J Am Heart Assoc. 2021 Nov 10:e022433. doi: 10.1161/JAHA.121.022433. Online ahead of print.

ABSTRACT

Background The relationship between COVID-19 and ischemic stroke is poorly understood due to potential unmeasured confounding and reverse causation. We aimed to leverage genetic data to triangulate reported associations. Methods and Results Analyses primarily focused on critical COVID-19, defined as hospitalization with COVID-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical COVID-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both COVID-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical COVID-19 was associated with increased risk of any cardiovascular outcome for which genetic correlation was identified. There was evidence of genetic correlation between critical COVID-19 and ischemic stroke (rg=0.29, false discovery rate [FDR]=0.012), body mass index (rg=0.21, FDR=0.00002), and C-reactive protein (rg=0.20, FDR=0.00035), but no other trait investigated. In Mendelian randomization, liability to critical COVID-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical COVID-19 liability 1.03, 95% CI 1.00-1.06, P-value=0.03). Similar estimates were obtained for ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking, and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical COVID-19. Conclusions These data support that liability to critical COVID-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe COVID-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.

PMID:34755518 | DOI:10.1161/JAHA.121.022433

Clin Transl Sci. 2021 Nov 10. doi: 10.1111/cts.13193. Online ahead of print.

ABSTRACT

As pharmacogenomic (PGx) testing increases in popularity, lay concepts of drug-gene interactions set the stage for shared decision-making in precision medicine. Few studies explore what recipients of PGx results think is happening in their bodies when a drug-gene interaction is discovered. To characterize biobank participants' understanding of PGx research results, we conducted afocus group study which took place after pharmacogenomic variants conferring increased risk of dihydropyrimidine dehydrogenase (DPD) deficiency were disclosed to biobank contributors. DPD deficiency confers an increased risk of adverse reaction to commonly used cancer chemotherapeutics. Ten focus groups were conducted, ranging from two to eight participants. 54 individuals participated in focus groups. A framework approach was used for descriptive and explanatory analysis. Descriptive themes included participants' efforts to make sense of PGx findings as they related to: (1) health implications, (2) drugs, and (3) genetics. Explanatory analysis supplied a functional framework of how participant word choices can perform different purposes in PGx communication.. Results bear three main implications for PGx research-related disclosure. First, participants' use of various terms suggest participants generally understanding their PGx results, including how positive PGx results differ from positive disease susceptibility genetic results. Second, PGx disclosure in biobanking can involve participant conflation of drug-gene interactions with allergies or other types of medical reactions. Third, the functional framework suggests a need to move beyond a deficit model of genetic literacy in PGx communication. Together, findings provide an initial evidence base for supporting bi-directional expert-recipient PGx results communication.

PMID:34755460 | DOI:10.1111/cts.13193

J Intern Med. 2021 Nov 10. doi: 10.1111/joim.13417. Online ahead of print.

ABSTRACT

BACKGROUND: Little is known about ANCA-associated vasculitis (AAV) in older patients.

OBJECTIVES: We aim to study relapse risk of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in patients diagnosed after 75 years and compare it with those of patients aged 65-75 years.

METHODS: Data from AAV patients aged ≥65 years were extracted from the French Vasculitis Study Group (FVSG) database and from a call for observation to FVSG members. Cox and Fine-Gray models were used to assess relapse risk, taking death into account either as a censoring or a competing event, respectively.

RESULTS: The analysis included 219 patients aged ≥75 years (median 79) and 80 aged 65-75 years (median 70), of whom 155 had GPA (52%), 136 MPA (45%), with 95 (32%) anti-proteinase 3 positivity and 179 (61%) anti-myeloperoxidase. Patients aged ≥75 years had a lower relapse risk in multivariate analysis (CSHR 0.54, 95%CI 0.33-0.89, p=0.016, Cox model; SHR 0.46, 95%CI 0.29-0.74, p=0.001, Fine-Gray model) after taking into account vasculitis type. Patients aged ≥75 years had a lower probability of being treated for remission-maintenance with a combination of glucocorticoids and immunosuppressants (versus glucocorticoids alone, HR 0.28, 95%CI 0.11-0.68, p=0.005) after adjusting to Five Factor Score, although relapse-free survival was significantly longer when receiving such combination (CSHR 0.40, 95%CI 0.24-0.67, p<0.001).

CONCLUSION: AAV patients ≥75 years have a lower relapse risk than patients aged 65-75 years despite a lower probability of having received maintenance therapy with a combination of glucocorticoids and immunosuppressants, but they still benefit from such treatment regimen. This article is protected by copyright. All rights reserved.

PMID:34755398 | DOI:10.1111/joim.13417

World J Diabetes. 2021 Oct 15;12(10):1693-1703. doi: 10.4239/wjd.v12.i10.1693.

ABSTRACT

The prevalence of diabetes has increased rapidly throughout the world in recent years. Currently, approximately 463 million people are living with diabetes, and the number has tripled over the last two decades. Here, we describe the global epidemiology of diabetes in 2019 and forecast the trends to 2030 and 2045 in China, India, USA, and the globally. The gut microbiota plays a major role in metabolic diseases, especially diabetes. In this review, we describe the interaction between diabetes and gut microbiota in three aspects: probiotics, antidiabetic medication, and diet. Recent findings indicate that probiotics, antidiabetic medications, or dietary interventions treat diabetes by shifting the gut microbiome, particularly by raising beneficial bacteria and reducing harmful bacteria. We conclude that targeting the gut microbiota is becoming a novel therapeutic strategy for diabetes.

PMID:34754371 | PMC:PMC8554376 | DOI:10.4239/wjd.v12.i10.1693

J Appl Biomed. 2021;19(2):113-124. doi: 10.32725/jab.2021.013.

ABSTRACT

Oplopanax elatus (Nakai) Nakai has a long history of use as an ethnomedicine by the people living in eastern Asia. However, its bioactive constituents and cancer chemopreventive mechanisms are largely unknown. The aim of this study was to prepare O. elatus extracts, fractions, and single compounds and to investigate the herb's antiproliferative effects on colon cancer cells and the involved mechanisms of action. Two polyyne compounds were isolated from O. elatus, falcarindiol and oplopandiol. Based on our HPLC analysis, falcarindiol and oplopandiol are major constituents in the dichloromethane (CH2Cl2) fraction. For the HCT-116 cell line, the dichloromethane fraction showed significant effects. Furthermore, the IC50 for falcarindiol and oplopandiol was 1.7 μM and 15.5 μM, respectively. In the mechanistic study, after treatment with 5 μg/ml for 48 h, dichloromethane fraction induced cancer cell apoptosis by 36.5% (p < 0.01% vs. control of 3.9%). Under the same treatment condition, dichloromethane fraction caused cell cycle arrest at the G2/M phase by 32.6% (p < 0.01% vs. control of 23.4%), supported by upregulation of key cell cycle regulator cyclin A to 21.6% (p < 0.01% vs. control of 8.6%). Similar trends were observed by using cell line HT-29. Data from this study filled the gap between phytochemical components and the cancer chemoprevention of O. elatus. The dichloromethane fraction is a bioactive fraction, and falcarindiol is identified as an active constituent. The mechanisms involved in cancer chemoprevention by O. elatus were apoptosis induction and G2/M cell cycle arrest mediated by a key cell cycle regulator cyclin A.

PMID:34754259 | PMC:PMC8575125 | DOI:10.32725/jab.2021.013

Mol Psychiatry. 2021 Nov 9. doi: 10.1038/s41380-021-01340-6. Online ahead of print.

ABSTRACT

Substantial inter-individual discrepancies exist in both therapeutic effectiveness and adverse effects of antidepressant and antipsychotic medications, which can, in part, be explained by genetic variation. Here, we searched the Pharmacogenomics Knowledge Base for gene-antidepressant and gene-antipsychotic pairs with the highest level of evidence. We then extracted and compared the associated prescribing recommendations for these pairs developed by the Clinical Pharmacogenomics Implementation Consortium, the Dutch Pharmacogenetics Working Group or approved product labels in the US, Canada, Europe, and Asia. Finally, we highlight key economical, educational, regulatory, and ethical issues that, if not appropriately considered, can hinder the implementation of these recommendations in clinical practice. Our review indicates that evidence-based guidelines are available to assist with the implementation of pharmacogenetic-guided antidepressant and antipsychotic prescribing, although the maximum impact of these guidelines on patient care will not be realized until key barriers are minimized or eliminated.

PMID:34754108 | DOI:10.1038/s41380-021-01340-6

Neurobiol Dis. 2021 Nov 6:105548. doi: 10.1016/j.nbd.2021.105548. Online ahead of print.

ABSTRACT

TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal lobar degeneration (FTLD). Namely, both diseases feature aggregated and phosphorylated TDP-43 containing inclusions in the cytoplasm and a loss of nuclear TDP-43 in affected neurons. It has been reported that tau tubulin kinase (TTBK)1/2 phosphorylate TDP-43 and TTBK1/2 overexpression induced neuronal loss and behavioral deficits in a C. elegans model of ALS. Here we aimed to elucidate the molecular mechanisms of TTBK1 in TDP-43 pathology. TTBK1 levels were observed to be elevated in ALS patients' post-mortem motor cortex. Also, TTBK1 was found to phosphorylate TDP-43 at disease-relevant sites in vitro directly, and this phosphorylation accelerated TDP-43 formation of high molecular species. Overexpression of TTBK1 in mammalian cells induced TDP-43 phosphorylation and the construction of high molecular species, concurrent with TDP-43 mis-localization and cytoplasmic inclusions. In addition, when TTBK1 was knocked down or pharmacologically inhibited, TDP-43 phosphorylation and aggregation were significantly alleviated. Functionally, TTBK1 knockdown could rescue TDP-43 overexpression-induced neurite and neuronal loss in iPSC-derived GABAergic neurons. These findings suggest that phosphorylation plays a critical role in the pathogenesis of TDP-43 pathology and that TTBK1 inhibition may have therapeutic potential for the treatment of ALS and FTLD.

PMID:34752923 | DOI:10.1016/j.nbd.2021.105548

Pharmacotherapy. 2021 Nov 9. doi: 10.1002/phar.2644. Online ahead of print.

ABSTRACT

INTRODUCTION: Bupropion is metabolized to its active metabolite, hydroxybupropion (HB), by the genetically polymorphic cytochrome P450 2B6 (CYP2B6) enzyme. Despite its significant role in bupropion metabolism, the magnitude of the impact of CYP2B6 genotype on the exposure of bupropion has not been quantified.

OBJECTIVES: A systematic review and meta-analysis was conducted to quantify the association of bupropion and HB exposure with CYP2B6 variant alleles and genotype-defined metabolizer phenotypes.

METHODS: MEDLINE, EMBASE, Web of Science, Scifinder, PsycINFO, and CENTRAL were screened to identify studies that met the following inclusion criteria (search updated on February 2021): (1) area under the plasma drug concentration-time curve (AUC) of bupropion and/or HB in relation to CYP2B6 genotypes was studied, and (2) study participants were genotyped for common CYP2B6 variant alleles including at least CYP2B6*6. The Newcastle-Ottawa Scale was used to assess risk of bias in each included study. The ratio of means (RoM) between CYP2B6 genotype or genotype-defined phenotype groups for bupropion exposure was calculated for each study and combined in a meta-analysis.

RESULTS: Eleven studies met the inclusion criteria for this systematic review, and 10 (N=413) were included in the meta-analysis. All 10 studies involved healthy adult volunteers, where other medications were not allowed. The AUCs of HB and the active moiety (bupropion + HB) were significantly reduced in CYP2B6*6 carriers compared to the non-carriers (HB: RoM 0.77, 95% CI 0.71-0.83; active moiety: RoM 0.81, 95% CI 0.75-0.88). Both CYP2B6 poor and intermediate metabolizers had significantly decreased exposures to HB and the active moiety than normal metabolizers.

CONCLUSION: The CYP2B6*6 allele and genotype-determined CYP2B6 poor and intermediate metabolizer phenotypes are associated with significantly lower exposures to HB and the total active moiety. The findings of this study suggest opportunities to further study precision dosing strategies for bupropion therapy based on CYP2B6 genotype.

PMID:34752647 | DOI:10.1002/phar.2644

Lipids Health Dis. 2021 Nov 8;20(1):157. doi: 10.1186/s12944-021-01586-7.

ABSTRACT

BACKGROUND: To determine the effect of genetic polymorphism of drug transporters on the efficacy of treatment with Rosuvastatin, Atorvastatin and Simvastatin in patients with hyperlipidemia.

METHODS: The study consists of 180 patients, aged 40-75 years, with hyperlipidemia. All patients were divided into two equal groups: patients with different SLCO1B1 (521CC, 521CT and 521TT) and MDR1 (3435CC, 3435TC and 3435TT) genotypes. Each group was divided into rosuvastatin-treated, atorvastatin-treated and simvastatin-treated subgroups. The lipid-lowering effect of statins was assessed by tracing changes in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels.

RESULTS: The use of statins over a 4-month period led to substantial reductions in TC and LDL-C levels. The hypolipidemic effect of studied agents was seen in both groups. However, it was less pronounced in patients with 521CC genotype. No statistically significantly differences were found between carriers of 3435TT, 3435CT and 3435CC genotypes.

CONCLUSIONS: The lipid-lowering efficacy of rosuvastatin was higher compared to other two statins. Patients with SLCO1B1 521CC genotype are more likely to encounter a decrease in the hypolipidemic effect of statins. Such a risk should be considered when treating this category of patients. MDR1 polymorphism had no significant effect on statin efficacy.

PMID:34749751 | DOI:10.1186/s12944-021-01586-7

Mitochondrion. 2021 Nov 5:S1567-7249(21)00150-1. doi: 10.1016/j.mito.2021.10.010. Online ahead of print.

ABSTRACT

Orang Asli are the oldest inhabitants in Peninsular Malaysia that forms as a national minority while the Malays are the majority. The study aimed to screen the mitochondrial genomes of the Orang Asli and the Malays to discover the disease-associated variants. A total of 99 Orang Asli from six tribes (Bateq, Cheq Wong, Orang Kanaq, Kensiu, Lanoh, and Semai) were recruited. Mitochondrial genome sequencing was conducted using a next-generation sequencing platform. Furthermore, we retrieved mitochondrial DNA sequences from the Malays for comparison. The clinical significance, pathogenicity prediction and frequency of variants were determined using online tools. Variants associated with mitochondrial diseases were detected in the 2 populations. A high frequency of variants associated with mitochondrial diseases, breast cancer, prostate cancer, and cervical cancer were detected in the Orang Asli and modern Malays. As medicine evolves to adopt prediction and prevention of diseases, this study highlights the need for intervention to adopt genomics medicine to strategise better healthcare management as a way forward for Precision Health.

PMID:34748985 | DOI:10.1016/j.mito.2021.10.010

J Am Assoc Nurse Pract. 2021 Nov 10;33(11):849-851. doi: 10.1097/JXX.0000000000000666.

ABSTRACT

Psychiatric pharmacogenetic testing is commonly used by providers in primary care and mental health settings. The purpose of this article is to describe the extent to which psychiatric pharmacogenetic testing supports clinical practice. human leukocyte antigen (HLA)-A and HLA-B should be tested before initiating carbamazepine and oxcarbazepine due to risk of serious skin reactions. For psychotropic medications metabolized through the liver, limited evidence suggests testing for variation in metabolism through CYP2D6 and CYP2D19. For specific medication and genotype-phenotype variations, guidance through the Clinical Pharmacogenetics Implementation Consortium (CPIC) or the International Society of Psychiatric Genetics (ISPG) should be reviewed. Commercial tests interpret this information differently and should not be used for broad guidance. Clinicians should follow current guidelines from professional bodies such as CPIC or ISPG and test for HLA-A or HLA-B before initiating carbamazepine or oxcarbazepine. Evidence is limited for psychiatric pharmacogenetic testing. Clinicians should continue to follow best practice and clinical practice guidelines.

PMID:34747904 | DOI:10.1097/JXX.0000000000000666

Pharmacogenomics. 2021 Nov 8. doi: 10.2217/pgs-2021-0076. Online ahead of print.

ABSTRACT

Aim: Pharmacogenomics (PGx) tests are performed on whole-blood or saliva specimens. In patients with a transplanted liver, PGx results may be discordant with hepatic drug metabolizing enzyme activity. We evaluate the incidence and impact of PGx testing in liver transplant recipients, detail potential errors and describe clinical decision support (CDS) solution implemented. Materials & methods: A retrospective cohort study of liver transplant recipients at Mayo Clinic who underwent PGx testing between 1 January 1996 and 7 October 2019 were characterized. Impact of a CDS solution was evaluated. Results: There were 129 PGx tests in 117 patients. PGx testing incidence increased before (per year incidence rate ratio = 1.45, 95% CI: 1.20-1.74, p < 0.001) and after transplant (incidence rate ratio = 1.48, 95% CI: 1.27-1.72, p < 0.001). Three erroneous PGx tests were avoided 6 months following CDS implementation. Conclusion: Incidence of PGx testing in liver transplant recipients is increasing, leading to erroneous therapeutic decisions. CDS interventions and education are needed to prevent errors.

PMID:34747639 | DOI:10.2217/pgs-2021-0076

Pharmacogenomics. 2021 Nov 8. doi: 10.2217/pgs-2021-0107. Online ahead of print.

ABSTRACT

Aim: To evaluate the associations between human leukocyte antigen (HLA)-DRB1 variants and the rs6021191 variant in nuclear factor of activated T cells 2 (NFATC2) with PEG-asparaginase hypersensitivity in children with acute lymphoblastic leukemia (ALL) treated according to the Chinese Children Leukemia Group (CCLG) ALL 2018 protocol. Methods: HLA-DRB1 genotyping was performed using PCR-sequence-based typing (SBT) method. NFATC2 rs6021191 was genotyped applying TaqMan Genotyping Assay. Results: T-ALL and higher risk groups were at higher risk for PEG-asparaginase hypersensitivity. No association was found between NFATC2 rs6021191 and PEG-asparaginase hypersensitivity. HLA-DRB1*16:02 variant was associated with PEG-asparaginase allergy both in univariate and multivariate logistic regression analysis. Conclusion: Our results confirm that variations in HLA-DRB1 might influence the development of asparaginase hypersensitivity.

PMID:34747637 | DOI:10.2217/pgs-2021-0107

Pharmacogenomics. 2021 Nov 8. doi: 10.2217/pgs-2020-0146. Online ahead of print.

ABSTRACT

Introduction: Leflunomide is one of the commonly used drugs in treatment of rheumatoid arthritis (RA), which on administration is converted into its active metabolite teriflunomide. Aim: Our aim is to evaluate the frequencies of dihydrooroate dehydrogenase (DHODH) (rs3213422), ABCG2 (rs2231142) and CYP2C19 (rs4244285) allele distribution among patients receiving leflunomide for RA and their possible impact on leflunomide performance in disease control. Patients & methods: Patients (>18 years) who fulfilled the 2010 ACR classification criteria for RA receiving leflunomide (20 mg/day) were included in the study. Disease activity score 28 was used to assess patients disease activity. Blood samples were collected for full blood count and blood chemistry. Genomic DNA was extracted from peripheral blood. The selection of SNPs was based on the criteria of minor allele frequency among Caucasians. Results: A significant association between the therapeutic outcome of leflunomide and DHODH genotyping was observed but not with CYP2C19 and ABCG2. Importantly, there is a significant association between DHODH (rs3213422) CC genotype and the number of patients with controlled disease. Conclusion: We strongly suggest that polymorphisms in the DHODH are the major factor affecting leflunomide pharmacogenetics and therapeutic efficacy.

PMID:34747629 | DOI:10.2217/pgs-2020-0146

Per Med. 2021 Nov 8. doi: 10.2217/pme-2021-0129. Online ahead of print.

NO ABSTRACT

PMID:34747188 | DOI:10.2217/pme-2021-0129

Front Genet. 2021 Oct 20;12:712602. doi: 10.3389/fgene.2021.712602. eCollection 2021.

ABSTRACT

Pharmacogenomics (PGx) studies how a person's genes affect the response to medications and is quickly becoming a significant part of precision medicine. The clinical application of PGx principles has consistently been cited as a major opportunity for improving therapeutic outcomes. Several recent studies have demonstrated that most individuals (> 90%) harbor PGx variants that would be clinically actionable if prescribed a medication relevant to that gene. In multiple well-conducted studies, the results of PGx testing have been shown to guide therapy choice and dosing modifications which improve treatment efficacy and reduce the incidence of adverse drug reactions (ADRs). Although the value of PGx testing is evident, its successful implementation in a clinical setting presents a number of challenges to molecular diagnostic laboratories, healthcare systems, providers and patients. Different molecular methods can be applied to identify PGx variants and the design of the assay is therefore extremely important. Once the genotyping results are available the biggest technical challenge lies in turning this complex genetic information into phenotypes and actionable recommendations that a busy clinician can effectively utilize to provide better medical care, in a cost-effective, efficient and reliable manner. In this paper we describe a successful and highly collaborative implementation of the PGx testing program at the University of Minnesota and MHealth Fairview Molecular Diagnostic Laboratory and selected Pharmacies and Clinics. We offer detailed descriptions of the necessary components of the pharmacogenomic testing implementation, the development and technical validation of the in-house SNP based multiplex PCR based assay targeting 20 genes and 48 SNPs as well as a separate CYP2D6 copy number assay along with the process of PGx report design, results of the provider and pharmacists usability studies, and the development of the software tool for genotype-phenotype translation and gene-phenotype-drug CPIC-based recommendations. Finally, we outline the process of developing the clinical workflow that connects the providers with the PGx experts within the Molecular Diagnostic Laboratory and the Pharmacy.

PMID:34745204 | PMC:PMC8564018 | DOI:10.3389/fgene.2021.712602

Front Pharmacol. 2021 Oct 21;12:757464. doi: 10.3389/fphar.2021.757464. eCollection 2021.

ABSTRACT

Objective: High-dose methotrexate (HDMTX) is a mainstay therapeutic agent for the treatment of diverse hematological malignancies, and it plays a significant role in interindividual variability regarding the pharmacokinetics and toxicity. The genetic association of HDMTX has been widely investigated, but the conflicting results have complicated the clinical utility. Therefore, this systematic review aims to determine the role of gene variants within the HDMTX pathway and to fill the gap between knowledge and clinical practice. Methods: Databases including EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and the Clinical Trials.gov were searched from inception to November 2020. We included twelve single-nucleotide polymorphisms (SNPs) within the HDMTX pathway, involving RFC1, SLCO1B1, ABCB1, FPGS, GGH, MTHFR, DHFR, TYMS, and ATIC. Meta-analysis was conducted by using Cochrane Collaboration Review Manager software 5.3. The odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (95% CI) were analyzed to evaluate the associations between SNPs and clinical outcomes. This study was performed according to the PRISMA guideline. Results: In total, 34 studies with 4102 subjects were identified for the association analysis. Nine SNPs involving MTHFR, RFC1, ABCB1, SLCO1B1, TYMS, FPGS, and ATIC genes were investigated, while none of studies reported the polymorphisms of GGH and DHFR yet. Two SNPs were statistically associated with the increased risk of HDMTX toxicity: MTHFR 677C>T and hepatotoxicity (dominant, OR=1.52, 95% CI=1.03-2.23; recessive, OR=1.68, 95% CI=1.10-2.55; allelic, OR=1.41, 95% CI=1.01-1.97), mucositis (dominant, OR=2.11, 95% CI=1.31-3.41; allelic, OR=1.91, 95% CI=1.28-2.85), and renal toxicity (recessive, OR=3.54, 95% CI=1.81-6.90; allelic, OR=1.89, 95% CI=1.18-3.02); ABCB1 3435C>T and hepatotoxicity (dominant, OR=3.80, 95% CI=1.68-8.61), whereas a tendency toward the decreased risk of HDMTX toxicity was present in three SNPs: TYMS 2R>3R and mucositis (dominant, OR=0.66, 95% CI=0.47-0.94); RFC1 80A>G and hepatotoxicity (recessive, OR=0.35, 95% CI=0.16-0.76); and MTHFR 1298A>C and renal toxicity (allelic, OR=0.41, 95% CI=0.18-0.97). Since the data of prognosis outcomes was substantially lacking, current studies were underpowered to investigate the genetic association. Conclusions: We conclude that genotyping of MTHFR and/or ABCB1 polymorphisms prior to treatment, MTHFR 677C>T particularly, is likely to be potentially useful with the aim of tailoring HDMTX therapy and thus reducing toxicity in patients with hematological malignancies.

PMID:34744734 | PMC:PMC8570281 | DOI:10.3389/fphar.2021.757464

Front Pharmacol. 2021 Oct 20;12:717932. doi: 10.3389/fphar.2021.717932. eCollection 2021.

ABSTRACT

Many factors have been described to contribute to voriconazole (VCZ) interpatient variability in plasma concentrations, especially CYP2C19 genetic variability. In 2014, Hicks et al. presented data describing the correlation between VCZ plasma concentrations and CYP2C19 diplotypes in immunocompromised pediatric patients and utilized pharmacokinetic modeling to extrapolate a more suitable VCZ dose for each CYP2C19 diplotype. In 2017, in our hospital, a clinical protocol was developed for individualization of VCZ in immunocompromised patients based on preemptive genotyping of CYP2C19 and dosing proposed by Hicks et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) clinical guidelines, and routine therapeutic drug monitoring (TDM). We made a retrospective review of a cohort of 28 immunocompromised pediatric patients receiving VCZ according to our protocol. CYP2C19 gene molecular analysis was preemptively performed using PharmArray®. Plasma trough concentrations were measured by immunoassay analysis until target concentrations (1-5.5 μg/ml) were reached. Sixteen patients (57.14%) achieved VCZ trough target concentrations in the first measure after the initial dose based on PGx. This figure is similar to estimations made by Hicks et al. in their simulation (60%). Subdividing by phenotype, our genotyping and TDM-combined strategy allow us to achieve target concentrations during treatment/prophylaxis in 90% of the CYP2C19 Normal Metabolizers (NM)/Intermediate Metabolizers (IM) and 100% of the Rapid Metabolizers (RM) and Ultrarapid Metabolizers (UM) of our cohort. We recommended modifications of the initial dose in 29% (n = 8) of the patients. In RM ≥12 years old, an increase of the initial dose resulted in 50% of these patients achieving target concentrations in the first measure after initial dose adjustment based only on PGx information. Our experience highlights the need to improve VCZ dose predictions in children and the potential of preemptive genotyping and TDM to this aim. We are conducting a multicenter, randomized clinical trial in patients with risk of aspergillosis in order to evaluate the effectiveness and efficiency of VCZ individualization: VORIGENIPHARM (EudraCT: 2019-000376-41).

PMID:34744712 | PMC:PMC8563584 | DOI:10.3389/fphar.2021.717932

Mediators Inflamm. 2021 Oct 27;2021:3125922. doi: 10.1155/2021/3125922. eCollection 2021.

ABSTRACT

IL-17A and IL-17F together with their coreceptor (IL-17RA/RC) were reported to play a significant role in the pathogenesis of spondyloarthritis. The group of axial spondyloarthritis comprises ankylosing spondylitis (AS), a rheumatic disease characterized by chronic inflammation of the joints in the spine. This study is aimed at investigating IL-17A, IL-17F, IL-17RA, and IL-17RC polymorphisms as potential biomarkers of disease susceptibility, clinical parameters, and anti-TNF treatment outcome in a cohort of Polish ankylosing spondylitis patients. In total, 328 subjects, including 138 AS patients and 190 healthy volunteers, participated in the study. Genotyping of IL-17A rs2275913 (G/A), IL-17F rs763780 (A/G), IL-17RA rs4819554 (A/G), and IL-17RC rs708567 (G/A) was performed on real-time PCR instrument using LightSNiP assays. No significant differences were revealed in genotype and allele distribution between patients and controls despite the association of the IL-17RC rs708567 AA homozygosity with the earlier onset of the disease. Moreover, some relationships between IL-17F rs763780 and IL-17RA rs4819554 polymorphisms with clinical parameters related to the disease activity and anti-TNF treatment outcome were observed. IL-17F rs763780 G allele was found to be associated with high disease activity and BASDAI after 6 months and poor response to the treatment while higher VAS values were more common among IL-17RA rs4819554 G variant carriers. In conclusion, the IL-17F rs763780 polymorphism should be considered as a promising biomarker of disease activity and anti-TNF treatment outcome. The IL-17RA rs48419554 G allele may serve as a potential marker of disease severity in Polish AS patients.

PMID:34744511 | PMC:PMC8566063 | DOI:10.1155/2021/3125922

Eur Neuropsychopharmacol. 2021 Nov 4;54:41-53. doi: 10.1016/j.euroneuro.2021.10.005. Online ahead of print.

ABSTRACT

Pharmacotranscriptomics is a still very new field of research that has just begun to flourish and promises to enable target discovery, inform biomarker and evaluate drug efficacy beyond pharmacogenomics. The aim of this review is to provide a critical overview of the biological foundations of transcriptomics, methodological approaches to transcriptomic studies, and their advantages and limitations. We present the different RNA species (rRNAs, tRNAs, mtRNAs, snRNAs, scRNAs, mRNAs, ncRNAs, LINE and SINE transcripts, circular RNAs, piRNAs, miRNAs, snoRNAs) and their potential for pharmacotranscriptomic studies as markers to predict treatment response in neurological and psychiatric disorders. We also review the accessible sources of RNA in patients peripheral blood cells (including platelets), plasma, microvesicles, exosomes, apoptotic bodies, and how those affect the integrity and relative abundances of RNAs and reflect the situation in the Central Nervous System (CNS). Finally, we discuss the suitability and indications of different techniques, such as microarrays and RNA-sequencing (RNA-Seq) techniques to understand gene expression differences or to reveal variation in expression levels of coding and non-coding genes. We conclude with some recommendations for future directions, e.g., gaps of knowledge and particular RNAs/tissues that have been overlooked.

PMID:34743061 | DOI:10.1016/j.euroneuro.2021.10.005