Identification of monocyte-related transcriptomic signature of peripheral blood mononuclear cells in type 1 diabetes.
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ABSTRACT:
SUBMITTER: Yin M
PROVIDER: S-EPMC9943828 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
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Identification of monocyte-related transcriptomic signature of peripheral blood mononuclear cells in type 1 diabetes.
Yin Min M Zhang Yan Y Huang Juan J Li Xinyu X Yu Haibo H Li Xia X
Chinese medical journal 20221105 21
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Project description:Autoimmune-mediated destruction of pancreatic islet β cells results in type 1 diabetes (T1D). Serum islet autoantibodies usually develop in genetically susceptible individuals in early childhood before T1D onset, with multiple islet autoantibodies predicting diabetes development. However, most at-risk children remain islet-antibody negative, and no test currently identifies those likely to seroconvert. We sought a genomic signature predicting seroconversion risk by integrating longitudinal peripheral blood gene expression profiles collected in high-risk children included in the BABYDIET and DIPP cohorts, of whom 50 seroconverted. Subjects were followed for 10 years to determine time of seroconversion. Any cohort effect and the time of seroconversion were corrected to uncover genes differentially expressed (DE) in seroconverting children. Gene expression signatures associated with seroconversion were evident during the first year of life, with 67 DE genes identified in seroconverting children relative to those remaining antibody negative. These genes contribute to T cell-, DC-, and B cell-related immune responses. Near-birth expression of ADCY9, PTCH1, MEX3B, IL15RA, ZNF714, TENM1, and PLEKHA5, along with HLA risk score predicted seroconversion (AUC 0.85). The ubiquitin-proteasome pathway linked DE genes and T1D susceptibility genes. Therefore, a gene expression signature in infancy predicts risk of seroconversion. Ubiquitination may play a mechanistic role in diabetes progression.
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Project description:BackgroundType 1 diabetes (T1D) is a T lymphocyte-mediated and B lymphocyte-assisted autoimmune disease. We aimed to identify abnormally expressed genes in peripheral blood mononuclear cells (PBMCs) of T1D and explore their possible molecular regulatory network.MethodsExpression datasets were downloaded from the Gene Expression Omnibus (GEO) database. Then, the differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRNAs) were identified, and functional enrichment and immune cell infiltration analysis were performed. The starBase, miRTarBase, TarBase, JASPAR, ENCODE, and TRRUST databases constructed the miRNA-mRNA-TF regulatory network. The ROC curves were plotted to evaluate the sensitivity and specificity of miRNAs and mRNAs.ResultA total of 216 DEGs directly or indirectly related to type I diabetes mellitus, natural killer cell-mediated cytotoxicity, Th1, and Th2 cell differentiation, and the IL-17 and TNF signaling pathways were obtained. The miRNA-mRNA-TF network indicates that miR-320a and SOX5 are the only miRNAs and TFs that both target ADM and RRAGD. The ROC curves showed that ADM (0.9375), RRAGD (0.8958), and hsa-mir-320a (0.9417) had high accuracy in T1D diagnosis.ConclusionThe constructed regulatory networks, including miR-320a/ADM/SOX5 and miR-320a/RRAGD/SOX5, may provide new insight into the mechanisms of development and progression in T1D.
| S-EPMC9087960 | biostudies-literature
Project description:Reference genes are obligatory for accurate normalization of mRNA transcript levels across samples and experimental conditions in Real Time-polymerase chain reaction (qRT-PCR) based quantitative gene expression assays. Selection of stably expressed reference genes is therefore crucial for ensuring reproducibility of such assays. However, there is a complete dearth of data on stability of commonly used reference genes in Peripheral Blood Mononuclear Cells (PBMCs) from Type 2 diabetes mellitus (T2DM) patients. We have evaluated the gene expression stability of 4 widely used reference genes (Beta-actin, ACTB; Peptidylprolyl Isomerase B, PPIB; Tyrosine 3 Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Zeta, YWHAZ; and Glyceraldehyde-3-Phosphate Dehydrogenase, GAPDH); in PBMCs from 39 T2DM patients and 47 normoglycemic (NGT) subjects. ACTB and YWHAZ were found to be the most stable genes in PBMCs from T2DM patients and therefore, can be recommended as suitable reference genes in similar contexts. GAPDH and PPIB expressions were not stable in PBMCs from T2DM patients. On using ACTB and YWHAZ as reference genes for measuring relative expression of GAPDH and PPIB in these subjects, relative GAPDH expression was found to be significantly lower in female T2DM patients, compared to female NGT subjects [GAPDH relative normalization unit (RNU): female T2DM (n = 19), median (Q1, Q3): 9.0 (8.1, 9.9); female NGT (n = 18): median (Q1, Q3): 10.1 (9.1, 11.0); P = 0.034]. Dysregulation of GAPDH in PBMCs from female T2DM patients could be associated with sex-specific differences in pathogenesis and outcomes of T2DM.
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Project description:BackgroundGBA mutations are the commonest genetic risk factor for Parkinson's disease (PD) and also impact disease progression.ObjectiveThe objective of this study was to define a biochemical profile that could distinguish GBA-PD from non-mutated PD.Methods29 GBA-PD, 37 non-mutated PD, and 40 controls were recruited; α-synuclein levels in plasma, exosomes, and peripheral blood mononuclear cells were analyzed, GCase and main GCase-related lysosomal proteins in peripheral blood mononuclear cells were measured.ResultsAssessment of plasma and exosomal α-synuclein levels did not allow differentiation between GBA-PD and non-mutated PD; conversely, measurements in peripheral blood mononuclear cells clearly distinguished GBA-PD from non-mutated PD, with the former group showing significantly higher α-synuclein levels, lower GCase activity, higher LIMP-2, and lower Saposin C levels.ConclusionWe propose peripheral blood mononuclear cells as an easily accessible and manageable model to provide a distinctive biochemical profile of GBA-PD, potentially useful for patient stratification or selection in clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC8247888 | biostudies-literature
Project description:BackgroundHepatitis B virus (HBV)-related liver disease induces liver damage by hepatic immune and inflammatory response. The association between aberrant peripheral blood mononuclear cell (PBMC) DNA methylation and progression of liver disease and fibrosis remains unclear.ResultsHere we applied Infinium 450 K BeadChip investigating PBMC genome-wide methylation profiling of 48 HBV-related liver disease patients including 24 chronic hepatitis B (CHB), 14 compensated liver cirrhosis (LC), and 10 decompensated liver cirrhosis (DLC). In total, there were 7888 differentially methylated CpG sites (36.06% hypermethylation, 63.94% hypomethylation) correlate with liver disease progression. LC was difficult to be diagnosed, intermediating between CHB and DLC. We used least absolute shrinkage and selection operator (LASSO)-logistic regression method to perform a LC predictive model. The predicted probability (P) of having LC was estimated by the combined model: P = 1/(1 - e-x), where X = 11.52 - 2.82 × (if AST within the normal range - 0.19 × (percent methylation of cg05650055) - 0.21 × (percent methylation of cg17149911 ). Pyrosequencing validation and confusion matrix analysis was used for internal testing, area under receiver operating characteristic curve (AUROC) of model was 0.917 (95% CI, 0.80-0.977). On the fibrosis progress, there were 1705 genes in LC compared with CHB, whose differentially methylated CpG sites loading within the "promoter" regions (including TSS1500, TSS200, 5'UTR, and the 1st exon of genes) subject into the enrichment analysis using Ingenuity Pathway Analysis (IPA). There were 113 enriched immune-related pathways indicated that HBV-related liver fibrosis progression caused epigenetic reprogramming of the immune and inflammatory response.ConclusionsThese data support idea that development of HBV-related chronic liver disease is linked with robust and broad alteration of methylation in peripheral immune system. CpG methylation sites serve as relevant biomarker candidates to monitor and diagnose LC, providing new insight into the immune mechanisms understanding the progression of HBV-related liver fibrosis and cirrhosis.
| S-EPMC7278209 | biostudies-literature
Project description:BackgroundThe onset and progression of type 1 diabetes mellitus (T1DM) is closely related to autoimmunity. Effective monitoring of the immune system and developing targeted therapies are frontier fields in T1DM treatment. Currently, the most available tissue that reflects the immune system is peripheral blood mononuclear cells (PBMCs). Thus, the aim of this study was to identify key PBMC biomarkers of T1DM.MethodsCommon differentially expressed genes (DEGs) were screened from the Gene Expression Omnibus (GEO) datasets GSE9006, GSE72377, and GSE55098, and PBMC mRNA expression in T1DM patients was compared with that in healthy participants by GEO2R. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) network analyses of DEGs were performed using the Cytoscape, DAVID, and STRING databases. The vital hub genes were validated by reverse transcription-polymerase chain reaction using clinical samples. The disease-gene-drug interaction network was built using the Comparative Toxicogenomics Database (CTD) and Drug Gene Interaction Database (DGIdb).ResultsWe found that various biological functions or pathways related to the immune system and glucose metabolism changed in PBMCs from T1DM patients. In the PPI network, the DEGs of module 1 were significantly enriched in processes including inflammatory and immune responses and in pathways of proteoglycans in cancer. Moreover, we focused on four vital hub genes, namely, chitinase-3-like protein 1 (CHI3L1), C-X-C motif chemokine ligand 1 (CXCL1), matrix metallopeptidase 9 (MMP9), and granzyme B (GZMB), and confirmed them in clinical PBMC samples. Furthermore, the disease-gene-drug interaction network revealed the potential of key genes as reference markers in T1DM.ConclusionThese results provide new insight into T1DM pathogenesis and novel biomarkers that could be widely representative reference indicators or potential therapeutic targets for clinical applications.
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Project description:Background and Objectives: Visceral obesity is associated with chronic low-grade inflammation that predisposes to metabolic syndrome. Indeed, infiltration of adipose tissue with immune-inflammatory cells, including 'classical' inflammatory M1 and anti-inflammatory 'alternative' M2 macrophages, causes the release of a variety of bioactive molecules, resulting in the metabolic complications of obesity. This study examined the relative expression of macrophage phenotypic surface markers, cholesterol efflux proteins, scavenger receptors, and adenosine receptors in human circulating peripheral blood mononuclear cells (PBMCs), isolated from patients with type 2 diabetes mellitus (T2DM), with the aim to phenotypically characterize and identify biomarkers for these ill-defined cells. Materials and Methodology: PBMCs were isolated from four groups of adults: Normal-weight non-diabetic, obese non-diabetic, newly diagnosed with T2DM, and T2DM on metformin. The mRNA expression levels of macrophage phenotypic surface markers (interleukin-12 (IL-12), C-X-C motif chemokine ligand 10 (CXCL10), C-C motif chemokine ligand 17 (CCL17), and C-C motif receptor 7 (CCR7)), cholesterol efflux proteins (ATP-binding cassette transporter-1 (ABCA1), ATP binding cassette subfamily G member 1 (ABCG1), and sterol 27-hydroxylase (CYP27A)), scavenger receptors (scavenger receptor-A (SR-A), C-X-C motif ligand 16 (CXCL16), and lectin-like oxidized LDL receptor-1 (LOX-1)), and adenosine receptors (adenosine A2A receptor (A2AR) and adenosine A3 receptor (A3R)) were measured using qRT-PCR. Results: In PBMCs from T2DM patients, the expression of IL-12, CCR7, ABCA1, and SR-A1 was increased, whereas the expression of CXCL10, CCL17, ABCG1,27-hydroxylase, LOX-1, A2AR and A3R was decreased. On the other hand, treatment with the antidiabetic drug, metformin, reduced the expression of IL-12 and increased the expression of 27-hydroxylase, LOX-1, CXCL16 and A2AR. Conclusions: PBMCs in the circulation of patients with T2DM express phenotypic markers that are different from those typically present in adipose tissue M1 and M2 macrophages and could be representative of metabolically activated macrophages (MMe)-like cells. Our findings suggest that metformin alters phenotypic markers of MMe-like cells in circulation.
| S-EPMC9787392 | biostudies-literature
Project description:Changes in cellular bioenergetics such as mitochondrial respiration and glycolysis may play a role in the pathogenesis of various diseases including type 1 diabetes (T1D). We used Seahorse extracellular flux technology to analyse the efficiency of glycolysis and mitochondrial oxidative phosphorylation in peripheral blood mononuclear cells (PBMCs) obtained from fresh blood samples from fifteen long-term T1D individuals with albuminuria (five females) with an average (±SD) age of 58 (±14) years and 15 age and sex-matched healthy non-diabetic controls. In T1D PBMCs, mitochondrial proton leak was higher (T1D: 21,3 ± 1,46 pmol/min; controls: 17,3 ± 1,24 pmol/min; p = 0,049) and glucose (5 mM) suppressed mitochondrial proton leak more than in healthy controls. Further, PBMCs from T1D individuals had higher glycolysis compared with healthy controls (T1D: 9,68 ± 0,94 mpH/min; controls: 7,07 ± 0,64 mpH/min; p = 0,032). Correlation analysis of circulating inflammatory factors identified Leukaemia Inhibitor factor 1 (LIF) being negatively correlated with PBMC glycolysis. Our results suggest that mitochondrial and glycolytic pathways of PBMCs from long-term T1D individuals with albuminuria might be dysfunctional, possibly due to increased cellular metabolic load and/or oxidative stress in which inflammatory factors could play a role.
| S-EPMC9803776 | biostudies-literature
Project description:Novel biomarkers of disease progression after type 1 diabetes onset are needed. We profiled peripheral blood (PB) monocyte gene expression in six healthy subjects and 16 children with type 1 diabetes diagnosed ?3 months previously and analyzed clinical features from diagnosis to 1 year. Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy control subjects, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose-adjusted HbA(1c) levels during the first year, compared with patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g., induction of HIF1A, DDIT3, DDIT4, and GRP78). Quantitative PCR (qPCR) of a 9-gene panel correlated with glycemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. A PB gene expression signature correlates with glycemic control in the first year after diabetes diagnosis and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and postonset and systemic stresses as contributors to innate immune function in type 1 diabetes.
| S-EPMC3331753 | biostudies-literature
Project description:OBJECTIVE: Novel biomarkers of disease progression after type 1 diabetes onset are needed. RESEARCH DESIGN AND METHODS: We profiled peripheral blood (PB) monocyte gene expression in 6 healthy subjects and 16 children with type 1 diabetes diagnosed ~3 months previously, and analyzed clinical features from diagnosis to 1 year. RESULTS: Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy controls, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose-adjusted HbA1c levels during the first year, compared to patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g. induction of HIF1A, DDIT3, DDIT4 and GRP78). qPCR quantitation of a 9-gene panel correlated with glycaemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. CONCLUSIONS: A PB gene expression signature correlates with glycaemic control in the first year after diabetes diagnosis, and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and post-onset, and systemic stresses as contributors to innate immune function in type 1 diabetes.
2012-06-01 | GSE33440 | GEO