Mayo Clin Proc Innov Qual Outcomes. 2021 Jan 13;5(1):35-45. doi: 10.1016/j.mayocpiqo.2020.08.009. eCollection 2021 Feb.

ABSTRACT

OBJECTIVE: To assess the potential impact of Pharmacogenomic (PGx) variation in cytochrome P450 2D6 (CYP2D6) enzyme function, using loss in quality-adjusted life years (QALYs) associated with treatment problems, and the willingness to pay to avoid treatment problems from patients' and payers' perspectives.

PATIENTS AND METHODS: The study included patients prescribed tramadol or codeine, or both, between January 1, 2005, and December 31, 2017. Demographic information and adverse drug events, including adverse drug events and poor pain control, were collected from the electronic health records using natural language processing techniques and review by trained abstractors. Patients' willingness to pay and QALY estimates were based on comprehensive literature review. The CYP2D6 phenotypes were divided into 4 groups: ultra-rapid metabolizers, normal metabolizers, intermediate metabolizers, and poor metabolizers.

RESULTS: Among the 2860 identified patients, 63 (2%) were ultrarapid metabolizers, 1449 (50%) were normal metabolizers, 1155 (40%) were intermediate metabolizers, and 193 (7%) were poor metabolizers. The patients' average estimated willingness-to-pay value to avoid treatment problems was $23 per month; poor metabolizers developed problems with the highest estimated willingness-to-pay value ($32 per month). The mean QALY loss among all patients was 0.024 QALYs (8.8 healthy days); poor metabolizers had the highest loss (0.027 QALYs, 9.9 healthy days).

CONCLUSION: Patients with various phenotypes developed different treatment problem profiles. Poor CYP2D6 metabolizers developed problems with highest willingness to pay, and they might potentially benefit most from PGx-guided treatment and problem prevention.

PMID:33718782 | PMC:PMC7930862 | DOI:10.1016/j.mayocpiqo.2020.08.009

Front Pharmacol. 2021 Feb 26;12:598925. doi: 10.3389/fphar.2021.598925. eCollection 2021.

ABSTRACT

Background: There is pressing urgency to identify therapeutic targets and drugs that allow treating COVID-19 patients effectively. Methods: We performed in silico analyses of immune system protein interactome network, single-cell RNA sequencing of human tissues, and artificial neural networks to reveal potential therapeutic targets for drug repurposing against COVID-19. Results: We screened 1,584 high-confidence immune system proteins in ACE2 and TMPRSS2 co-expressing cells, finding 25 potential therapeutic targets significantly overexpressed in nasal goblet secretory cells, lung type II pneumocytes, and ileal absorptive enterocytes of patients with several immunopathologies. Then, we performed fully connected deep neural networks to find the best multitask classification model to predict the activity of 10,672 drugs, obtaining several approved drugs, compounds under investigation, and experimental compounds with the highest area under the receiver operating characteristics. Conclusion: After being effectively analyzed in clinical trials, these drugs can be considered for treatment of severe COVID-19 patients. Scripts can be downloaded at https://github.com/muntisa/immuno-drug-repurposing-COVID-19.

PMID:33716737 | PMC:PMC7952300 | DOI:10.3389/fphar.2021.598925

Tob Use Insights. 2021 Feb 26;14:1179173X21998355. doi: 10.1177/1179173X21998355. eCollection 2021.

ABSTRACT

Cigarette use is the leading cause of preventable death in the United States. Despite the well documented dangers of smoking, nearly 20% of adults report regular use of tobacco. A majority desire to discontinue but the long-term cessation success rate remains near 4%. One challenge to reducing the prevalence of tobacco use is an incomplete understanding of the individual correlates that reinforce continued use. Evidence from research on nicotine and tobacco suggests that Tobacco Use Disorder is a complex, and multifactorial condition. Personality traits, comorbidities, habits and lifestyle, genetics, socioeconomic status, and mental and physical health all contribute to the risk for dependence and to the likelihood of quitting. This perspective review provides an overview of some common factors that contribute to liability risk for Tobacco Use Disorder and a framework for assessing individual tobacco users. The framework includes 5 areas that research suggests contribute to continued tobacco use: nicotine addiction, psychological influences, behavioral dependencies, neurobiological factors, and social reinforcement. Nicotine addiction includes drug-seeking behavior and the role of withdrawal avoidance. Psychological and emotional states contribute to a perceived reliance on tobacco. Behavioral dependence is reinforced by associative and non-associative learning mechanisms. Neurobiological factors include genetic variables, variations in neurotransmitters and receptors, pharmacogenetics, and interaction between psychiatric illnesses and nicotine use and dependence. Finally, social reinforcement of smoking behavior is explained by a network phenomenon and consistent visual cues to smoke. A comprehensive assessment of individual tobacco users will help better determine appropriate treatment options to achieve improved efficacy and outcomes.

PMID:33716514 | PMC:PMC7922618 | DOI:10.1177/1179173X21998355

Curr Probl Cancer. 2021 Mar 6:100729. doi: 10.1016/j.currproblcancer.2021.100729. Online ahead of print.

ABSTRACT

Acute myeloid leukaemia (AML) is a very heterogeneous malignancy in which standard treatment is based on chemotherapy. Resistance to chemotherapeutic agents remains a big problem in AML, because negatively influences patient overall survival. Several resistance mechanisms have been described, the best of which is the process of drug removal from the cell and/or nucleus by membrane transport proteins. The aim of the study was to investigate the effect of polymorphism of genes coding ABCC3, GSTM5 involved in the transport and metabolism of drugs. For this purpose 95 newly diagnosed AML patients and 125 healthy controls were genotyped. We showed that ABCC3 rs4148405 and GSTM5 rs3754446, but not ABCC33 rs4793665, affected overall survival in Polish AML patients.

PMID:33714589 | DOI:10.1016/j.currproblcancer.2021.100729

Biomed Pharmacother. 2021 Mar 10;138:111456. doi: 10.1016/j.biopha.2021.111456. Online ahead of print.

ABSTRACT

Methotrexate is used as first-line treatment of moderate to severe psoriasis. Despite the marked variability in treatment outcomes, no pharmacogenetic markers are currently used for personalised management of therapy. In this retrospective study, we investigated the effects of genetic predisposition on efficacy and toxicity of low-dose methotrexate in a cohort of 137 patients with moderate to severe plaque psoriasis. We genotyped 16 polymorphisms in genes for enzymes involved in the folate-methionine pathway and in methotrexate transport, and analysed their association with treatment efficacy and toxicity using classification and regression tree analysis and logistic regression. The most pronounced effect observed in this study was for GNMT rs10948059, which was identified as a risk factor for inadequate efficacy leading to treatment discontinuation. Patients carrying at least one variant allele had ~7-fold increased risk of treatment failure compared to patients with the wild-type genotype, as shown by the classification and regression tree analysis and logistic regression (odds ratio [OR], 6.94; p = 0.0004). Another risk factor associated with insufficient treatment responses was DNMT3b rs2424913, where patients carrying at least one variant allele had a 4-fold increased risk of treatment failure compared to patients with the wild-type genotype (OR, 4.10; p = 0.005). Using classification and regression tree analysis, we show that DNMT3b rs2424913 has a more pronounced role in patients with the variant GNMT genotype, and hence we suggest an interaction between these two genes. Further, we show that patients with the BHMT rs3733890 variant allele had increased risk of hepatotoxicity (OR, 3.17; p = 0.022), which is the most prominent reason for methotrexate discontinuation. We also show that variants in the genes for methotrexate transporters OATP1B1 (rs2306283/rs4149056 SLCO1B1 haplotypes) and ABCC2 (rs717620) are associated with increased risk of treatment failure. The associations identified have not been reported previously. These data suggest that polymorphisms in genes for enzymes of the methionine cycle (which affect cell methylation potential) might have significant roles in treatment responses to methotrexate of patients with psoriasis. Further studies are warranted to validate the potential of the pharmacogenetic markers identified.

PMID:33714108 | DOI:10.1016/j.biopha.2021.111456

Genomics Proteomics Bioinformatics. 2021 Mar 10:S1672-0229(21)00056-5. doi: 10.1016/j.gpb.2019.09.008. Online ahead of print.

ABSTRACT

Transcriptional regulators (TRs) participate in essential processes in cancer pathogenesis and are critical therapeutic targets. Identification of drug response-related TRs from cell line-based compound screening data is often challenging due to low mRNA expression levels of TRs, protein modifications, and other confounders. In this study, we developed a regression-based pharmacogenomic and ChIP-seq data integration method (RePhine) to infer the impact of TRs on drug response through integrative analysis of pharmacogenomic and ChIP-seq data. RePhine was evaluated in simulation and pharmacogenomic data and was applied to pan-cancer datasets with the goal of biological discovery. In simulation data with added noise or confounders and in pharmacogenomic data RePhine demonstrated an improved performance in comparison with several commonly used methods such as correlation analysis and gene set enrichment analysis. Utilizing RePhine and Cancer Cell Line Encyclopedia data, we observed that RePhine-derived TR signatures could effectively cluster drugs with different mechanisms of action. RePhine predicted that loss of function of EZH2/PRC2 reduces cancer cell sensitivity toward the BRAF inhibitor PLX4720. Experimental validation confirmed that pharmacological EZH2 inhibition increases the resistance of cancer cells to PLX4720 treatment. Our results support that RePhine is a useful tool for inference of the TRs related to drug response and for potential therapeutic applications. The source code for RePhine is freely available at https://github.com/coexps/RePhine.

PMID:33713851 | DOI:10.1016/j.gpb.2019.09.008

Rev Endocr Metab Disord. 2021 Mar 12. doi: 10.1007/s11154-021-09637-1. Online ahead of print.

ABSTRACT

We present current knowledge concerning the pharmacogenomics of growth hormone therapy in children with short stature. We consider the evidence now emerging for the polygenic nature of response to recombinant human growth hormone (r-hGH). These data are related predominantly to the use of transcriptomic data for prediction. The impact of the complex interactions of developmental phenotype over childhood on response to r-hGH are discussed. Finally, the issues that need to be addressed in order to develop a clinical test are described.

PMID:33712998 | DOI:10.1007/s11154-021-09637-1

Pharmacogenomics J. 2021 Mar 12. doi: 10.1038/s41397-021-00230-y. Online ahead of print.

ABSTRACT

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and does not have sufficient prognostic indicators. Interferon gamma inducible protein 16 (IFI16) plays a crucial role in B-cell differentiation. Several studies have shown that IFI16 predicted prognosis in many cancers. However, the relationship between MM prognosis and IFI16 expression has not been studied. In our study, we analyzed the prognostic role of IFI16 expression and explored the possible mechanism in MM progression by using 4498 myeloma patients and 52 healthy donors from 13 independent gene expression omnibus (GEO) datasets. The IFI16 expression increased with myeloma progression, ISS stage, 1q21 amplification, and relapse (all P < 0.01). MM patients with higher IFI16 expression had shorter survival in six datasets (all P < 0.05). Furthermore, multivariate analysis indicated that enhanced IFI16 expression was an independent poor prognostic factor for EFS and OS (P = 0.007, 0.009, respectively). And PPI, GO, KEGG, and GSEA also confirmed that IFI16 promoted MM progression by participating in tumor-related pathways. In conclusion, our study confirmed that IFI16 was a poor prognostic biomarker in MM.

PMID:33712724 | DOI:10.1038/s41397-021-00230-y

Cytokine. 2021 Mar 6;142:155492. doi: 10.1016/j.cyto.2021.155492. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: The interferon-induced transmembrane protein 3 (IFITM3) plays an important role in the adaptive and innate immune response by inhibiting viral membrane hemifusion between the host and viral cell cytoplasm. Single nucleotide polymorphisms (SNPs) in the gene IFITM3 have been associated with susceptibility and severity of influenza or other viral infections. We aimed to analyze the role of SNPs in the gene IFITM3 in SARS-CoV-2 infection.

METHODS: We performed genotyping of the SNPs rs12252 and rs34481144 in the gene IFITM3 in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19.

RESULTS: SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics. Neither IFITM3 rs12252 nor rs34481144 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. Interestingly, we observed the putative deleterious rs12252 CC genotype only in SARS-CoV-2-positive patients (N = 2). Also, we found a non-significant higher frequency of rs34481144 A-allele carriers in the patients with 'serious' COVID-19.

CONCLUSIONS: In summary, we could not confirm the recently reported influence of polymorphisms in the gene IFITM3 on SARS-CoV-2 infection risk or severity of COVID-19 in a German cohort. Additional studies are needed to clarify the influence of the rs12252 CC genotype on SARS-CoV-2 infection risk and the rs34481144 A-allele on course of COVID-19.

PMID:33711707 | DOI:10.1016/j.cyto.2021.155492

ESMO Open. 2021 Mar 9;6(2):100064. doi: 10.1016/j.esmoop.2021.100064. Online ahead of print.

ABSTRACT

BACKGROUND: Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes.

METHODS: To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors.

RESULTS: A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients.

CONCLUSIONS: Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.

PMID:33711672 | DOI:10.1016/j.esmoop.2021.100064

Mol Cell Endocrinol. 2021 Mar 9:111221. doi: 10.1016/j.mce.2021.111221. Online ahead of print.

ABSTRACT

As the most frequent women's cancer, breast cancer causes the second most cancer-related death in women worldwide. Majority of the breast cancers are hormone receptor-positive and commonly treated by hormone therapy. Thus, the expression levels of hormone receptors signaling pathways are pivotal in the development and therapy of breast cancer. The expression of hormone receptors signaling pathways is not only regulated at the transcription level but also at the post-transcription level by both proteins and RNAs. In addition to that, the function of hormone receptors can also be regulated by RNAs. In this review, we summarize the roles of RNAs in hormone receptor-positive breast cancer. We introduce how mRNA stability and protein function of genes in hormone receptors signaling pathways are regulated by RNA-binding proteins, miRNAs, and lncRNAs. We believe these proteins and RNAs can be potential therapeutic targets of breast cancer.

PMID:33711334 | DOI:10.1016/j.mce.2021.111221

Ther Drug Monit. 2021 Apr 1;43(2):150-200. doi: 10.1097/FTD.0000000000000871.

ABSTRACT

When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.

PMID:33711005 | DOI:10.1097/FTD.0000000000000871

EMBO Mol Med. 2021 Mar 11:e13366. doi: 10.15252/emmm.202013366. Online ahead of print.

ABSTRACT

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.

PMID:33709473 | DOI:10.15252/emmm.202013366

Indian J Crit Care Med. 2021 Feb;25(2):228-230. doi: 10.5005/jp-journals-10071-23738.

ABSTRACT

Thiopurines by their glucocorticoid-sparing property help in maintaining remission for patients with inflammatory bowel disease (IBD), when glucocorticoids are reduced and withdrawn. However, due to bone marrow suppression, it cannot be used in various conditions where it is indicated. A 17-year-old patient presented with pancytopenia with neutropenic sepsis and alopecia after 3 weeks of starting azathioprine for her underlying Crohn's disease. Thiopurine S-methyltransferase (TPMT;*2, *3A, *3C) analysis resulted in a wild-type genotype, whereas homozygous Nudix hydrolase 15 (NUDT 15 C415T) variant was positive. Azathioprine was stopped immediately, and she was started on broad-spectrum antibiotics that led to some clinical improvements initially, but later on, the patient developed intestinal obstruction along with postoperative complications leading to death. In this report, we highlight a case of serious hematological toxicity associated with azathioprine use in a patient with Crohn's disease with homozygous NUDT 15 variant, thus favoring the implementation of a pharmacogenomic approach before starting azathioprine, particularly in the Asian population.

HOW TO CITE THIS ARTICLE: Debnath P, Nair S, Jain S, Udgirkar S, Contractor Q, Rathi P. Thiopurine-induced Myelosuppression with Severe Sepsis in a Patient with Crohn's Disease: A Case Report. Indian J Crit Care Med 2021;25(2):228-230.

PRIOR PRESENTATION OF CASE REPORT AT PROFESSIONAL MEETING: The case was presented in abstract form at the American College of Gastroenterology Annual Scientific Meeting, held at San Antonio, TX, USA 2019.

INFORMED CONSENT FOR PUBLICATION OF CASE DETAILS: Obtained from patient's relatives.

PMID:33707905 | PMC:PMC7922446 | DOI:10.5005/jp-journals-10071-23738

Sci Rep. 2021 Mar 11;11(1):5662. doi: 10.1038/s41598-021-84960-w.

ABSTRACT

OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p < 0.0078). The localized cancer subgroup (n = 11) demonstrated earlier enhancement compared to the mCRPC group, but no retention over time (p > 0.05). OATP1B3 expression on IHC trended higher contrast enhancement between 20-40 min (p ≤ 0.064) and was associated with contrast enhancement at 60 min (p = 0.0422). OATP1B1 haplotype, with N130D and V174A substitutions, impacted enhancement at 40-60 min (p ≤ 0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance, gadoxetate disodium has potential as a biomarker in prostate cancer.

PMID:33707581 | DOI:10.1038/s41598-021-84960-w

Sci Rep. 2021 Mar 11;11(1):5696. doi: 10.1038/s41598-021-85086-9.

ABSTRACT

A subset of prostate cancer displays a poor clinical outcome. Therefore, identifying this poor prognostic subset within clinically aggressive groups (defined as a Gleason score (GS) ≧8) and developing effective treatments are essential if we are to improve prostate cancer survival. Here, we performed a bioinformatics analysis of a TCGA dataset (GS ≧8) to identify pathways upregulated in a prostate cancer cohort with short survival. When conducting bioinformatics analyses, the definition of factors such as "overexpression" and "shorter survival" is vital, as poor definition may lead to mis-estimations. To eliminate this possibility, we defined an expression cutoff value using an algorithm calculated by a Cox regression model, and the hazard ratio for each gene was set so as to identify genes whose expression levels were associated with shorter survival. Next, genes associated with shorter survival were entered into pathway analysis to identify pathways that were altered in a shorter survival cohort. We identified pathways involving upregulation of GRB2. Overexpression of GRB2 was linked to shorter survival in the TCGA dataset, a finding validated by histological examination of biopsy samples taken from the patients for diagnostic purposes. Thus, GRB2 is a novel biomarker that predicts shorter survival of patients with aggressive prostate cancer (GS ≧8).

PMID:33707553 | DOI:10.1038/s41598-021-85086-9

Pediatr Allergy Immunol. 2021 Mar 11. doi: 10.1111/pai.13494. Online ahead of print.

ABSTRACT

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associate with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium.

METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma.

RESULTS: Genome-wide association results for a total of 82,996common SNPs (MAF ≥ 1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (p-value threshold ≤ 5x10-6 ) associated with exacerbations despite LABA use.

CONCLUSION: No strong effects of SNPs on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7), that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

PMID:33706416 | DOI:10.1111/pai.13494

Cancer Sci. 2021 Mar 11. doi: 10.1111/cas.14872. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer related death worldwide. In spite of the identification of epidermal growth factor receptor (EGFR) driver mutations has improved the therapeutics for lung cancer, patients harboring EGFR mutations usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying wild-type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. The results show that the expressions of transmembrane glycoprotein non-metastatic melanoma protein B (GPNMB) is positively correlated with the status of mutated EGFR in non-small cell lung cancer (NSCLC). It is not only overexpressed but also highly glycosylated in EGFR-mutated, especially the EGFR-L858R mutated, NSCLC cells. Further examinations indicate that GPNMB could activate mutated EGFR without ligand stimulation. It could bind to the C-terminus of EGFR, facilitate its' phosphorylation at Y845, turn on the downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that the Asn134 (N134) glycosylation of GPNMB plays a crucial role in this ligand-independent regulation. Depleting the N134-glycosylation of GPNMB could dramatically inhibit the binding of GPNMB to mutated EGFR, block its downstream signaling, and ultimately inhibit cancer metastasis in NSCLC. Clarifying the role of N-glycosylated GPNMB in regulating the ligand-independent activation of mutated EGFR may provide a new insight for developing novel therapeutics for NSCLC in the near future.

PMID:33706413 | DOI:10.1111/cas.14872

Neurosci Lett. 2021 Mar 8:135802. doi: 10.1016/j.neulet.2021.135802. Online ahead of print.

ABSTRACT

In view of inconsistencies in the association studies of alpha synuclein (SNCA) rs7684318 (chr4: 90655003 T > C) with Parkinson's disease (PD), we conducted a meta-analysis to establish the association of this variant with PD and examined changes in transcription factor binding. SNCA rs7684318 C-allele was identified as genetic risk factor for PD in fixed (OR: 1.53, 95% CI: 1.40 - 1.68, p < 0.0001) and random effect (OR: 1.65, 95% CI: 1.30 - 2.09, p = 0.0003) models. Heterogeneity was observed in association (Tau2: 0.0576, H: 2.32, I2: 0.815, Q: 21.64, p = 0.0002). Egger's test showed no evidence of publication bias (p = 0.37). Subgroup analysis showed that rs7684318 is contributing to PD risk in Japanese (OR: 1.46, 95% CI: 1.30 - 1.64) and Indian (OR: 2.63, 95% CI: 1.79 - 3.86) populations while showing no significant association in Chinese population (OR: 1.68, 95% CI: 0.93 - 3.02). Sensitivity analysis showed that exclusion of any one of the studies has no significant impact on the association, which justifies the robustness of the analysis. Tissue-specific DNase foot print analysis revealed that this variant contributes to increased transcription factor binding in midbrain, putamen and caudate nucleus. The substitution of T > C increased binding of RBPJ and GATA-family transcription factors; and decreased binding of NKX2 family, SNAI2, SNAI3, DMRT1, HOXA13, HOXB13, HOXC13, HOXD13, WT1, POU4F1, POU4F2, POU4F3 transcriptional factors. TRANSFAC and DNA curvature analyses substantiate the association of this variant with increased binding of GATA1 that contribute to intensity of DNA curvature peaks and splitting pattern. These studies along with the meta-analysis strongly suggest that the rs7684318 variant contributes to the pathophysiology of PD by modulating binding of transcription factors related to Notch and Wnt signalling pathways that are likely to impair dopmanergic transmission.

PMID:33705925 | DOI:10.1016/j.neulet.2021.135802

Pharmacol Res. 2021 Mar 8:105538. doi: 10.1016/j.phrs.2021.105538. Online ahead of print.

ABSTRACT

Undoubtedly, pharmacogenomics (PGx) aims in optimizing drug treatment responses whilst also improving the patients' quality of life, either via a reduction of adverse drug reactions and/or an enhancement of drug treatment efficacy. To achieve this, PGx guidance is provided by the two major regulatory bodies in a worldwide level, specifically the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and occasionally some research consortia, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) or the Dutch Pharmacogenomics Working Group (DPWG). However, so far, there is a limited number of studies focusing on the delineation of the similarities and more importantly, the discrepancies in the PGx guidance by the different regulatory bodies and consortia. Herein, we use real-life clinical PGx data to highlight such discrepancies and similarities for genome-guided interventions in psychiatric disorders, thus demonstrating the need for harmonization of the guidelines and recommendations. More precisely, we used the PharmCAT genome-informed drug treatment reports from 304 Greek individuals with psychiatric disorders in order to emphasize on the discrepancies in the PGx guidance/guidelines between FDA vs EMA and CPIC vs DPWG, respectively. For example, CYP2D6-pimozide pair is characterized as 'Testing Required' according to FDA and is accompanied by a DPWG PGx guideline, whilst no EMA or CPIC PGx guidance is found for this drug-gene pair. Moreover, discrepancies are observed regarding the type of PGx guidance for CYP2C19-doxepin pair, with 89 individuals from our study cohort requiring a dose prescribing change based on FDA, whilst only 5 individuals have to receive genome-guided treatment adjustment according to CPIC. To our knowledge, this is the first study, in which discrepancies regarding the type of PGx guidance and the number of actionable drug-gene pairs amongst FDA and EMA, as well as CPIC and DPWG, are brought to light with an emphasis on psychiatric disorders.

PMID:33705851 | DOI:10.1016/j.phrs.2021.105538