Pharmacogenomics And Personalized Medicine[JOURNAL]
Sun
200 papers
Bioinformatics-Based Identification of Key Prognostic Genes in Neuroblastoma with a Focus on Immune Cell Infiltration and Diagnostic Potential of VGF.
Guo Q, Xiao Y, Chu J … +3 more , Sun Y, Li S, Zhang S
Pharmgenomics Pers Med · 2024 · PMID 39403102 · Full text
OBJECTIVE: This study aims to identify differentially expressed genes (DEGs) in neuroblastoma (NB) through comprehensive bioinformatics analysis and machine learning techniques. We seek to elucidate these DEGs' biologica...
OBJECTIVE: This study aims to identify differentially expressed genes (DEGs) in neuroblastoma (NB) through comprehensive bioinformatics analysis and machine learning techniques. We seek to elucidate these DEGs' biological functions and associated signaling pathways. Furthermore, our objective extends to predicting upstream microRNAs (miRNAs) and relevant transcription factors of pivotal genes, with the ultimate goal of guiding clinical diagnostics and informing future treatment strategies for Neuroblastoma. METHODS: In this study, we sourced datasets GSE49710 and TARGET from the GEO and UCSC-XENA databases, respectively. Differentially expressed genes (DEGs) were identified using the R language "limma" package. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of these DEGs were conducted using the "clusterProfiler" package. We employed Weighted Gene Co-expression Network Analysis (WGCNA) to isolate the most significant modules associated with death and MYCN amplification, specifically MEpink and MEbrown modules. These modules were then cross-referenced with the DEGs for further GO and KEGG pathway analyses. LASSO regression analysis, facilitated by the "glmnet" package, was utilized to pinpoint three hub genes. We performed differential analysis on these genes and constructed Receiver Operating Characteristic (ROC) curves for disease diagnosis purposes. Immune infiltration analysis was conducted using the "GSVA" package's ssGSEA function. Additionally, single-gene Gene Set Enrichment Analysis (GSEA) on the hub gene was carried out based on Reactome and KEGG databases. Upstream miRNA and transcription factors associated with the hub gene were predicted using RegNetwork, with visual representations created in Cytoscape. Furthermore, to validate the three identified markers in neuroblastoma tissues, quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) analysis was conducted. RESULTS: We identified 483 differentially expressed genes (DEGs) in neuroblastoma. These genes predominantly function in protein translation, membrane composition, and RNA transcription regulation, and are implicated in multiple signaling pathways relevant to neurodegenerative diseases. Utilizing LASSO regression analysis, we pinpointed three hub genes: , and . The Receiver Operating Characteristic (ROC) curve analysis yielded Area Under Curve (AUC) values of 0.751 and 0.722 for , 0.79 and 0.656 for , and 0.8 and 0.753 for , respectively. Our immune infiltration analysis revealed significant correlations among monocytes, follicular helper T cells, and CD4+ T cells. Notably, in the death group, we observed heightened infiltration levels of activated CD4+ T cells, macrophages, and Th2 cells. exhibited a close association with the infiltration of monocytes, CD4+ T cells, and Th2 cells, with P-values less than 0.05. Furthermore, qRT-PCR analysis corroborated the upregulation of in neuroblastoma tissues, further validating our findings. CONCLUSION: The hub genes (, and ) of neuroblastoma are screened. , one of the hub genes, may have a high diagnostic value and is involved in the immune cell infiltration in neuroblastoma tissue, which may be used as a biomarker for the diagnosis of neuroblastoma and provides a new direction for clinical prognosis prediction and management improvement.
Serum IFN-γ Predicts the Therapeutic Effect of Belimumab in Refractory Lupus Nephritis Patients.
Liu S, Li J, Zhang Z … +2 more , Meng D, Wang K
Pharmgenomics Pers Med · 2024 · PMID 39376665 · Full text
OBJECTIVE: To evaluate belimumabf's efficacy in refractory lupus nephritis (LN) patients and identify predictive serum biomarkers for treatment response. METHODS: In this single-arm retrospective study, we assessed clini...
OBJECTIVE: To evaluate belimumabf's efficacy in refractory lupus nephritis (LN) patients and identify predictive serum biomarkers for treatment response. METHODS: In this single-arm retrospective study, we assessed clinical responses in LN patients at baseline and six months after initiating belimumab. Serum cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) were quantified using multiplex magnetic bead flow immunoassay before and after treatment. RESULTS: Fourteen patients with various subtypes of refractory LN participated in the study: seven with class III and V LN, three with type V alone, two with class III, and two with class IV+V and V LN. Post six months of belimumab therapy, all participants exhibited a reduction in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K scores from their respective baseline values. Notably, most patients showed a decrease in the dosage of prednisone, levels of 24-hour urinary protein, immunoglobulins, erythrocyte sedimentation rate (ESR), and anti-double-stranded DNA antibody IgM, along with serum levels of IL-4, IL-6, IL-10, and IFN-γ. Meanwhile, levels of C3, C4, IL-2, and TNF-α were observed to increase. Of the participants, nine (64.29%) achieved a complete renal response, one (7.14%) showed a partial response, and four (28.57%) exhibited no response. Significantly, higher baseline serum IFN-γ levels were found in patients who did not achieve complete renal response (CR) compared to those who did (p = 0.009). Receiver operating characteristic (ROC) curve analysis demonstrated that baseline IFN-γ levels had an area under curve (AUC) of 0.96 (0.70-1.00), with a sensitivity of 0.89 and a specificity of 1.00 (p < 0.001). CONCLUSION: Belimumab shows potential efficacy in treating refractory LN. Baseline serum IFN-γ levels may predict response to belimumab therapy, potentially enabling more targeted treatment approaches for this challenging condition.
A Case Report of Hemiplegic Migraine with Mutation in the ATP1A2 Gene.
Guan DM, Shan YZ, Zhao HT … +3 more , Meng Y, Yan ZR, Zhang HL
Pharmgenomics Pers Med · 2024 · PMID 39319208 · Full text
BACKGROUND: Hemiplegic migraine, a less common variant of migraine, is the focus of this paper. Within the scope of this study, we present a case of hemiplegic migraine that bears the potential for misdiagnosis, particul...
BACKGROUND: Hemiplegic migraine, a less common variant of migraine, is the focus of this paper. Within the scope of this study, we present a case of hemiplegic migraine that bears the potential for misdiagnosis, particularly as encephalitis. BRIEF INTRODUCTION TO THE DISEASE: The patient developed a right-sided headache a day prior to admission, accompanied by fever, nausea, vomiting, and left-sided limb weakness. On the fourth day, the patient experienced a grand mal epilepsy, marked by unconsciousness, leftward deviation of both eyes, limb convulsions, and foaming at the mouth. Cerebrospinal fluid analysis revealed no apparent abnormalities, Electroencephalography showed abnormal slow waves, imaging studies indicated swelling and meningeal thickening in the right cortex, and genetic testing identified a heterozygous mutation in the ATPIA2 gene. The diagnosis was hemiplegic migraine, and the patient received symptomatic supportive treatment, leading to improvement and subsequent discharge. Flunarizine and sodium valproate were prescribed post-discharge, and the patient achieved complete recovery after a one-month follow-up. CONCLUSION: Apart from experiencing headaches, patients with hemiplegic migraine may exhibit additional symptoms like fever, epilepsy, and hemiplegia. These manifestations warrant clinical attention, and if deemed necessary, genetic testing should be conducted, and this is an autosomal dominant pattern.
TICRR Overexpression Enhances Disease Aggressiveness and Immune Infiltration of Cutaneous Melanoma.
Chen C, Zou Y, Zheng X … +6 more , Hu T, Ni J, Kan D, Yin Z, Ye L, Liu B
Pharmgenomics Pers Med · 2024 · PMID 39246575 · Full text
OBJECTIVE: To investigate the role of the TopBP1 interacting checkpoint and replication regulator (TICRR) in cutaneous melanoma (CM) as a prognostic biomarker and therapeutic target. METHODS: TICRR expression in tumour s...
OBJECTIVE: To investigate the role of the TopBP1 interacting checkpoint and replication regulator (TICRR) in cutaneous melanoma (CM) as a prognostic biomarker and therapeutic target. METHODS: TICRR expression in tumour samples was explored using the TCGA and the GTEx database. The Kaplan-Meier survival curve, nomogram model and risk score curve were established to evaluate the prognostic role of TICRR in CM. Tissue samples of CM patients were obtained to validate the TICRR expression further. Several experiments in vitro were conducted to investigate the effect of TICRR upon CM aggressiveness and to explore underlying mechanisms. RESULTS: TICRR was overexpressed in CM tissue and was correlated with poor prognosis of CM patients. The knockdown of TICRR decreased the proliferation, migration, and invasion of CM cells, whereas overexpression produced the opposite effect. Furthermore, TICRR suppression substantially attenuated the activation of PI3K/AKT/mTOR signalling, while the PI3K/AKT inhibitor LY294002 could partially reverse the aggressiveness-enhancing effect induced by TICRR overexpression. It was further confirmed that TICRR was closely related to immune cell infiltration activities by using immune infiltration and immunofluorescence analysis. CONCLUSION: TICRR overexpression may enhance CM aggressiveness by activating the PI3K/Akt/mTOR pathway and promoting immune infiltration. TICRR was verified as a potential prognostic biomarker and therapeutic target for CM.
Acyl-CoA Thioesterase 8 (ACOT8) is a Poor Prognostic Biomarker in Breast Cancer.
Wang Z, Wang H
Pharmgenomics Pers Med · 2024 · PMID 39188355 · Full text
PURPOSE: This study aimed to investigate the expression of Acyl-CoA thioesterase 8 (ACOT8) in breast cancer (BC) and its association with clinicopathological characteristics, patient survival, and immune infiltration. ME...
PURPOSE: This study aimed to investigate the expression of Acyl-CoA thioesterase 8 (ACOT8) in breast cancer (BC) and its association with clinicopathological characteristics, patient survival, and immune infiltration. METHODS: We conducted a comprehensive analysis of ACOT8 mRNA differential expression across various cancer types, followed by survival analysis. We focused on BC, where ACOT8 expression was evaluated at both the mRNA and protein levels using online databases, qRT-PCR, and immunohistochemistry. Associations between ACOT8 expression and clinicopathological parameters were assessed using different databases. Additionally, we investigated the prognostic significance of ACOT8 in BC patients by analyzing various cohorts and databases. Furthermore, we predicted a potential signaling pathway and identified miR-1-3p as a possible upstream regulator of ACOT8. Finally, the relationship between ACOT8 and immune system infiltration, as well as immune checkpoint molecules, was examined. RESULTS: Our findings demonstrated upregulated ACOT8 mRNA and protein levels in BC. Elevated ACOT8 expression correlated positively with various clinicopathological characteristics, indicating an unfavorable prognosis for patients. Functional enrichment analysis suggested ACOT8 involvement in lipid metabolism, mitochondrial components, and ribosomal functions. Moreover, we identified connections between ACOT8 and immune system markers, immune cell infiltration, and immune checkpoints. CONCLUSION: This study provides compelling evidence for ACOT8 upregulation in BC and its association with clinicopathological features and patient outcomes. Additionally, our findings suggest that targeting ACOT8 and immune checkpoints might enhance the effectiveness of immunotherapy in BC patients.
Mitochondrial Diabetes May Not Be the Only Phenotypic Presentation of the m.5826A>G mtDNA Variant [Letter].
Finsterer J
Pharmgenomics Pers Med · 2024 · PMID 39081827 · Full text
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M2 Macrophage Classification of Colorectal Cancer Reveals Intrinsic Connections with Metabolism Reprogramming and Clinical Characteristics.
Huang F, Wang Y, Shao Y … +4 more , Zhang R, Li M, Liu L, Zhao Q
Pharmgenomics Pers Med · 2024 · PMID 39011168 · Full text
INTRODUCTION: Immune cell interactions and metabolic changes are crucial in determining the tumor microenvironment and affecting various clinical outcomes. However, the clinical significance of metabolism evolution of im...
INTRODUCTION: Immune cell interactions and metabolic changes are crucial in determining the tumor microenvironment and affecting various clinical outcomes. However, the clinical significance of metabolism evolution of immune cell evolution in colorectal cancer (CRC) remains unexplored. METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data were acquired from TCGA and GEO datasets. For the analysis of macrophage differentiation trajectories, we employed the R packages Seurat and Monocle. Consensus clustering was further applied to identify the molecular classification. Immunohistochemical results from AOM and AOM/DSS models were used to validate macrophage expression. Subsequently, GSEA, ESTIMATE scores, prognosis, clinical characteristics, mutational burden, immune cell infiltration, and the variance in gene expression among different clusters were compared. We constructed a prognostic model and nomograms based on metabolic gene signatures identified through the MEGENA framework. RESULTS: We found two heterogeneous groups of M2 macrophages with various clinical outcomes through the evolutionary process. The prognosis of Cluster 2 was poorer. Further investigation showed that Cluster 2 constituted a metabolically active group while Cluster 1 was comparatively metabolically inert. Metabolic variations in M2 macrophages during tumor development are related to tumor prognosis. Additionally, Cluster 2 showed the most pronounced genomic instability and had highly elevated metabolic pathways, notably those associated with the ECM. We identified eight metabolic genes (PRELP, NOTCH3, CNOT6, ASRGL1, SRSF1, PSMD4, RPL31, and CNOT7) to build a predictive model validated in CRC datasets. Then, a nomogram based on the M2 risk score improved predictive performance. Furthermore, our study demonstrated that immune checkpoint inhibitor therapy may benefit patients with low-risk. DISCUSSION: Our research reveals underlying relationships between metabolic phenotypes and immunological profiles and suggests a unique M2 classification technique for CRC. The identified gene signatures may be key factors linking immunity and tumor metabolism, warranting further investigations.
Identification and Validation of Glycosylation-Related Genes in Obesity and MASH: Insights from Human Liver Samples and a High-Fat Diet Mouse Model.
Yu W, Chen J, Jin S … +2 more , Fan X, Cai X
Pharmgenomics Pers Med · 2024 · PMID 38983907 · Full text
BACKGROUND: Obesity is reaching epidemic proportions in the developed world. The biosynthesis and degradation of human glycoproteins take place at the highest level in the liver. However, the association between glycosyl...
BACKGROUND: Obesity is reaching epidemic proportions in the developed world. The biosynthesis and degradation of human glycoproteins take place at the highest level in the liver. However, the association between glycosylation and the factors affecting obesity and metabolism-associated steatohepatitis (MASH) is still unclear. MATERIALS AND METHODS: Gene expression data of liver samples from obese patients were retrieved from GSE83452 and GSE89632 databases. Difference analysis and machine learning were used to identify hub genes involved in glycosylation and associated with the response of weight loss treatment. A total of 7 glycosylation-related hub genes were identified and then subjected to correlation analysis, immune cells infiltration analysis and ROC (Receiver Operating Characteristic) analysis. We also evaluated the potential function of 7 hub genes in obesity patients. MASH mice were used to validate the glycosylation-related hub genes. RESULTS: A total of 25 overlapped glycosylation-related genes were identified by DEGs analysis. ACER2, STX17, ARF5, GPC4, ENTPD5, NANP, and DPY19L2 were identified as hub genes. Among these hub genes, ACER2, STX17, ARF5, and ENTPD5 were also differential expressed in MASH patients. ENTPD5 showed increased transcription in obese MASH mice. CONCLUSION: The current study identified seven glycosylation-related genes, ACER2, STX17, ARF5, GPC4, ENTPD5, NANP, and DPY19L2, that might play key roles in the development of obesity. ENTPD5 might play a key role in the development of MASH. These findings provide fresh perspectives for expanding the investigation of obesity and MASH.
Influence of Long Non-Coding RNAs on Human Oocyte Development.
Wang L, Li B, Cheng D
Pharmgenomics Pers Med · 2024 · PMID 38979513 · Full text
Recent research findings have highlighted the pivotal roles played by lncRNAs in both normal human development and disease pathogenesis. LncRNAs are expressed in oocytes and early embryos, and their expression levels cha...
Recent research findings have highlighted the pivotal roles played by lncRNAs in both normal human development and disease pathogenesis. LncRNAs are expressed in oocytes and early embryos, and their expression levels change dynamically once the embryonic genome is activated during early human embryonic development. Abnormal expression of lncRNAs was found in follicular fluid, granulosa cells and oocytes of patients, and these lncRNAs were related to cell proliferation and apoptosis, nuclear maturation and follicle development. The expression levels of some lncRNAs in cumulus cells demonstrate correlations with the quality of oocytes and early embryos. This paper aims to present a comprehensive overview of the influence of LncRNAs on the developmental process of human oocytes as well as their involvement in certain infertility-related diseases.
The Role of Pharmacogenomics Studies for Precision Medicine Among Ethiopian Patients and Their Clinical Implications: A Scoping Review.
Getahun KA, Angaw DA, Asres MS … +5 more , Kahaliw W, Petros Z, Abay SM, Yimer G, Berhane N
Pharmgenomics Pers Med · 2024 · PMID 38974617 · Full text
BACKGROUND: Pharmacogenomics research is currently revolutionizing treatment optimization by discovering molecular markers. Medicines are the cornerstone of treatment for both acute and chronic diseases. Pharmacogenomics...
BACKGROUND: Pharmacogenomics research is currently revolutionizing treatment optimization by discovering molecular markers. Medicines are the cornerstone of treatment for both acute and chronic diseases. Pharmacogenomics associated treatment response varies from 20% to 95%, resulting in from lack of efficacy to serious toxicity. Pharmacogenomics has emerged as a useful tool for therapy optimization and plays a bigger role in clinical care going forward. However, in Africa, in particular in Ethiopia, such studies are scanty and not generalizing. Therefore, the objective of this review was to outline such studies, generating comprehensive evidence and identify studied variants' association with treatment responses in Ethiopian patients. METHODS: The Joanna Briggs Institute's updated 2020 methodological guidelines for conducting and guidance for scoping reviews were used. We meticulously adhered to the systemic review reporting items checklist and scoping review meta-analyses extension. RESULTS: Two hundred twenty-nine possibly relevant studies were searched. These include: 64, 54, 21, 48 and 42 from PubMed, Scopus, Google Scholar, EMBASE, and manual search, respectively. Seventy-seven duplicate studies were removed. Thirty-nine papers were rejected with justification, whereas 58 studies were qualified for full-text screening. Finally 19 studies were examined. The primary pharmacogene that was found to have a significant influence on the pharmacokinetics of efavirenz was CYP2B6. Drug-induced liver injury has frequently identified toxicity among studied medications. CONCLUSION AND FUTURE PERSPECTIVES: Pharmacogenomics studies in Ethiopian populations are less abundant. The studies conducted focused on infectious diseases, specifically on HAART commonly efavirenz and backbone first-line anti-tuberculosis drugs. There is a high need for further pharmacogenomics research to verify the discrepancies among the studies and for guiding precision medicine. Systematic review and meta-analysis are also recommended for pooled effects of different parameters in pharmacogenomics studies.
Cuproptosis-Related lncRNA Predict Prognosis and Immune Response of LUAD.
Zhou Q, Liu Y, Gao Y … +3 more , Quan L, Wang L, Wang H
Pharmgenomics Pers Med · 2024 · PMID 38952778 · Full text
BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide, primarily due to lung adenocarcinoma (LUAD). However, the heterogeneity of programmed cell death results in varied prognostic and predictive outcom...
BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide, primarily due to lung adenocarcinoma (LUAD). However, the heterogeneity of programmed cell death results in varied prognostic and predictive outcomes. This study aimed to develop an LUAD evaluation marker based on cuproptosis-related lncRNAs. METHODS: First, transcriptome data and clinical data related to LUAD were downloaded from the Cancer Genome Atlas (TCGA), and cuproptosis-related genes were analyzed to identify cuproptosis-related lncRNAs. Univariate, LASSO, and multivariate Cox regression analyses were conducted to construct cuproptosis-associated lncRNA models. LUAD patients were categorized into high-risk and low-risk groups using prognostic risk values. Kaplan-Meier analysis, PCA, GSEA, and nomograms were employed to evaluate and validate the results. RESULTS: 7 cuproptosis-related lncRNAs were identified, and a risk model was created. High-risk tumors exhibited cuproptosis-related gene alterations in 95.54% of cases, while low-risk tumors showed alterations in 85.65% of cases, mainly involving TP53. The risk value outperformed other clinical variables and tumor mutation burden as a predictor of 1-, 3-, and 5-year overall survival. The cuproptosis-related lncRNA-based risk model demonstrated high validity for LUAD evaluation, potentially influencing individualized treatment approaches. Expression analysis of four candidate cuproptosis-related lncRNAs (AL606834.1, AL161431.1, AC007613.1, and LINC02835) in LUAD tissues and adjacent normal tissues revealed significantly higher expression levels of AL606834.1 and AL161431.1 in LUAD tissues, positively correlating with tumor stage, lymph node metastasis, and histopathological grade. Conversely, AC007613.1 and LINC02835 exhibited lower expression levels, negatively correlating with these factors. High expression of AL606834.1 and AL161431.1 indicated poor prognosis, while low expression of AC007613.1 and LINC02835 was associated with unfavorable outcomes. Univariate and multivariate analyses confirmed these lncRNAs as independent risk factors for LUAD prognosis. CONCLUSION: The 4 cuproptosis-related (lncRNAsAL606834.1, AL161431.1, AC007613.1, and LINC02835) can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.
The Correlation of Centromere Protein Q with Diagnosis and Prognosis in Hepatocellular Carcinoma.
He K, Xie MY, Gao XJ … +2 more , Wang H, Li JD
Pharmgenomics Pers Med · 2024 · PMID 38827182 · Full text
INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the major types of liver cancer. Previous studies have shown that the centromere protein family is associated with malignant biological behaviors such as HCC prolife...
INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the major types of liver cancer. Previous studies have shown that the centromere protein family is associated with malignant biological behaviors such as HCC proliferation. As a member of the centromere protein family, centromere protein Q (CENPQ) is closely associated with immunotherapy and immune cell infiltration in various tumors. However, the role and mechanism of CENPQ in HCC remain unclear. METHODS: Multiple public databases and RT-qPCR were used to study the expression of CENPQ in HCC. Based on TCGA data, the correlation between CENPQ and clinicopathological characteristics and prognosis of HCC patients was analyzed, and its diagnostic value was evaluated. The potential biological functions of CENPQ in HCC were explored by functional enrichment analysis of differentially expressed genes. The distribution of tumor-infiltrating immune cell types was assessed using single-sample GSEA, and immune checkpoint gene expression was analyzed using Spearman correlation. Subsequently, loss-of-function experiments were performed to determine the function of CENPQ on the cell cycle and proliferation of HCC cells in vitro. RESULTS: CENPQ was found highly expressed in HCC and correlated with weight, BMI, age, AFP, T stage, pathologic stage, histologic grade, and prothrombin time (all p < 0.05). ROC and Kaplan-Meier analyses indicated that CENPQ may be potentially used as a diagnostic marker for HCC (AUC = 0.881), and its upregulation is associated with decreased OS (p = 0.002), DSS (p < 0.001), and PFI (p = 0.002). Functional enrichment analysis revealed an association of CENPQ with biological processes such as immune cell infiltration, cell cycle, and hippo-merlin signaling deregulation in HCC. Furthermore, knockdown of CENPQ manifested in HCC cells with G0/1 phase cycle arrest and decreased proliferative capacity. CONCLUSION: CENPQ expression was higher in HCC tissues than in normal liver tissues. It was significantly associated with poor prognosis, immune cell infiltration, cell cycle, and proliferation. Therefore, CENPQ may become a promising prognostic biomarker for HCC patients.
Preliminary Study on Clinical Characteristics and Pathogenesis of Mutations Patients.
Ren Y, Luo X, Tong H … +4 more , Wang S, Yan J, Lin L, Chen Y
Pharmgenomics Pers Med · 2024 · PMID 38827181 · Full text
BACKGROUND: The IQ motif and Sec7 domain ArfGEF 2 (), an X-linked gene that encodes the BRAG1 protein, is a guanine nucleotide exchange factor for the ADP ribosylation factor (ARF) protein family in the small guanosine t...
BACKGROUND: The IQ motif and Sec7 domain ArfGEF 2 (), an X-linked gene that encodes the BRAG1 protein, is a guanine nucleotide exchange factor for the ADP ribosylation factor (ARF) protein family in the small guanosine triphosphate (GTP) binding protein. Mutations in this gene result in disorders such as intellectual disability (ID) and epilepsy. In this study, we analyze the clinical features of two patients with -mutation-related disease and discuss their possible pathogenesis. METHODS: The two patients were diagnosed with ID and epilepsy. Genetic testing was performed using whole-exome sequencing, and the three-dimensional protein structure was analyzed. UCSC Genome Browser was used to analyze the conservation of in different species. We compared expression in the proband families with that in a control group, as well as the expression of the postsynaptic identity protein 95 (PSD-95), synapse-associated protein 97 (SAP97), ADP ribosylation factor 6 (ARF-6), and insulin receptor substrate 53kDa () genes interacting with . RESULTS: We identified two semi-zygote mutations located in conserved positions in different species: an unreported mutation, C.3576C>A (p. Tyr1192*), and a known mutation, c.2983C>T (p. Arg995Trp). mutations resulted in significant changes in the predicted three-dimensional protein structure, while its expression in the two probands was significantly lower than that in the age-matched control group, and expression in proband 1 was lower than that in his family members. The expression levels of , and , which interact with , were also significantly different from those in the family members and age-matched healthy children. CONCLUSION: The clinical phenotype resulting from mutations can be explained by the significant decrease in its expression, loss of function of the mutant protein, and change in the expression of related genes. Our results provide novel insights into the molecular phenotype conferred by the variants.
16S rRNA Gene Sequencing of Gut Microbiota in Rheumatoid Arthritis Treated with 99Tc-MDP.
Huang Z, Chen C, Tan L … +3 more , Ling Y, Ma W, Zhang J
Pharmgenomics Pers Med · 2024 · PMID 38807628 · Full text
BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease with the main symptoms being joint swelling and pain. In severe cases, joint deformity or even complete loss of function occurs. Technetium methylene d...
BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease with the main symptoms being joint swelling and pain. In severe cases, joint deformity or even complete loss of function occurs. Technetium methylene diphosphonate (99Tc-MDP) is widely used for RA treatment in China, but there are no studies on the effects of 99Tc-MDP on intestinal flora. OBJECTIVE: To explore the effects of 99Tc-MDP treatment on the composition and function of the intestinal flora and to provide new information on the mechanism of 99Tc-MDP in RA treatment. METHODS: Stool samples from RA patients before and after 99Tc-MDP treatment were collected to form two groups (Before and After). Total genomic DNA of the samples was extracted for 16S rRNA gene sequencing. The altered composition of the intestinal flora, the key target bacteria regulated by 99Tc-MDP, and the pathways of action of 99 Tc-MDP were analyzed by bioinformatics. RESULTS: A total of 64 fresh stool samples were collected from 32 RA patients. Compared to the Before group, the After group showed increased Bacteroidetes abundance and decreased Firmicutes abundance. At the genus level, Prevotella increased whereas Escherichia decreased. Both α and β diversity analyses showed that 99Tc-MDP treatment did not affect gut microbial diversity in RA patients. LEfSe analyses and random forest analyses showed Bacteroidetes, Prevotella, Enterococcus, Escherichia and Ruminococcaceae were the main 99Tc-MDP regulating bacteria. Functional enrichment analysis revealed that the functional differences in gut flora of the two groups centered on Metabolism and Genetic Information Processing. CONCLUSION: This study revealed differences in the composition of the gut microbiota in RA patients before and after 99Tc-MDP treatment. The therapeutic effect of 99Tc MDP is mainly achieved through Bacteroidetes, Prevotella, and Enterococcus. Regulating metabolism and genetic information processing of gut flora may be the mechanism of 99Tc-MDP in treating RA.
An Aging-Related lncRNA Signature Establishing for Breast Cancer Prognosis and Immunotherapy Responsiveness Prediction.
Zhou Y, Yang Z, Zeng H
Pharmgenomics Pers Med · 2024 · PMID 38803444 · Full text
PURPOSE: Emerging evidence demonstrates the vital role of aging and long non-coding RNAs (lncRNAs) in breast cancer (BC) progression. Our study intended to develop a prognostic risk model based on aging-related lncRNAs (...
PURPOSE: Emerging evidence demonstrates the vital role of aging and long non-coding RNAs (lncRNAs) in breast cancer (BC) progression. Our study intended to develop a prognostic risk model based on aging-related lncRNAs (AG-lncs) to foresee BC patients' outcomes. PATIENTS AND METHODS: 307 aging-related genes (AGs) were sequenced from the TCGA project. Then, 697 AG-lncs were identified by the co-expression analysis with AGs. Using multivariate and univariate Cox regression analysis, and LASSO, 6 AG-lncs, including , and , were validated to compute the risk score and establish a risk signature. Expression levels of , and were higher in low-risk BC patients, whereas expression was higher in high-risk BC patients. In the training and testing set, high-risk patients performed shorter PFI, OS, and DFS than low-risk patients. RESULTS: Our risk signature had the highest concordance index among other established prognostic signatures and displayed ideal predictive ability for 1-, 3- and 5-year patient OS in the nomogram. Additionally, BC patients with different risk score levels showed different immune statuses and responses to immunotherapy via GSEA, ssGSEA, ESTIMATE algorithm, and TIDE algorithm analysis. Of note, the qRT-PCR analysis validated that these 6 AG-lncs expressed quite differentially in BC tissues at various clinical stages. CONCLUSION: The risk signature of 6 AG-lncs might offer a novel prognostic biomarker and promisingly enhance BC immunotherapy's effectiveness.
To Investigate the Influence of Smoking Cessation Intention and Common Downstream Variants of Gene on Large Artery Atherosclerotic Cerebral Infarction.
Yu L, Zhao Y
Pharmgenomics Pers Med · 2024 · PMID 38765789 · Full text
OBJECTIVE: To investigate the association of smoking cessation intention and single nucleotide polymorphism of gene with LAA-S in Han people in Hainan province. METHODS: A case-control study was conducted. Six single nu...
OBJECTIVE: To investigate the association of smoking cessation intention and single nucleotide polymorphism of gene with LAA-S in Han people in Hainan province. METHODS: A case-control study was conducted. Six single nucleotide polymorphisms (SNPS) of HDAC9 gene were genotyped by SNPscan genotyping technique in 248 patients with LAA-S and 237 controls in Hainan Han population. SNP loci (rs10227612, rs12669496, rs1548577, rs2074633, rs2526626, and rs2717344) were genotyped, and the genotype and allele frequencies were compared between the case and control group. At the same time, the distribution of smoking between the case and control group was compared, and the 3-year and 7-year follow-up smoking cessation between the case and control group was compared, so as to find out the effects of smoking cessation intention and HDAC9 SNP on LAA-S. RESULTS: (1) The GT genotype at rs10227612, GG genotype at rs2717344, and GA genotype at rs1548577 in the case group were significantly higher than those in the control group, and the differences were statistically significant. (2) There were significant differences in the distribution of smoking between the case and control group (P < 0.05), and there were significant differences in the smoking cessation after 3 years and 7 years of follow-up between the case and control group (P < 0.05). The intention to quit smoking was positively correlated with the incidence of LAA-S. CONCLUSION: (1) The rs10227612, rs1548577, rs2074633, rs2717344 of HDAC9 gene may be significantly related to atherosclerotic cerebral infarction of great arteries in Hainan Han population, while rs12669496 and rs2526626 may not be related. (2) According to the statistics of smoking in the case and control group, smoking was related to large artery atherosclerotic cerebral infarction, and the intention to quit smoking was a very important factor affecting the success of smoking cessation.
Evaluation of Genetic Variant and Its Lack of Association with Valproic Acid Plasma Concentrations Among Zhuang and Han Schizophrenia Patients in Guangxi.
Teng JM, Qin S, Lu D … +5 more , Gu Y, Tang SJ, Yan Q, Yao J, Zhang C
Pharmgenomics Pers Med · 2024 · PMID 38765788 · Full text
PURPOSE: To investigate the genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between genetic variants and standardized blood levels of V...
PURPOSE: To investigate the genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between genetic variants and standardized blood levels of Valproic Acid (VPA) in schizophrenic patients, and evaluate the effects of age, gender, and Body Mass Index (BMI) on standardized VPA blood concentrations. PATIENTS AND METHODS: Between February and December 2022, 192 Zhuang and Han schizophrenia patients treated with VPA were studied. Steady-state VPA concentrations were determined using homogeneous enzyme immunoassays, and *1, *2, and *3 loci via q-PCR. genotype distributions between Zhuang and Han groups in Nanning were compared using chi-square tests and contrasted with other ethnicities. Non-parametric tests analyzed VPA variations, identifying critical factors through multivariate stepwise regression. RESULTS: The study identified five genotypes at the *2 and *3 loci, with the *3/*3 genotype absent in both cohorts. The distribution in Guangxi Zhuang and Han mirrors, yet diverges significantly from Hui and Kazakh groups. Among 192 subjects, VPA blood levels remained consistent across metabolic types and ages 18-60 but varied significantly by gender. Multivariate analysis revealed gender and BMI as significant factors, overshadowing genotype and age. CONCLUSION: In Guangxi, genetic variants in Zhuang and Han schizophrenia patients demonstrate statistically indistinguishable allelic and metabolic distributions. Gender and BMI can influence standardized VPA blood concentrations in schizophrenia patients. However, in our study cohort, the genotype and age are not the primary determinants of standardized VPA blood levels.
Understanding Gene Involvement in Hepatocellular Carcinoma: Implications for Gene Therapy and Personalized Medicine.
Younis MA, Harashima H
Pharmgenomics Pers Med · 2024 · PMID 38737776 · Full text
Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side e...
Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side effects. Gene therapy, however, now offers hope for the treatment of many disorders previously considered incurable, and gene therapy is beginning to address many of the shortcomings of conventional therapies. Herein, we summarize the involvement of genes in the pathogenesis and prognosis of HCC, with a special focus on dysregulated signaling pathways, genes involved in immune evasion, and non-coding RNAs as novel two-edged players, which collectively offer potential targets for the gene therapy of HCC. Herein, the opportunities and challenges of HCC gene therapy are discussed. These include innovative therapies such as genome editing and cell therapies. Moreover, advanced gene delivery technologies that recruit nanomedicines for use in gene therapy for HCC are highlighted. Finally, suggestions are offered for improved clinical translation and future directions in this area of endeavor.
Association of the Reduced Function Met420del Polymorphism of SLC22A1 with Metformin-Induced Gastrointestinal Intolerance in Ethiopian Patients with Type 2 Diabetes Mellitus.
Degaga A, Sirgu S, Huri HZ … +6 more , Sim MS, Loganadan NK, Kebede T, Tegene B, Engidawork E, Shibeshi W
Pharmgenomics Pers Med · 2024 · PMID 38715682 · Full text
BACKGROUND: Despite its widespread use and favored profile, there are extensive variations in the treatment outcome of metformin therapy. Furthermore, studies reported that the inter-individual variability in the occurre...
BACKGROUND: Despite its widespread use and favored profile, there are extensive variations in the treatment outcome of metformin therapy. Furthermore, studies reported that the inter-individual variability in the occurrence of metformin treatment associated side effects were related to the differences in individual genetic profiles. Thus, this study aimed to evaluate whether the reduced function methionine deletion at codon 420 (M) variant of (rs72552763) is associated with metformin induced gastrointestinal intolerance in Ethiopian patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: A retrospective observational study was conducted on 47 T2DM patients on metformin treatment for <3 years to assess the association of (rs72552763) polymorphism with metformin induced gastrointestinal intolerance. Accordingly, 24 metformin tolerant and 23 metformin intolerant individuals with T2DM were recruited. Genotyping of rs72552763 was performed using TaqMan Drug Metabolism Enzyme Genotyping Assay and its association to metformin induced gastrointestinal intolerance was assessed based on switching to a new class of glucose lowering agents or failure to up titrate dose due to metformin induced gastrointestinal intolerance. Chi-square, logistic regression and Mann-Whitney statistical tests were used as appropriate. Statistical significance was set at p < 0.05. RESULTS: In our study, no significant association was observed between rs72552763 and metformin induced gastrointestinal intolerance. We found that the female gender and physical inactivity were risk factors for metformin gastrointestinal intolerance. CONCLUSION: Our study found that the M variant of (rs72552763) was not associated with metformin induced gastrointestinal intolerance in Ethiopian patients with T2DM. This is the study first to investigate the association of rs72552763 with metformin intolerance in the Ethiopian population with T2DM. However, the findings need to be cautiously interpreted given the relatively small sample size. In addition, a more complete investigation of variants would be required to fully assess the effect of the gene on metformin induced gastrointestinal intolerance as several variants with a more severe loss of function have been described.
Three Liquid-Liquid Phase Separation-Related Genes Associated with Prognosis in Glioma.
Lv L, Zhang X, Liu Y … +3 more , Zhu X, Pan R, Huang L
Pharmgenomics Pers Med · 2024 · PMID 38681062 · Full text
PURPOSE: Dysregulated liquid-liquid phase separation (LLPS) instigates tumorigenesis through biomolecular condensate dysfunction. However, the association between LLPS-associated genes and glioma remains underexplored. P...
PURPOSE: Dysregulated liquid-liquid phase separation (LLPS) instigates tumorigenesis through biomolecular condensate dysfunction. However, the association between LLPS-associated genes and glioma remains underexplored. PATIENTS AND METHODS: Differentially expressed genes (DEGs) of glioma were obtained from the GSE50161 dataset, including 34 glioma and 13 normal samples. We analyzed differentially expressed LLPS-related genes in glioma from public databases. These genes informed refined molecular subtyping on the TCGA-glioma dataset. CIBERSORT assessed immune cell infiltration across three subclusters. A prognostic model was devised using univariate and lasso Cox regressions on intersecting genes. Prognostic gene expression was validated in glioma cells via RT-qPCR. RESULTS: A total of 673 differentially expressed LLPS-associated genes were identified in glioma. Three distinct molecular subtypes (C1, C2, and C3) of glioma were obtained with a marked variance in the expression of immune checkpoint genes PD1 and PDL1. Differences in immune cell infiltration were observed across subtypes. In addition, a tri-gene prognostic signature (, and ) was derived with significant survival differences between high and low-risk groups. The prognostic model displayed impressive AUC values for 1, 3, and 5-year survival in both training and validation sets. Further analysis highlighted a notable correlation between the three prognostic genes and immune cells in glioma samples. Furthermore, we found the upregulation of TAGLN2 and IGF2BP2 and the downregulation of NTNG2 in glioma tumors and cells. CONCLUSION: This study innovatively uncovers the significant role of LLPS-related genes in glioma tumor grading and prognosis. The constructed tri-gene prognostic model holds promise for enhancing personalized prognosis assessments and optimizing immunotherapy strategies for glioma patients.
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