Front Genet. 2021 Apr 1;12:658983. doi: 10.3389/fgene.2021.658983. eCollection 2021.

ABSTRACT

Background: The goal of the study was to assess the relationship between single nucleotide variants (SNVs) in calcineurin inhibitor (CNI) pharmacokinetic and pharmacodynamic genes and renal dysfunction in adult heart transplant (HTx) recipients. Methods: This retrospective analysis included N = 192 patients receiving a CNI at 1-year post-HTx. Using a candidate gene approach, 93 SNVs in eight pharmacokinetic and 35 pharmacodynamic genes were chosen for investigation. The primary outcome was renal dysfunction 1-year after HTx, defined as an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m2. Results: Renal dysfunction was present in 28.6% of patients 1-year after HTx. Two SNVs [transforming growth factor beta 1 (TGFB1) rs4803455 C > A and phospholipase C beta 1 (PLCB1) rs170549 G > A] were significantly associated with renal dysfunction after accounting for a false discovery rate (FDR) of 20%. In a multiple-SNV adjusted model, variant A allele carriers of TGFB1 rs4803455 had lower odds of renal dysfunction compared to C/C homozygotes [odds ratio (OR) 0.28, 95% CI 0.12-0.62; p = 0.002], whereas PLCB1 rs170549 variant A allele carriers had higher odds of the primary outcome vs. patients with the G/G genotype (OR 2.66, 95% CI 1.21-5.84, p = 0.015). Conclusion: Our data suggest that genetic variation in TGFB1 and PLCB1 may contribute to the occurrence of renal dysfunction in HTx recipients receiving CNIs. Pharmacogenetic markers, such as TGFB1 rs4803455 and PLCB1 rs170549, could help identify patients at increased risk of CNI-associated renal dysfunction following HTx, potentially allowing clinicians to provide more precise and personalized care to this population.

PMID:33868389 | PMC:PMC8047196 | DOI:10.3389/fgene.2021.658983

Front Pharmacol. 2021 Mar 25;12:638882. doi: 10.3389/fphar.2021.638882. eCollection 2021.

ABSTRACT

Although the mood stabilizer lithium is a first-line treatment in bipolar disorder, a substantial number of patients do not benefit from it and experience side effects. No clinical tool is available for predicting lithium response or the occurrence of side effects in everyday clinical practice. Multiple genetic research efforts have been performed in this field because lithium response and side effects are considered to be multifactorial endophenotypes. Available results from linkage and segregation, candidate-gene, and genome-wide association studies indicate a role of genetic factors in determining response and side effects. For example, candidate-gene studies often report GSK3β, brain-derived neurotrophic factor, and SLC6A4 as being involved in lithium response, and the latest genome-wide association study found a genome-wide significant association of treatment response with a locus on chromosome 21 coding for two long non-coding RNAs. Although research results are promising, they are limited mainly by a lack of replicability and, despite the collaboration of consortia, insufficient sample sizes. The need for larger sample sizes and "multi-omics" approaches is apparent, and such approaches are crucial for choosing the best treatment options for patients with bipolar disorder. In this article, we delineate the mechanisms of action of lithium and summarize the results of genetic research on lithium response and side effects.

PMID:33867988 | PMC:PMC8044839 | DOI:10.3389/fphar.2021.638882

Front Pharmacol. 2021 Apr 1;12:635345. doi: 10.3389/fphar.2021.635345. eCollection 2021.

ABSTRACT

The response to medications in children differs not only in comparison to adults but also between children of the different age groups and according to the disease. This is true for anti-infectives that are widely prescribed in children with malignancy. In the absence of pharmacokinetic/pharmacodynamic paediatric studies, dosage is frequently based on protocols adapted to adults. After a short presentation of the drugs, we reviewed the population pharmacokinetic studies available for glycopeptides (vancomycin and teicoplanin, n = 5) and antifungals (voriconazole, posaconazole, and amphotericin B, n = 9) currently administered in children with onco-hematological malignancies. For each of them, we reported the main study characteristics including identified covariates affecting pharmacokinetics and proposed paediatric dosage recommendations. This review highlighted the very limited amount of data available, the lack of consensus regarding PK/PD targets used for dosing optimization and regarding dosage recommendations when available. Additional PK studies are urgently needed in this specific patient population. In addition to pharmacokinetics, efficacy may be altered in immunocompromised patients and prospective clinical evaluation of new dosage regimen should be provided as they are missing in most cases.

PMID:33867986 | PMC:PMC8048069 | DOI:10.3389/fphar.2021.635345

Front Pharmacol. 2021 Mar 19;12:620043. doi: 10.3389/fphar.2021.620043. eCollection 2021.

NO ABSTRACT

PMID:33867983 | PMC:PMC8044957 | DOI:10.3389/fphar.2021.620043

EBioMedicine. 2021 Apr 14:103339. doi: 10.1016/j.ebiom.2021.103339. Online ahead of print.

ABSTRACT

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities.

METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients.

FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease.

INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2.

FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

PMID:33867313 | DOI:10.1016/j.ebiom.2021.103339

Expert Rev Proteomics. 2021 Apr 19:1-8. doi: 10.1080/14789450.2021.1915775. Online ahead of print.

ABSTRACT

Elucidating the dysregulated metabolic pathways in cancer cells and their relevance to cisplatin resistance could yield new insights into cancer therapy. We previously reported that eight metabolites involved in the tricarboxylic acid (TCA) cycle and glutamine metabolism were associated with platinum-based chemotherapy efficacy in human lung cancer. Here, we investigated the metabolic differences upon cisplatin treatment in lung cancer in vitro and in vivo. A simple and partially validated standard addition method was applied for the quantification of five metabolites involved in the TCA cycle and glutamine metabolism using amide hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). The present study investigated the levels of these biomarkers in A549 cells and the cisplatin-resistant A549-DDP cells, as well as in the plasma before and after cisplatin treatment in A549 xenograft mice. Levels of five metabolites, including 2-hydroxyglutaric acid (2-HG), α-ketoglutarate (α-KG), succinate, glutamine, and glutamate, showed a decreasing trend in A549-DDP cells. In addition, 2-HG and glutamine were the most significantly altered metabolites in cisplatin-treated A549 xenograft mice. These data indicate that the TCA cycle and glutamine metabolism play important roles in cisplatin-based chemotherapy resistance in lung cancer. Our results provide a new angle for exploring the molecular mechanisms underlying cisplatin resistance.

PMID:33866908 | DOI:10.1080/14789450.2021.1915775

Semin Arthritis Rheum. 2021 Mar 4;51(3):513-522. doi: 10.1016/j.semarthrit.2021.03.004. Online ahead of print.

ABSTRACT

The incidence of autoimmune diseases is increasing worldwide, thus stimulating studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors. Genetic association studies have shown the PTPN22 gene as a shared genetic risk factor with implications in multiple autoimmune disorders. By encoding a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems, the PTPN22 gene may have a fundamental role in the development of immune dysfunction. PTPN22 polymorphisms are associated with rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and many other autoimmune conditions. In this review, we discuss the progress in our understanding of how PTPN22 impacts autoimmunity in both humans and animal models. In addition, we highlight the pathogenic significance of the PTPN22 gene, with particular emphasis on its role in T and B cells, and its function in innate immune cells, such as monocytes, dendritic and natural killer cells. We focus particularly on the complexity of PTPN22 interplay with biological processes of the immune system. Findings highlight the importance of studying the function of disease-associated PTPN22 variants in different cell types and open new avenues of investigation with the potential to drive further insights into mechanisms of PTPN22. These new insights will reveal important clues to the molecular mechanisms of prevalent autoimmune diseases and propose new potential therapeutic targets.

PMID:33866147 | DOI:10.1016/j.semarthrit.2021.03.004

Asian Pac J Allergy Immunol. 2021 Apr 18. doi: 10.12932/AP-110920-0955. Online ahead of print.

ABSTRACT

BACKGROUND: Severe cutaneous adverse drug reactions (SCARs) are rare but deadly drug reactions with severe damages to patients. One of the most well-known SCARs risk factors is the human leukocyte antigen (HLA) genes polymorphism. Among the HLA polymorphic alleles, the HLA-A*33:03 allele has been found in association with SCARs induced by various drugs, especially in Asian people. There has not been any report on the specific detection protocol of the HLA-A*33:03 allele.

OBJECTIVE: This study aimed to design a nested AS-PCR protocol for detecting and distinguishing diplotype genotype of the HLA-A*33:03 allele.

METHODS: A nested allele-specific (AS)-PCR protocol with four primer sets was designed. The method was compared with the Sanger sequencing method on 100 samples of unknown genotypes of unrelated Vietnamese people.

RESULTS: The nested AS-PCR method could identify the HLA-A*33:03 allele and the HLA-A*33:03 diplotype genotypes. Comparison with the Sanger sequencing method showed an absolute agreement (κ = 1.00, p < 0.001). The nested ASPCR protocol had a sensitivity of 100% (95%CI: 92.13-100%) and a specificity of 100% (95%CI: 93.51-100%). The protocol was used for the determination of HLA-A*33:03 allele distribution in 810 unrelated Vietnamese Kinh people, showing a frequency of HLA-A*33:03 carriers of 19.6% and an allele frequency of 10.55%.

CONCLUSIONS: A novel nested AS-PCR method with a hundred-percent sensitivity and a specificity for the HLA-A*33:03 allele detection was reported. The protocol can be applied for the stratification of patients at SCAR risks with various drugs.

PMID:33865300 | DOI:10.12932/AP-110920-0955

Neuro Oncol. 2021 Apr 17:noab095. doi: 10.1093/neuonc/noab095. Online ahead of print.

ABSTRACT

BACKGROUND: The transcription factor NFκB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFκB activity can suppress central oncogenic signalling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive.

METHODS: In a pharmacogenomics study with a panel of transgenic glioma cells we observed that NFκB can be converted into a tumor suppressor by the non-psychotropic cannabinoid Cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study we performed pharmacological assays, gene expression profiling, biochemical and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM-datasets.

RESULTS: We found that CBD promotes DNA binding of the NFκB subunit RELA and simultaneously prevents RELA-phosphorylation on serine-311, a key residue which permits genetic transactivation. Strikingly, sustained DNA binding by RELA lacking phospho-serine 311 was found to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen-species (ROS), while high ROS-content in other tumors blocked CBD induced hGSC death. Consequently, ROS levels served as predictive biomarker for CBD-sensitive tumors.

CONCLUSIONS: This evidence demonstrates how a clinically approved drug can convert NFκB into a tumor suppressor and suggests a promising repurposing option for GBM-therapy.

PMID:33864076 | DOI:10.1093/neuonc/noab095

Mol Cancer Res. 2021 Apr 16:molcanres.MCR-21-0099-A.2021. doi: 10.1158/1541-7786.MCR-21-0099. Online ahead of print.

ABSTRACT

NF-κB activation has been linked to prostate cancer (PCa) progression and is commonly observed in castrate-resistant disease. It has been suggested that NF-κB-driven resistance to androgen deprivation therapy (ADT) in PCa cells may be mediated by aberrant androgen receptor (AR) activation and AR splice variant production. Preventing resistance to ADT may therefore be achieved by utilizing NF-κB inhibitors. However, low oral bioavailability and high toxicity of NF-κB inhibitors is a major challenge for clinical translation. Dimethylaminoparthlide (DMAPT) is an oral NF-κB inhibitor in clinical development and has already shown favorable pharmacokinetic and pharmacodyanamic data in patients with heme malignancies including decrease of NF-κB in circulating leuchemic blasts. Here we report that activation of NF-κB/p65 by castration in mouse and human PCa models resulted in a significant increase in AR variant-7 (AR-V7) expression and modest upregulation of AR. In vivo castration of VCaP-CR tumors resulted in significant upregulation of phosphorylated-p65 and AR-V7, which was attenuated by combination with DMAPT and DMAPT increased the efficacy of AR inhibition. We further demonstrate that the effects of DMAPT sensitizing PCa cells to castration were dependent on the ability of DMAPT to inhibit phosphorylated-p65 function. Implications: Our study shows that DMAPT, an oral NF-κB inhibitor in clinical development, inhibits phosphorylated-p65 upregulation of AR-V7 and delays PCa castration resistance. This provides rationale for the development of DMAPT as a novel therapeutic strategy to increase durable response in patients receiving AR targeted therapy.

PMID:33863813 | DOI:10.1158/1541-7786.MCR-21-0099

Diabetes Care. 2021 Apr 16:dc202700. doi: 10.2337/dc20-2700. Online ahead of print.

ABSTRACT

OBJECTIVE: Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals.

RESEARCH DESIGN AND METHODS: ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D would reduce CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality.

RESULTS: We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD (hazard ratio [HR] 0.34; P = 2.01 × 10-3) and microvascular outcomes (HR 0.86; P = 0.015) than those receiving standard treatment. A single-nucleotide polymorphism, rs220721, in MAS1 reached suggestive significance in C4 (P = 4.34 × 10-7). PS predicted C4 with high accuracy (area under the receiver operating characteristic curve 0.98), and this predicted C4 displayed reduced CVD risk with intensive versus standard glycemia treatment (HR 0.53; P = 4.02 × 10-6), but not reduced risk of microvascular outcomes (P < 0.05). Mendelian randomization indicated causality between PS, on-trial HbA1c, and reduction in CVD outcomes (P < 0.05).

CONCLUSIONS: We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership in this group could be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development in this landmark clinical trial warranting further investigation.

PMID:33863751 | DOI:10.2337/dc20-2700

Breast Cancer Res Treat. 2021 Apr 15. doi: 10.1007/s10549-021-06191-x. Online ahead of print.

ABSTRACT

PURPOSE: Genomic tests can guide the decision to administer adjuvant chemotherapy in women with hormone receptor (HR)-positive, Human Epidermal growth Factor 2 (HER2)-negative breast cancer (BC) at intermediate risk of recurrence. We assessed the decision-making and economic impact of the Prosigna test in a real-life setting.

METHODS: Retrospective cohort study of HR + , HER2- BC patients managed from 2016 to 2020, potential candidates for adjuvant chemotherapy, at intermediate risk of recurrence, in whom a Prosigna test was performed according to contemporary guidelines. The additional cost of chemotherapy over one year in terms of direct medical and non-medical costs was estimated in this study to be €9,737 (derived from a previous study, NCT02813317). The cost of the Prosigna test, as defined by the reimbursement system, was €1,849.

RESULTS: Among the 809 patients included in this study, 2.3 Prosigna tests had to be performed to avoid adjuvant chemotherapy for one patient. The number of tests that had to be performed to avoid chemotherapy for one patient was higher for patients with grade 3 tumors and pN1mic axillary node involvement and lower for grade 1 tumors or in the absence of axillary node involvement (pN0), but did not vary according to the 10-year overall survival gain predicted by the Predict online test. The cost saving related to withholding of adjuvant chemotherapy for one patient on the basis of the Prosigna test results was €5,485.

CONCLUSION: We present one of the largest cohorts of HR + , HER2- BC patients at intermediate risk of recurrence, in whom a Prosigna test was used to guide the adjuvant therapy decision in a real-life setting, resulting in a 44% decrease in the indication for chemotherapy.

PMID:33860387 | DOI:10.1007/s10549-021-06191-x

Endosc Int Open. 2021 Apr;9(4):E562-E571. doi: 10.1055/a-1353-4849. Epub 2021 Apr 12.

ABSTRACT

Background and study aims Adherence to colorectal cancer (CRC) screening is still unsatisfactory in many countries, thereby limiting prevention of CRC. Colon capsule endoscopy (CCE), a minimally invasive procedure, could be an alternative to fecal immunochemical tests or optical colonoscopy for CRC screening, and might increase adherence in CRC screening. This systematic review and meta-analysis evaluates the diagnostic accuracy of CCE compared to optical colonoscopy (OC) as the gold standard, adequacy of bowel preparation regimes and the patient perspective on diagnostic measures. Methods We conducted a systematic literature search in PubMed, EMBASE and the Cochrane Register for Clinical Trials. Pooled estimates for sensitivity, specificity and the diagnostic odds ratio with their respective 95 % confidence intervals (CI) were calculated for studies providing sufficient data. Results Of 840 initially identified studies, 13 were included in the systematic review and up to 9 in the meta-analysis. The pooled sensitivities and specificities for polyps ≥ 6 mm were 87 % (95 % CI: 83 %-90 %) and 87 % (95 % CI: 76 %-93 %) in 8 studies, respectively. For polyps ≥ 10 mm, the pooled estimates for sensitivities and specificities were 87 % (95 % CI: 83 %-90 %) and 95 % (95 % CI: 92 %-97 %) in 9 studies, respectively. A patients' perspective was assessed in 31 % (n = 4) of studies, and no preference of CCE over OC was reported. Bowel preparation was adequate in 61 % to 92 % of CCE exams. Conclusions CCE provides high diagnostic accuracy in an adequately cleaned large bowel. Conclusive findings on patient perspectives require further studies to increase acceptance/adherence of CCE for CRC screening.

PMID:33860073 | PMC:PMC8041571 | DOI:10.1055/a-1353-4849

Sci Rep. 2021 Apr 15;11(1):8298. doi: 10.1038/s41598-021-87921-5.

ABSTRACT

Two 3-oxo-Δ4 fetal bile acids, 3-oxachola-4,6-dien-24-oic acid (1) and 7α-hydroxy-3-oxochol-4-en-24-oic acid (2), occur normally in the human fetus but remain elevated in neonates and children with severe cholestatic liver disease due to an autosomal recessive inborn error of metabolism affecting Δ4-3-oxo-steroid 5β-reductase (AKR1D1). Relatively little is known about 1 and 2 in adult patients with liver disease. The chemical synthesis of 1 and 2 is therefore described and their quantitation in plasma by ultrarapid chromatography-triple quadrupole mass spectrometry. Plasma concentrations of 1 and 2 were investigated in 25 adult patients with varying degrees of liver cirrhosis with and without hepatocellular carcinoma (HCC). Highly statistically significant correlations (P < 0.0001) were found between severity of liver cirrhosis, determined by the Child-Pugh and MELD scores, with plasma 1 and 2 concentrations, both alone and combined. The presence of HCC did not influence these correlations. Plasma cholic, chenodeoxycholic, deoxycholic, lithocholic or ursodeoxycholic acids, free and as their glycine or taurine conjugates, did not correlate with Child-Pugh or MELD score when corrected for multiple comparisons. These findings demonstrate that plasma levels of fetal bile acids 3-oxachola-4,6-dien-24-oic acid and 7α-hydroxy-3-oxochol-4-en-24-oic acid and likely deteriorating AKR1D1 activity indicate the severity of liver cirrhosis measured by the Child-Pugh and MELD scores.

PMID:33859329 | DOI:10.1038/s41598-021-87921-5

J Transl Med. 2021 Apr 15;19(1):151. doi: 10.1186/s12967-021-02816-3.

ABSTRACT

BACKGROUND: Pharmacogenomics describes the link between gene variations (polymorphisms) and drug responses. In view of the implementation of precision medicine in personalized healthcare, pharmacogenetic tests have recently been introduced in the clinical practice. However, the translational aspects of such tests have been limited due to the lack of robust population-based evidence.

MATERIALS: In this paper we present a novel pharmacogenetic panel (iDNA Genomics-PGx-CNS or PGx-CNS), consisting of 24 single nucleotide polymorphisms (SNPs) on 13 genes involved in the signaling or/and the metabolism of 28 approved drugs currently administered to treat diseases of the Central Nervous System (CNS). We have tested the PGx-CNS panel on 501 patient-derived DNA samples from a southeastern European population and applied biostatistical analyses on the pharmacogenetic associations involving drug selection, dosing and the risk of adverse drug events (ADEs).

RESULTS: Results reveal the occurrences of each SNP in the sample and a strong correlation with the European population. Nonlinear principal component analysis strongly indicates co-occurrences of certain variants. The metabolization efficiency (poor, intermediate, extensive, ultra-rapid) and the frequency of clinical useful pharmacogenetic, associations in the population (drug relevance), are also described, along with four exemplar clinical cases illustrating the strong potential of the PGx-CNS panel, as a companion diagnostic assay. It is noted that pharmacogenetic associations involving copy number variations (CNVs) or the HLA gene were not included in this analysis.

CONCLUSIONS: Overall, results illustrate that the PGx-CNS panel is a valuable tool supporting therapeutic medical decisions, urging its broad clinical implementation.

PMID:33858454 | DOI:10.1186/s12967-021-02816-3

Pharmacogenomics. 2021 Apr 16. doi: 10.2217/pgs-2021-0004. Online ahead of print.

ABSTRACT

Aim: Teaching of genetics and pharmacogenetics with personal genotyping (PGT) is becoming commonplace. We aimed to perform a systematic review and meta-analysis to understand the effects of PGT on student outcomes. Methods: A systematic review was performed on studies that reported the effects of PGT on student attitudes, perceptions or knowledge. Extracted data were summarized qualitatively and when possible, quantitatively. Results: Student PGT has a positive effect on student attitude and perceptions survey responses in studies without a control group (p = 0.009) and in studies with a control group (p = 0.025). Knowledge increased after the use of PGT (p < 0.001) in studies without a control group. Conclusion: The findings here suggest that perceptions, attitudes and knowledge increase with PGT in the classroom.

PMID:33858193 | DOI:10.2217/pgs-2021-0004

Pharmacogenomics. 2021 Apr 16. doi: 10.2217/pgs-2020-0171. Online ahead of print.

ABSTRACT

Aim: Explore the possible association between clinical factors and genetic variants of the dopamine pathways and negative symptoms. Materials & methods: Negative symptoms were assessed in 206 patients with schizophrenia using the Arabic version of the self-evaluation of negative symptoms scale and the Positive and Negative Syndrome Scale. Genotyping for COMT, DRD2, MTHFR and OPRM1 genes was performed. Results: Multivariable analysis showed that higher self-evaluation of negative symptoms scale scores were significantly associated with higher age, higher chlorpromazine-equivalent daily dose for typical antipsychotics and in married patients. Higher negative Positive and Negative Syndrome Scale scores were significantly associated with women and having the CT genotype for MTHFR c.677C>T (β = 4.25; p = 0.008) compared with CC patients. Conclusion: Understanding both clinical/genetic factors could help improve the treatment of patients.

PMID:33858192 | DOI:10.2217/pgs-2020-0171

Pharmacogenomics. 2021 Apr 16. doi: 10.2217/pgs-2020-0197. Online ahead of print.

ABSTRACT

Although statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) have proven effective in reducing plasma low-density lipoprotein levels and risk of cardiovascular disease, their lipid lowering efficacy is highly variable among individuals. Furthermore, statin treatment carries a small but significant risk of adverse effects, most notably myopathy and new onset diabetes. Hence, identification of biomarkers for predicting patients who would most likely benefit from statin treatment without incurring increased risk of adverse effects can have a significant public health impact. In this review, we discuss the rationale for the use of subject-derived lymphoblastoid cell lines in studies of statin pharmacogenomics and describe a variety of approaches we have employed to identify novel genetic markers associated with interindividual variation in statin response.

PMID:33858191 | DOI:10.2217/pgs-2020-0197

Pharmacol Res. 2021 Apr 12:105610. doi: 10.1016/j.phrs.2021.105610. Online ahead of print.

ABSTRACT

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes for LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413L/h. In addition, the UGT2B7 rs4356975 C>T and ABCB1 rs1128503 A>G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = -30.899 vs. -20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33% to 50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33% to 66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

PMID:33857625 | DOI:10.1016/j.phrs.2021.105610

Commun Biol. 2021 Apr 14;4(1):370. doi: 10.1038/s42003-021-01897-6.

ABSTRACT

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.

PMID:33854168 | DOI:10.1038/s42003-021-01897-6