Pharmacogenomics. 2021 May 18. doi: 10.2217/pgs-2020-0128. Online ahead of print.

ABSTRACT

Aim: To evaluate the application of next-generation sequencing-based targeted protocol for full-length CYP3A4 gene sequencing analysis. Materials & methods: The developed sequencing protocol was applied to analyze human DNA samples (n = 7) obtained from tuberculosis patients admitted to the Riga East University Hospital, Center of Tuberculosis and Lung diseases. Results: The sequencing data quality was sufficient for the detection of already known genetic variants, as well as for identifying rare and novel variants dispersed throughout the CYP3A4 gene with a high degree of confidence. Conclusion: Developed protocol can be applied in subpopulation level association studies to determine whether specific genetic variants or variant combinations from multiple regions of the CYP3A4 gene are of clinical significance.

PMID:34003019 | DOI:10.2217/pgs-2020-0128

Nat Genet. 2021 May 17. doi: 10.1038/s41588-021-00857-4. Online ahead of print.

ABSTRACT

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

PMID:34002096 | DOI:10.1038/s41588-021-00857-4

Pharmacogenet Genomics. 2021 May 14. doi: 10.1097/FPC.0000000000000436. Online ahead of print.

ABSTRACT

OBJECTIVES: The RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Cell entry is mediated by the human angiotensin-converting enzyme II (ACE2). ACE2 and its close homolog angiotensin-converting enzyme I (ACE) are currently discussed candidate genes, in which single-nucleotide polymorphisms (SNPs) could alter binding or entry of SARS-CoV-2 and enhance tissue damage in the lung or other organs. This could increase the susceptibility for SARS-CoV-2 infection and the severity of COVID-19.

PATIENTS AND METHODS: We performed genotyping of SNPs in the genes ACE2 and ACE in 297 SARS-CoV-2-positive and 253 SARS-CoV-2-negative tested patients. We analyzed the association of the SNPs with susceptibility for SARS-CoV-2 infection and the severity of COVID-19.

RESULTS: SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics and clinical characteristics. For ACE2 rs2285666, the GG genotype or G-allele was significantly associated with an almost two-fold increased SARS-CoV-2 infection risk and a three-fold increased risk to develop serious disease or COVID-19 fatality. In contrast, the ACE polymorphism was not related to infection risk or severity of disease. In a multivariable analysis, the ACE2 rs2285666 G-allele remained as an independent risk factor for serious disease besides the known risk factors male gender and cardiovascular disease.

CONCLUSIONS: In summary, our report appears to be the first showing that a common ACE2 polymorphism impacts the risk for SARS-CoV-2 infection and the course of COVID-19 independently from previously described risk factors.

PMID:34001841 | DOI:10.1097/FPC.0000000000000436

Xenobiotica. 2021 May 18:1-22. doi: 10.1080/00498254.2021.1931554. Online ahead of print.

ABSTRACT

We explored the potential effects of genetic variations on the concentration to dose ratio (CDR) of VPA in pediatric epilepsy patients.Two hundred and twenty-nine epileptic children on VPA monotherapy were included, and the VPA trough concentrations at steady-state of all subjects were determined.Nineteen single nucleotide polymorphisms (SNPs) of seven selected genes related to the metabolizing enzymes and transporters of VPA were identified, and their influences on CDRVPA (a logarithmic transformation was performed if abnormally distributed) were evaluated.UGT2B7 rs7668258 (C > T) TT genotype was associated with a decrease in lnCDRVPA among epileptic children receiving VPA monotherapy (β = -0.191, p = 0.036). Significantly lower lnCDRVPA was also observed in pediatric patients with UGT1A6 rs2070959 (A > G) GG genotype compared to those AA genotype (β = -0.270, p = 0.021).This research indicated that UGT2B7 rs7668258 (C > T) and UGT1A6 rs2070959 (A > G) polymorphisms may be correlated to the normalized plasma concentrations of VPA in Chinese epileptic children. The associations could be abolished after Bonferroni's correction and our findings need to be validated in further and larger investigations.

PMID:34000957 | DOI:10.1080/00498254.2021.1931554

J Oncol Pharm Pract. 2021 May 18:10781552211017193. doi: 10.1177/10781552211017193. Online ahead of print.

ABSTRACT

INTRODUCTION: Functional variants of the Methylenetetrahydrofolate reductase (MTHFR) gene, the C677T and A1298C, have largely investigated in pharmacogenomics of Methotrexate (MTX) in acute lymphoblastic leukemia (ALL), yet the conclusions are inconsistent. In addition; most of these studies do not analyze haplotypes. Here, we investigate the MTHFR 677/1298 genotypes and the 677-1298 haplotype and characterize the MTX response in Northern African ALL patients.

METHODS: Genomic DNA was extracted from whole venous from a total of 28 patients with ALL. Genotyping were carried out with restriction fragment length polymorphism (RFLP). A toxicity score (TS) is calculated for each patient and correlate to the haplotype.

RESULTS: The allelic frequency of MTHFR 677T-1298C haplotype was 10.7% in ALL patients. According to the toxicity's score (TS) there was no significant differences between haplotype groups (p = 0.79): TS was higher with wild type of MTHFR (TS = 3.43; SEM ± 0.85) followed by combined genotype (677T-1298C) (TS = 2.67; SEM ± 0.88) and isolated variant (C677T or A1298C) (TS = 2.64; SEM ± 0.92).

CONCLUSION: Despite the limitation of this study; our results suggest that the MTHFR 677T-1298C haplotype is common in ALL and may be a promising HD-MTX chemotherapy-related adverse effects biomarker.

PMID:34000920 | DOI:10.1177/10781552211017193

Clin Pharmacol Ther. 2021 May 17. doi: 10.1002/cpt.2289. Online ahead of print.

ABSTRACT

Inter-individual differences in drug response are a common concern in both drug development and across layers of care. While genetics clearly influence drug response and toxicity of many drugs, a substantial fraction of the heritable pharmacological and toxicological variability remains unexplained by known genetic polymorphisms. In recent years, population-scale sequencing projects have unveiled tens of thousands of coding and non-coding pharmacogenetic variants with unclear functional effects that might explain at least part of this missing heritability. However, translating these personalized variant signatures into drug response predictions and actionable advice remains challenging and constitutes one of the most important frontiers of contemporary pharmacogenomics. Conventional prediction methods are primarily based on evolutionary conservation, which drastically reduces their predictive accuracy when applied to poorly conserved pharmacogenes. Here, we review the current state-of-the-art of computational variant effect predictors across variant classes and critically discuss their utility for pharmacogenomics. Besides missense variants, we discuss recent progress in the evaluation of synonymous, splice and non-coding variations. Furthermore, we discuss emerging possibilities to assess haplotypes and structural variations. We advocate for the development of algorithms trained on pharmacogenomic instead of pathogenic data sets to improve the predictive accuracy in order to facilitate the utilization of NGS data for personalized clinical decision-support and precision pharmacogenomics.

PMID:33998671 | DOI:10.1002/cpt.2289

Pharmacogenomics. 2021 May 17. doi: 10.2217/pgs-2021-0013. Online ahead of print.

ABSTRACT

Aim: Several CYP2D6 Luminex xTAG genotype calls were identified as inconsistent or suspicious among Thai subjects and further characterized to identify the root causes. Material & methods: Forty-eight subjects were followed-up with long-range-PCR, quantitative copy number assays and/or Sanger sequencing. Results: Most of the Luminex-duplication calls were either negative or had hybrid structures involving CYP2D6*36 in various configurations. Ten samples were inaccurately called as CYP2D6*2, *29 or *35 alleles. Sequencing revealed three novel haplotypes, CYP2D6*142, *143 and *144 of which two are nonfunctional. Conclusion: The Luminex platform produced a relatively high number of false genotype calls for Thai subjects. Our findings underscore the need for the systematic characterization of the CYP2D6 locus in diverse populations and rigorous platform validation.

PMID:33998274 | DOI:10.2217/pgs-2021-0013

Front Cardiovasc Med. 2021 Apr 29;8:645122. doi: 10.3389/fcvm.2021.645122. eCollection 2021.

ABSTRACT

Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, p = 0.0004) and higher abundance of lactate (FC = 2.4, p = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, p = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.

PMID:33996940 | PMC:PMC8116486 | DOI:10.3389/fcvm.2021.645122

Front Immunol. 2021 Apr 22;12:663203. doi: 10.3389/fimmu.2021.663203. eCollection 2021.

ABSTRACT

The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.

PMID:33995390 | PMC:PMC8120991 | DOI:10.3389/fimmu.2021.663203

Front Immunol. 2021 Apr 29;12:658593. doi: 10.3389/fimmu.2021.658593. eCollection 2021.

ABSTRACT

HLA-B*13:01-positive patients in Thailand can develop frequent co-trimoxazole hypersensitivity reactions. This study aimed to characterize drug-specific T cells from three co-trimoxazole hypersensitive patients presenting with either Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms. Two of the patients carried the HLA allele of interest, namely HLA-B*13:01. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones were generated from T cell lines of co-trimoxazole hypersensitive HLA-B*13:01-positive patients. Clones were characterized for antigen specificity and cross-reactivity with structurally related compounds by measuring proliferation and cytokine release. Surface marker expression was characterized via flow cytometry. Mechanistic studies were conducted to assess pathways of T cell activation in response to antigen stimulation. Peripheral blood mononuclear cells from all patients were stimulated to proliferate and secrete IFN-γ with nitroso sulfamethoxazole. All sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones expressed the CD4+ phenotype and strongly secreted IL-13 as well as IFN-γ, granzyme B and IL-22. No secretion of IL-17 was observed. A number of nitroso sulfamethoxazole-specific clones cross-reacted with nitroso dapsone but not sulfamethoxazole whereas sulfamethoxazole specific clones cross-reacted with nitroso sulfamethoxazole only. The nitroso sulfamethoxazole specific clones were activated in both antigen processing-dependent and -independent manner, while sulfamethoxazole activated T cell responses via direct HLA binding. Furthermore, activation of nitroso sulfamethoxazole-specific, but not sulfamethoxazole-specific, clones was blocked with glutathione. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones from hypersensitive patients were CD4+ which suggests that HLA-B*13:01 is not directly involved in the iatrogenic disease observed in co-trimoxazole hypersensitivity patients.

PMID:33995375 | PMC:PMC8117787 | DOI:10.3389/fimmu.2021.658593

Front Pharmacol. 2021 Apr 30;12:671298. doi: 10.3389/fphar.2021.671298. eCollection 2021.

ABSTRACT

Biomarkers that can guide cancer therapy based on patients' individual cancer molecular signature can enable a more effective treatment with fewer adverse events. Data on actionable somatic mutations and germline genetic variants, studied by personalized medicine and pharmacogenomics, can be obtained from tumor tissue or blood samples. As tissue biopsy cannot reflect the heterogeneity of the tumor or its temporal changes, liquid biopsy is a promising alternative approach. In recent years, extracellular vesicles (EVs) have emerged as a potential source of biomarkers in liquid biopsy. EVs are a heterogeneous population of membrane bound particles, which are released from all cells and accumulate into body fluids. They contain various proteins, lipids, nucleic acids (miRNA, mRNA, and DNA) and metabolites. In cancer, EV biomolecular composition and concentration are changed. Tumor EVs can promote the remodeling of the tumor microenvironment and pre-metastatic niche formation, and contribute to transfer of oncogenic potential or drug resistance during chemotherapy. This makes them a promising source of minimally invasive biomarkers. A limited number of clinical studies investigated EVs to monitor cancer progression, tumor evolution or drug resistance and several putative EV-bound protein and RNA biomarkers were identified. This review is focused on EVs as novel biomarker source for personalized medicine and pharmacogenomics in oncology. As several pharmacogenes and genes associated with targeted therapy, chemotherapy or hormonal therapy were already detected in EVs, they might be used for fine-tuning personalized cancer treatment.

PMID:33995103 | PMC:PMC8120271 | DOI:10.3389/fphar.2021.671298

Front Pharmacol. 2021 Apr 29;12:660639. doi: 10.3389/fphar.2021.660639. eCollection 2021.

ABSTRACT

Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p < 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2*1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes (p < 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (p < 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW (p < 0.05 in multivariate analysis). The remaining studied transporter genes (ABCC2, SLC22A1, and SLCO1B1) and metabolizing enzyme genes (CYP3A5, CYP2C19, CYP2C9, CYP2C8, CYP3A4, CYP2A6, and UGT1A1) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6, CYP2D6, CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.

PMID:33995083 | PMC:PMC8117330 | DOI:10.3389/fphar.2021.660639

Front Pharmacol. 2021 Apr 30;12:651720. doi: 10.3389/fphar.2021.651720. eCollection 2021.

ABSTRACT

Adverse drug reactions (ADRs) are an important and frequent cause of morbidity and mortality. ADR can be related to a variety of drugs, including anticonvulsants, anaesthetics, antibiotics, antiretroviral, anticancer, and antiarrhythmics, and can involve every organ or apparatus. The causes of ADRs are still poorly understood due to their clinical heterogeneity and complexity. In this scenario, genetic predisposition toward ADRs is an emerging issue, not only in anticancer chemotherapy, but also in many other fields of medicine, including hemolytic anemia due to glucose-6-phosphate dehydrogenase (G6PD) deficiency, aplastic anemia, porphyria, malignant hyperthermia, epidermal tissue necrosis (Lyell's Syndrome and Stevens-Johnson Syndrome), epilepsy, thyroid diseases, diabetes, Long QT and Brugada Syndromes. The role of genetic mutations in the ADRs pathogenesis has been shown either for dose-dependent or for dose-independent reactions. In this review, we present an update of the genetic background of ADRs, with phenotypic manifestations involving blood, muscles, heart, thyroid, liver, and skin disorders. This review aims to illustrate the growing usefulness of genetics both to prevent ADRs and to optimize the safe therapeutic use of many common drugs. In this prospective, ADRs could become an untoward "stress test," leading to new diagnosis of genetic-determined diseases. Thus, the wider use of pharmacogenetic testing in the work-up of ADRs will lead to new clinical diagnosis of previously unsuspected diseases and to improved safety and efficacy of therapies. Improving the genotype-phenotype correlation through new lab techniques and implementation of artificial intelligence in the future may lead to personalized medicine, able to predict ADR and consequently to choose the appropriate compound and dosage for each patient.

PMID:33995067 | PMC:PMC8120428 | DOI:10.3389/fphar.2021.651720

Front Pharmacol. 2021 Apr 12;12:640032. doi: 10.3389/fphar.2021.640032. eCollection 2021.

ABSTRACT

Effective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients' genetic heterogeneity and low compliance-related to frequent adverse events. Only one third of patients respond to treatment and experience remission. Pharmacogenetics is a relatively young field which focusses on genetic analyses in the context of the metabolism and outcome of drug treatment. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Recently, a clinical guideline was authorized by the Dutch Clinical Psychiatric Association (NVvP) on the clinical use of pharmacogenetics in psychiatry. The main goal was to provide guidance, based on current evidence, on how to best use genotyping in clinical psychiatric practice. A systematic literature search was performed, and available publications were assessed using the GRADE methodology. General recommendations for psychiatric clinical practice were provided, and specific recommendations per medication were made available. This clinical guideline for caregivers prescribing psychotropic drugs is the product of a broad collaboration of professionals from different disciplines, making use of the information available at the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) so far. We summarize the relevant literature and all recommendations in this article. General recommendations are provided and also detailed recommendations per medication. In summary we advise to consider genotyping, when there are side effects or inefficacy for CYP2C19 and CYP2D6. When genotype information is available use this to select the right drug in the right dose for the right patient.

PMID:33995044 | PMC:PMC8117336 | DOI:10.3389/fphar.2021.640032

Front Pharmacol. 2021 Apr 28;12:636352. doi: 10.3389/fphar.2021.636352. eCollection 2021.

ABSTRACT

Adefovir dipivoxil (ADV) is widely used for chronic hepatitis B therapy in China. To explore the clinical features and prognosis of ADV-induced osteomalacia and to analyze the association between osteomalacia and genetic variants in 51 drug transporters genes. Clinical and follow-up data of the ADV-treated patients were collected. Target capture sequencing was used to identify genetic variations of 51 drug transporter genes. A total of 193 hepatitis B patients treated with ADV were enrolled, of whom 140 had osteomalacia. The other 53 without osteomalacia were included in the control group. The median duration of ADV treatment before the onset of osteomalacia was 6.5 years (range:1.5-7 years). We found that most patients with osteomalacia had hypophosphatemia, high serum alkaline phosphatase levels, hypouricemia, nondiabetic glycosuria, proteinuria. Stopping ADV administration, supplementing calcitriol and calcium were effective treatments. During 3-6 months of follow-up, the clinical symptoms and biochemical indicators of patients with osteomalacia have been significantly improved. There was no significant difference in duration of adefovir treatment in patients with or without osteomalacia (p = 0.791). Through regression analysis, we found that age was a risk factor for osteomalacia [per 1 year, odds ratio (OR), 1.053; 95% confidence interval (95% CI), 1.020-1.087; p = 0.015]. 1992 single nucleotide variants were found using target capture sequencing. However, the associations of genetic variants of 51 drug transporter genes and the risk of osteomalacia were negligible. Osteomalacia is prone to occur in patients with chronic hepatitis B treated with long-term ADV at a therapeutic dose. After standard treatment, the prognosis is mostly good. We failed to find genetic variants that can predict the risk of ADV-induced osteomalacia.

PMID:33995038 | PMC:PMC8113870 | DOI:10.3389/fphar.2021.636352

Arch Bronconeumol. 2020 Oct;56(10):679-681. doi: 10.1016/j.arbr.2020.06.002. Epub 2020 Oct 1.

NO ABSTRACT

PMID:33994635 | PMC:PMC7528906 | DOI:10.1016/j.arbr.2020.06.002

Expert Rev Clin Pharmacol. 2021 May 15. doi: 10.1080/17512433.2021.1927709. Online ahead of print.

ABSTRACT

INTRODUCTION: Clopidogrel is the most frequently utilized P2Y12 inhibitor and is characterized by broad interindividual response variability resulting in impaired platelet inhibition and increased risk of thrombotic complications in a considerable number of patients. The potent P2Y12 inhibitors, prasugrel and ticagrelor, can overcome this limitation but at the expense of an increased risk of bleeding. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been strongly associated with clopidogrel response profiles prompting investigations of genetic-guided selection of antiplatelet therapy.

AREAS COVERED: The present manuscript focuses on the rationale for the use of genetic testing to guide the selection of platelet P2Y12 inhibitors among patients undergoing percutaneous coronary intervention (PCI). Moreover, a comprehensive appraisal of the available evidence and practical recommendations are provided.

EXPERT COMMENTARY: Implementation of genetic testing as a strategy to guide the selection of therapy can result into escalation (i.e., switching to prasugrel or ticagrelor) or de-escalation (i.e., switching to clopidogrel) of P2Y12 inhibiting therapy. Most recent investigations support the clinical benefit of a genetic guided selection of antiplatelet therapy in patients undergo PCI. Integrating the results of genetic testing with clinical and procedural variables represents a promising strategy for a precision medicine approach for the selection of antiplatelet therapy among patients undergoing PCI.

PMID:33993817 | DOI:10.1080/17512433.2021.1927709

Adv Gerontol. 2021;34(1):48-53.

ABSTRACT

We have analyzed influence of genetic variants CYP2D6*3 (2549delA) and CYP2D6*4 (1846G>A), as well as other factors on effects of bisoprolol in patients with acute coronary syndrome. The study included 97 patients with acute coronary syndrome. Mean age was 63±10 years; 60 men and 37 women. We have found association between carriage of CYP2D6*4 (1846G>A) and maximal heart rate at exertion (R-0,21; р<0,05). When the correction for potential confounders was made, age was the only significant predictor of maximal heart rate (β=0,6; SE=0,07; p<0,001). At the same time it was found that CYP2D6*4 was associated with more advanced age of the patients (r=0,2; p<0,05).

PMID:33993661

Rheumatology (Oxford). 2021 May 16:keab443. doi: 10.1093/rheumatology/keab443. Online ahead of print.

ABSTRACT

OBJECTIVES: Combination of genomic data of different pathologies as a single phenotype has emerged as a useful strategy to identify genetic risk loci shared among immune-mediated diseases. Our study aimed to increase our knowledge of the genetic contribution to Kawasaki disease (kDa) and IgA vasculitis (IgAV) by performing the first comprehensive large-scale analysis on the genetic overlap between both pediatric vasculitis.

METHODS: A total of 1,190 vasculitis patients and 11 302 healthy controls were analyzed. First, in the discovery phase, genome-wide data of 405 kDa patients and 6,252 controls and 215 IgAV patients and 1,324 controls, all of European origin, were combined using an inverse variance meta-analysis. Second, the top associated polymorphisms were selected for replication in additional independent cohorts (570 cases and 3,726 controls). Polymorphisms with p-values ≤ 5x1 0 -8 in the global IgAV-kDa meta-analysis were considered as shared genetic risk loci.

RESULTS: A genetic variant, rs3743841, located in an intron of the NAGPA gene, reached genome-wide significance in the cross-disease meta-analysis (p= 8.06x10-10). Additionally, when IgAV was individually analyzed, a strong association between rs3743841 and this vasculitis was also evident (p= 1.25x10-7; OR (95% CI)=1.47 (1.27-1.69)). In silico functional annotation showed that this polymorphism acts as a regulatory variant modulating the expression levels of the NAGPA and SEC14L5 genes.

CONCLUSION: We have identified a new risk locus with pleiotropic effects on the two vasculitis of childhood analyzed. This locus represents the strongest non-HLA signal described for IgAV to date.

PMID:33993232 | DOI:10.1093/rheumatology/keab443

Br J Clin Pharmacol. 2021 May 14. doi: 10.1111/bcp.14895. Online ahead of print.

ABSTRACT

Remdesivir is one of the most encouraging treatments against SARS-CoV-2 infection. After intravenous infusion, RDV is rapidly metabolized (T1/2 1h) within the cells to its active adenosine triphosphate analogue form (GS-443902) and, then, it can be found in plasma in its nucleoside analogue form (GS-441524). In this real life study we describe the Remdesivir and GS-441524 concentrations at 3 time points in nine ICU patients, through a validated UHPLC-MS/MS method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half-life of GS-441524. The mean Cmin , Cmax , AUC0-24 , were < 0.24 ng/mL and 122.3 ng/ml, 2637,3 ng/mL and 157,8 ng/ml, 5171.2 ng*h/mL and 3676.5 ng*h/ml respectively for RDV and GS-441524. Three out of nine patients achieved a Cmax > 2610 ng/mL and 140 ng/mL and AUC0-24 > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS-441524, respectively. The mean T1/2 value for GS-441524 was 26.3 h. Although the low number of patients, these data can represent an interesting preliminary report of the variability of RDV and GS-441524 concentrations in real-life ICU setting.

PMID:33990984 | DOI:10.1111/bcp.14895