inhibits cystine/glutamate antiporters and causes ferroptosis. However, despite recent evidence for the mechanisms underlying ferroptosis, molecular biomarkers of erastin-dependent ferroptosis have not been identified. Here, we employed isogenic lung cancer cell models to show that a redox imbalance leads to glutathione depletion and ferroptosis. Subsequent transcriptome analysis of pan-cancer cell lines revealed that the activity of transcription factors, including NRF2 and AhR, serve as important markers of erastin resistance. Based on the integrated expression of genes in the nuclear receptor meta-pathway (NRM), we constructed an NRM model and validated its robustness using an independent pharmacogenomics dataset. The NRM model was further evaluated by sensitivity tests on nine cancer cell lines for which erastin sensitivities had not been determined. Our pharmacogenomics approach has the potential to pave the way for the efficient classification of patients for therapeutic intervention using erastin.

PMID: 32979793 [PubMed - as supplied by publisher]

PharmGKB tutorial for pharmacogenomics of drugs potentially used in the context of COVID-19.

Clin Pharmacol Ther. 2020 Sep 26;:

Authors: Huddart R, Whirl-Carrillo M, Altman RB, Klein TE

Abstract
Pharmacogenomics is a key area of precision medicine which is already being implemented in some health systems and may help guide clinicians towards effective therapies for individual patients. Over the last two decades, the Pharmacogenomics Knowledgebase (PharmGKB) has built a unique repository of pharmacogenomic knowledge, including annotations of clinical guideline and regulator-approved drug labels in addition to evidence-based drug pathways and annotations of the scientific literature. All of this knowledge is freely accessible on the PharmGKB website. In the first of a series of PharmGKB tutorials, we introduce the PharmGKB COVID-19 portal and, using examples of drugs found in the portal, demonstrate some of the main features of PharmGKB. This paper is intended as a resource to help users become quickly acquainted with the wealth of information stored in PharmGKB.

PMID: 32978778 [PubMed - as supplied by publisher]

Pharmacogenomics in Pediatric Oncology: Mitigating Adverse Drug Reactions While Preserving Efficacy.

Annu Rev Pharmacol Toxicol. 2020 Sep 25;:

Authors: Elzagallaai AA, Carleton BC, Rieder MJ

Abstract
Cancer is the leading cause of death in American children older than 1 year of age. Major developments in drugs such as thiopurines and optimization in clinical trial protocols for treating cancer in children have led to a remarkable improvement in survival, from approximately 30% in the 1960s to more than 80% today. Short-term and long-term adverse effects of chemotherapy still affect most survivors of childhood cancer. Pharmacogenetics plays a major role in predicting the safety of cancer chemotherapy and, in the future, its effectiveness. Treatment failure in childhood cancer-due to either serious adverse effects that limit therapy or the failure of conventional dosing to induce remission-warrants development of new strategies for treatment. Here, we summarize the current knowledge of the pharmacogenomics of cancer drug treatment in children and of statistically and clinically relevant drug-gene associations and the mechanistic understandings that underscore their therapeutic value in the treatment of childhood cancer. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 7, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 32976737 [PubMed - as supplied by publisher]

Drug metabolism and pharmacokinetics of praziquantel: A review of variable drug exposure during schistosomiasis treatment in human hosts and experimental models.

PLoS Negl Trop Dis. 2020 Sep;14(9):e0008649

Authors: Zdesenko G, Mutapi F

Abstract
Schistosomiasis control is heavily reliant on the drug praziquantel (PZQ), which is used as preventive chemotherapy as part of national helminth control strategies. Given the heavy reliance on PZQ for mass drug administration, there has been considerable research on the potential of parasites developing resistance to the drug, resulting in decreased drug efficacy. However, there have been comparatively fewer studies of other factors that can potentially alter PZQ efficacy. Here, we investigate whether host PZQ metabolism contributes towards variable cure rates. We evaluate factors that can influence the metabolism of PZQ and the resultant effect on the efficacy of PZQ treatment to determine factors that potentially influence an individual's response to the drug. The literature search was directed at published studies from three online databases: Web of Science, PubMed, and EMBASE. The search terms for the review comprised of ([praziquantel OR PZQ] AND [schistosom* OR bilharzia] AND [pharmaco*]) and included studies evaluating PZQ metabolism. Publications were categorised into pharmacokinetics, drug-drug interactions, pharmacogenetics, and metabolite analysis. Forty publications describing human and experimental studies fitted the inclusion criteria and were subjected to data extraction and analysis. The analyses showed that variable exposure to PZQ was associated with alterations in the liver's capacity to metabolise PZQ and observed drug-drug interactions. Other factors influencing the efficacy of PZQ were brand, formulation, and co-administered food. Although some work has been performed on metabolite identification, there was minimal information on PZQ's metabolic pathway, and no pharmacogenetics studies were identified. The study indicated that in both human and experimental studies alterations in the liver's capacity to metabolise PZQ as well as drug-drug interactions affected systemic levels of PZQ that could result in variable cure rates. The study confirmed previous findings of higher antischistosomal activity of (R)-PZQ enantiomer when administered alone compared to the racemate at the same dose as well as improved efficacy when the drug is administered with food. The study also highlighted the need for more comprehensive studies of the PZQ metabolic pathway and PZQ pharmacogenetic studies in humans.

PMID: 32976496 [PubMed - as supplied by publisher]

Clinical implementation of pharmacogenetics and personalized drug prescription based on e-health: the MedeA initiative.

Drug Metab Pers Ther. 2020 Sep 01;35(3):

Authors: LLerena A, Peñas-LLedó E, de Andrés F, Mata-Martín C, Sánchez CL, Pijierro A, Cobaleda J

PMID: 32975200 [PubMed - in process]

Treatment Response Biomarkers in Anxiety Disorders: From Neuroimaging to Neuronally-Derived Extracellular Vesicles and Beyond.

Biomark Neuropsychiatry. 2020 Dec;3:

Authors: Strawn JR, Levine A

Abstract
Multiple and diverse psychotherapeutic or psychopharmacologic treatments effectively reduce symptoms for many patients with anxiety disorders, but the trajectory and magnitude of response vary considerably. This heterogeneity of treatment response has invigorated the search for biomarkers of treatment response in anxiety disorders, across the lifespan. In this review, we summarize evidence for biomarkers of treatment response in children, adolescents and adults with generalized, separation and social anxiety disorders as well as panic disorder. We then discuss the relationship between these biomarkers of treatment response and the pathophysiology of anxiety disorders. Finally, we provide context for treatment response biomarkers of the future, including neuronally-derived extracellular vesicles in anxiety disorders and discuss challenges that must be overcome prior to the debut of treatment response biomarkers in the clinic. A number of promising treatment response biomarkers have been identified, although there is an urgent need to replicate findings and to identify which biomarkers might guide clinicians in selecting from available treatments rather than just simply identifying patients who may be less likely to respond to a given intervention.

PMID: 32974615 [PubMed]

High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis.

Front Genet. 2020;11:951

Authors: Cismaru AL, Grimm L, Rudin D, Ibañez L, Liakoni E, Bonadies N, Kreutz R, Hallberg P, Wadelius M, EuDAC Collaborators, Haschke M, Largiadèr CR, Amstutz U

Abstract
Background and Objective: Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. While the mechanism underlying this adverse drug reaction is not well understood, involvement of the immune system has been suggested. In addition, associations between genetic variants in the Human Leukocyte Antigen (HLA) region and agranulocytosis induced by other drugs have been reported. The aim of the present study was to assess whether genetic variants in classical HLA genes are associated with the susceptibility to metamizole-induced agranulocytosis (MIA) in a European population by targeted resequencing of eight HLA genes. Design: A case-control cohort of Swiss patients with a history of neutropenia or agranulocytosis associated with metamizole exposure (n = 53), metamizole-tolerant (n = 39) and unexposed controls (n = 161) was recruited for this study. A high-throughput resequencing (HTS) and high-resolution typing method was used to sequence and analyze eight HLA loci in a discovery subset of this cohort (n = 31 cases, n = 38 controls). Identified candidate alleles were investigated in the full Swiss cohort as well as in two independent cohorts from Germany and Spain using HLA imputation from genome-wide SNP array data. In addition, variant calling based on HTS data was performed in the discovery subset for the class I genes HLA-A, -B, and -C using the HLA-specific mapper hla-mapper. Results: Eight candidate alleles (p < 0.05) were identified in the discovery subset, of which HLA-C∗04:01 was associated with MIA in the full Swiss cohort (p < 0.01) restricted to agranulocytosis (ANC < 0.5 × 109/L) cases. However, no candidate allele showed a consistent association in the Swiss, German and Spanish cohorts. Analysis of individual sequence variants in class I genes produced consistent results with HLA typing but did not reveal additional small nucleotide variants associated with MIA. Conclusion: Our results do not support an HLA-restricted T cell-mediated immune mechanism for MIA. However, we established an efficient high-resolution (three-field) eight-locus HTS HLA resequencing method to interrogate the HLA region and demonstrated the feasibility of its application to pharmacogenetic studies.

PMID: 32973882 [PubMed]

Heterogeneity of telomerase reverse transcriptase mutation and expression, telomerase activity and telomere length across human cancer cell lines cultured in vitro.

Exp Cell Res. 2020 Sep 21;:112298

Authors: Dratwa M, Wysoczanska B, Turlej E, Anisiewicz A, Maciejewska M, Wietrzyk J, Bogunia-Kubik K

Abstract
Promoter region of the telomerase reverse transcriptase gene (TERTp) constitutes a regulatory element capable to affect TERT expression (TE), telomerase activity (TA) and telomere length (TL). TERTp mutation status, TL, TA and TE were assessed in 27 in vitro cultured human cell lines, including 11 solid tumour, 13 haematological and 3 normal cell lines. C228T and C250T TERTp mutations were detected in 5 solid tumour and none of haematological cell lines (p = 0.0100). As compared to other solid tumour cell lines, those with the presence of somatic mutations were characterized by: shorter TL, lower TA and TE. Furthermore, cell lines carrying TERTp mutations showed a linear correlation between TE and TA (R = 0.9708, p = 0.0021). Moreover, haematological cell lines exhibited higher TE compared to solid tumour cell lines (p = 0.0007). TL and TA were correlated in both solid tumour (R = 0.4875, p = 0.0169) and haematological (R = 0.4719, p = 0.0095) cell lines. Our results based on the in vitro model suggest that oncogenic processes may differ between solid tumours and haematological malignancies with regard to their TERT gene regulation mechanisms.

PMID: 32971118 [PubMed - as supplied by publisher]

Liver enzyme CYP2D6 gene and tardive dyskinesia.

Pharmacogenomics. 2020 Sep 24;:

Authors: Lu JY, Tiwari AK, Freeman N, Zai GC, Luca V, Müller DJ, Tampakeras M, Herbert D, Emmerson H, Cheema SY, King N, Voineskos AN, Potkin SG, Lieberman JA, Meltzer HY, Remington G, Kennedy JL, Zai CC

Abstract
Background: Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with an unclear pathogenesis. CYP2D6 is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. Materials & methods: We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n = 198, of which 82 had TD). Results: TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. Conclusion: Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.

PMID: 32969762 [PubMed - as supplied by publisher]

Assessment of primary care practitioners' attitudes and interest in pharmacogenomic testing.

Pharmacogenomics. 2020 Sep 24;:

Authors: Smith DM, Namvar T, Brown RP, Springfield TB, Peshkin BN, Walsh RJ, Welsh JC, Levin B, Brandt N, Swain SM

Abstract
Aims: Identify the attitudes and interests of primary care providers (PCPs) in applying clinical pharmacogenomics (PGx) test results. Materials & methods: A questionnaire was designed and then disseminated to PCPs across the MedStar Health System. Results: Ninety of 312 (29%) PCPs responded and were included in analyses. Seventy-six (84%) had heard of PGx and 12 (13%) previously ordered PGx testing. Most, 68 (76%), believed PGx can improve care; however, a minority, 23 (26%), reported confidence in using PGx in prescribing decisions. Sixty-four (70%) wanted a pharmacist consultation. PCPs desired PGx for antidepressants (75%), proton pump inhibitors (72%) and other medications. Conclusion: Most PCPs felt unprepared to interpret PGx results and desired pharmacist consultations. These data can inform future PGx implementations with PCPs.

PMID: 32969759 [PubMed - as supplied by publisher]

Interactions among Genetic Background, Anesthetic Agent, and Oxygen Concentration Shape Blunt Traumatic Brain Injury Outcomes in Drosophila melanogaster.

Int J Mol Sci. 2020 Sep 21;21(18):

Authors: Scharenbrock AR, Schiffman HJ, Olufs ZPG, Wassarman DA, Perouansky M

Abstract
Following traumatic brain injury (TBI), the time window during which secondary injuries develop provides a window for therapeutic interventions. During this time, many TBI victims undergo exposure to hyperoxia and anesthetics. We investigated the effects of genetic background on the interaction of oxygen and volatile general anesthetics with brain pathophysiology after closed-head TBI in the fruit fly Drosophila melanogaster. To test whether sevoflurane shares genetic risk factors for mortality with isoflurane and whether locomotion is affected similarly to mortality, we used a device that generates acceleration-deceleration forces to induce TBI in ten inbred fly lines. After TBI, we exposed flies to hyperoxia alone or in combination with isoflurane or sevoflurane and quantified mortality and locomotion 24 and 48 h after TBI. Modulation of TBI-induced mortality and locomotor impairment by hyperoxia with or without anesthetics varied among fly strains and among combinations of agents. Resistance to increased mortality from hyperoxic isoflurane predicted resistance to increased mortality from hyperoxic sevoflurane but did not predict the degree of locomotion impairment under any condition. These findings are important because they demonstrate that, in the context of TBI, genetic background determines the latent toxic potentials of oxygen and anesthetics.

PMID: 32967238 [PubMed - in process]

Can Implementation of Genetics and Pharmacogenomics Improve Treatment of Chronic Low Back Pain?

Pharmaceutics. 2020 Sep 21;12(9):

Authors: Suntsov V, Jovanovic F, Knezevic E, Candido KD, Knezevic NN

Abstract
Etiology of back pain is multifactorial and not completely understood, and for the majority of people who suffer from chronic low back pain (cLBP), the precise cause cannot be determined. We know that back pain is somewhat heritable, chronic pain more so than acute. The aim of this review is to compile the genes identified by numerous genetic association studies of chronic pain conditions, focusing on cLBP specifically. Higher-order neurologic processes involved in pain maintenance and generation may explain genetic contributions and functional predisposition to formation of cLBP that does not involve spine pathology. Several genes have been identified in genetic association studies of cLBP and roughly, these genes could be grouped into several categories, coding for: receptors, enzymes, cytokines and related molecules, and transcription factors. Treatment of cLBP should be multimodal. In this review, we discuss how an individual's genotype could affect their response to therapy, as well as how genetic polymorphisms in CYP450 and other enzymes are crucial for affecting the metabolic profile of drugs used for the treatment of cLBP. Implementation of gene-focused pharmacotherapy has the potential to deliver select, more efficacious drugs and avoid unnecessary, polypharmacy-related adverse events in many painful conditions, including cLBP.

PMID: 32967120 [PubMed]

Comprehensive Custom NGS Panel Validation for the Improvement of the Stratification of B-Acute Lymphoblastic Leukemia Patients.

J Pers Med. 2020 Sep 21;10(3):

Authors: Montaño A, Hernández-Sánchez J, Forero-Castro M, Matorra-Miguel M, Lumbreras E, Miguel C, Santos S, Ramírez-Maldonado V, Fuster JL, de Las Heras N, García-de Coca A, Sierra M, Dávila J, de la Fuente I, Olivier C, Olazabal J, Martínez J, Vega-García N, González T, Hernández-Rivas JM, Benito R

Abstract
BACKGROUND: B-acute lymphoblastic leukemia (B-ALL) is a hematological neoplasm of the stem lymphoid cell of the B lineage, characterized by the presence of genetic alterations closely related to the course of the disease. The number of alterations identified in these patients grows as studies of the disease progress, but in clinical practice, the conventional techniques frequently used are only capable of detecting the most common alterations. However, techniques, such as next-generation sequencing (NGS), are being implemented to detect a wide spectrum of new alterations that also include point mutations.
METHODS: In this study, we designed and validated a comprehensive custom NGS panel to detect the main genetic alterations present in the disease in a single step. For this purpose, 75 B-ALL diagnosis samples from patients previously characterized by standard-of-care diagnostic techniques were sequenced.
RESULTS: The use of the custom NGS panel allowed the correct detection of the main genetic alterations present in B-ALL patients, including the presence of an aneuploid clone in 14 of the samples and some of the recurrent fusion genes in 35 of the samples. The panel was also able to successfully detect a number of secondary alterations, such as single nucleotide variants (SNVs) and copy number variations (CNVs) in 66 and 46 of the samples analyzed, respectively, allowing for further refinement of the stratification of patients. The custom NGS panel could also detect alterations with a high level of sensitivity and reproducibility when the findings obtained by NGS were compared with those obtained from other conventional techniques.
CONCLUSIONS: The use of this custom NGS panel allows us to quickly and efficiently detect the main genetic alterations present in B-ALL patients in a single assay (SNVs and insertions/deletions (INDELs), recurrent fusion genes, CNVs, aneuploidies, and single nucleotide polymorphisms (SNPs) associated with pharmacogenetics). The application of this panel would thus allow us to speed up and simplify the molecular diagnosis of patients, helping patient stratification and management.

PMID: 32967112 [PubMed]

SIRT1 Gene SNP rs932658 is Associated with Medication-Related Osteonecrosis of the Jaw.

J Bone Miner Res. 2020 Sep 23;:

Authors: Yang G, Collins JM, Rafiee R, Singh S, Langaee T, McDonough CW, Holliday LS, Wang D, Lamba J, Kim YS, Pelliccioni GA, Vaszilko M, Kosa JP, Balla B, Lakatos PA, Katz J, Moreb J, Gong Y

Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug reaction. Our previous whole-exome sequencing study found SIRT1 intronic region SNP rs7896005 to be associated with MRONJ in cancer patients treated with intravenous (IV) bisphosphonates (BPs). This study aimed to identify causal variants for this association. In silico analyses identified three SNPs (rs3758391, rs932658, and rs2394443) in the SIRT1 promoter region that are in high linkage disequilibrium (r2 > 0.8) with rs7896005. To validate the association between these SNPs and MRONJ, we genotyped these three SNPs on the germline DNA from 104 cancer patients of European ancestry treated with IV BPs (46 cases and 58 controls). Multivariable logistic regression analysis showed the minor alleles of these three SNPs were associated with lower odds for MRONJ. The odds ratios (95% confidence interval) and p values were 0.351 (0.164-0.751) (p=0.007) for rs3758391, 0.351 (0.164-0.751) (p=0.007) for rs932658, and 0.331 (0.157-0.697) (p=0.0036) for rs2394443, respectively. In the reporter gene assays, constructs containing rs932658 with variant allele A had higher luciferase activity than the reference allele, while constructs containing SNP rs3758391 and/or rs2394443 did not significantly affect activity. These results indicate that the promoter SNP rs932658 regulates the expression of SIRT1 and presumably lowers the risk of MRONJ by increasing SIRT1 expression.

PMID: 32967053 [PubMed - as supplied by publisher]

Circulating choline is associated with coronary artery stenosis in patients with hypertension: A cross-sectional study of Chinese adults.

J Clin Hypertens (Greenwich). 2020 Sep 23;:

Authors: Guo F, Qiu X, Zhu Y, Tan Z, Li Z, Ouyang D

Abstract
Choline is an important nutrient involved in multiple biosynthesis pathways. However, whether circulating choline levels are associated with the risk of hypertension (HTN) and artery stenosis in HTN remains unknown. We investigated the correlations of plasma choline with HTN and coronary artery injury and explored the utility of plasma choline as a diagnostic biomarker for HTN and artery stenosis. 193 HTN patients and 154 age- and sex-matched healthy controls (CON) were recruited in this study. Fasting plasma choline was detected using liquid chromatography tandem mass spectrometry. Choline levels were significantly higher in HTN without artery stenosis (HTN-AS) than CON (8.07 [7.19-9.24] μM vs 7.03 [6.21-8.13] μM, P < .01) group and were further upregulated in HTN with artery stenosis (HTN + AS) (8.63 [7.09-10.59] μM, P < .01) group. Patients with multivessel disease (MVD) also exhibited higher choline levels than those with single vessel disease (SVD) (8.64 [7.16-10.55] μM vs 8.04(6.74-9.38) μM, P < .01). Increased choline levels were independently associated with the risk of HTN (OR = 1.2, 95% CI: 1-1.45, P = .05), HTN + AS (OR = 1.27, 95% CI: 1.09-1.48, P < .01), and MVD (OR = 1.16, 95% CI: 1.02-1.31, P = .02) after adjustment for multiple risk factors. Receiver operating characteristic (ROC) analysis showed that choline had an area under curve (AUC) score of 0.69, 0.67, and 0.63 in determining HTN, HTN + AS, and MVD. In conclusion, higher choline levels were associated with increased risk of HTN and artery stenosis in hypertensive patients.

PMID: 32966687 [PubMed - as supplied by publisher]

Assessment of the clinical utility of pharmacogenetic guidance in a comprehensive medication management service.

J Am Coll Clin Pharm. 2020 Sep;3(6):1028-1037

Authors: Rodríguez-Escudero I, Cedeño JA, Rodríguez-Nazario I, Reynaldo-Fernández G, Rodríguez-Vera L, Morales N, Jiménez-Vélez B, Ruaño G, Duconge J

Abstract
Introduction: Pharmacists are poised to be the health care professionals best suited to provide medication-related consults and services based on a patient's genetics. Despite its potential benefits, the implementation of pharmacogenetic (PGx) testing into primary clinical settings has been slow among medically underserved populations. To our knowledge, this is the first time that PGx-driven recommendations have been incorporated into a Comprehensive Medication Management (CMM) service in a Hispanic population.
Objectives: The aim of this study is to evaluate the clinical utility of adding PGx guidance into pharmacist-driven CMM.
Methods: This is a pre- and post-interventional design study. Patients were recruited from a psychologist's clinic. A total of 24 patients had a face-to-face interview with a pharmacist to complete a CMM, Personal Medication Record, and Medication-Related Action Plan (MAP) blind to PGx findings. Collected buccal DNA samples were genotyped using drug-metabolizing enzymes and transporters (DMET) Plus Array.
Results: The pharmacist generated new MAPs for each patient based on PGx results. Genetic variants that could potentially affect the safety and effectiveness of at least one drug in the pharmacotherapy were identified in 96% of patients, for whom the pharmacist changed the initial recommendations. Polymorphisms in genes encoding for isoenzymes CYP2D6, CYP2C19, and CYP2C9 were identified in 83%, 52%, and 41% of patients, respectively. Pharmacists performing CMM identified 22 additional medication problems after PGx determinations. Moreover, they agreed with the clinical utility of PGx in the studied sample based on perceived value of adding PGx to traditional CMM and its utility in the decision-making process of pharmacists.
Conclusions: The study confirmed the critical role to be played by pharmacists in facilitating the clinical usage of relevant genetic information to optimize drug therapy decisions as well as their involvement on many levels of these multidisciplinary implementation efforts, including championing and leading PGx-guided CMM services.

PMID: 32964197 [PubMed - as supplied by publisher]