Long term all-cause mortality after myocardial infarction with non-obstructed vs obstructed coronary artery disease: a meta-analysis of adjusted data.

BACKGROUND: The difference in the long-term outcomes of myocardial infarction in patients with non-obstructed coronary arteries (MINOCA) and patients with myocardial infarction with obstructed coronary artery disease (MI-CAD) is not clear. The current study aimed to pool adjusted data to compare long-term outcomes of MINOCA vs MI-CAD. METHODS: Electronic literature search of PubMed, Embase, CENTRAL, and Google Scholar databases was done for publications up to 18th June 2023. Only studies reporting multivariable-adjusted data with > 1 year of follow-up were included. RESULTS: Sixteen studies met the inclusion criteria. Our meta-analysis revealed no statistically significant difference in the risk of all-cause mortality between MINOCA and MI-CAD patients (HR: 0.90 95% CI 0.68, 1.19 I2 = 94% p = 0.48). Analysis of the limited data showed a reduced combined risk of all-cause mortality and MI (HR: 0.54 95% CI 0.39, 0.76 I2 = 72% p = 0.003) and major adverse cardiac events (MACE) (HR: 0.66 95% CI 0.51, 0.84 I2 = 51% p = 0.0009) in patients with MINOCA vs MI-CAD, and no difference in the risk of cardiovascular mortality (HR: 0.81 95% CI 0.54, 1.22 I2 = 0% p = 0.31) and readmission between the two groups (HR: 0.85 95% CI 0.61, 1.19 I2 = 90% p = 0.35). CONCLUSION: A pooled analysis of adjusted outcomes from the available studies indicated that MINOCA and MI-CAD patients have similar long-term all-cause mortality risk. Our conclusions on the risk of cardiovascular mortality, MACE and readmission rates need to be taken with caution due to a lack of adequate studies. Further research is needed to strengthen the evidence on this important subject.

Increased expression of ficolin-1 is associated with airway obstruction in asthma.

BACKGROUND: The activated complement cascade is involved in asthmatic airway inflammation. Ficolins are essential for innate immunity and can activate the complement lectin pathway. Despite this, the significance of ficolins in asthma has yet to be determined. This study aimed to explore the presence of ficolins in individuals with asthma and to determine the relationship between ficolins and clinical characteristics. METHODS: For the study, 68 asthmatic patients and 30 healthy control subjects were recruited. Enzyme-linked immunosorbent assay was used to determine plasma ficolin-1, ficolin-2, and ficolin-3 concentrations both before and after inhaled corticosteroid (ICS) therapy. Further, the associations of plasma ficolin-1 level with pulmonary function and asthma control questionnaire (ACQ) score were examined in the asthma patients. RESULTS: Patients with asthma exhibited significantly elevated plasma ficolin-1 levels (median, 493.9 ng/mL; IQR, 330.2-717.8 ng/mL) in comparison to healthy controls (median, 330.6 ng/mL; IQR, 233.8-371.1 ng/mL). After ICS treatment, plasma ficolin-1 (median, 518.1 ng/mL; IQR, 330.2-727.0 ng/mL) in asthmatic patients was significantly reduced (median, 374.7 ng/mL; IQR, 254.8-562.5 ng/mL). Additionally, ficolin-1 expressions in plasma were significantly correlated with pulmonary function parameters and ACQ score in asthmatic patients. Asthma patients with higher plasma ficolin-1 levels demonstrated poorer lung function than those with lower plasma ficolin-1 levels. CONCLUSIONS: The results revealed that asthmatic patients had higher plasma ficolin-1 concentrations, which decreased after ICS treatment and were linked to their lung function, implying a potential involvement of ficolin-1 in asthma pathogenesis.

Genetic Programs Between Steroid-Sensitive and Steroid-Insensitive Interstitial Lung Disease.

The effectiveness of corticosteroids (GCs) varies greatly in interstitial lung diseases (ILDs). In this study, we aimed to compare the gene expression profiles of patients with cryptogenic organizing pneumonia (COP), idiopathic pulmonary fibrosis (IPF), and non-specific interstitial pneumonia (NSIP) and identify the molecules and pathways responsible for GCs sensitivity in ILDs. Three datasets (GSE21411, GSE47460, and GSE32537) were selected. Differentially expressed genes (DEGs) among COP, IPF, NSIP, and healthy control (CTRL) groups were identified. Functional enrichment analysis and protein-protein interaction network analysis were performed to examine the potential functions of DEGs. There were 128 DEGs when COP versus CTRL, 257 DEGs when IPF versus CTRL, 205 DEGs when NSIP versus CTRL, and 270 DEGs when COP versus IPF. The DEGs in different ILDs groups were mainly enriched in the inflammatory response. Further pathway analysis showed that "interleukin (IL)-17 signaling pathway" (hsa04657) and "tumor necrosis factor (TNF) signaling pathway" were associated with different types of ILDs. A total of 10 genes associated with inflammatory response were identified as hub genes and their expression levels in the IPF group were higher than those in the COP group. Finally, we identified two GCs' response-related differently expressed genes (FOSL1 and DDIT4). Our bioinformatics analysis demonstrated that the inflammatory response played a pathogenic role in the progression of ILDs. We also illustrated that the inflammatory reaction was more severe in the IPF group compared to the COP group and identified two GCs' response-related differently expressed genes (FOSL1 and DDIT4) in ILDs.

Cholesterol Metabolism in Cancer and Cell Death.

Significance: Cholesterol is a type of lipid that plays a crucial role in building and maintaining cell membranes, producing certain hormones, and aiding in digestion. The two main types of cholesterol are low-density lipoprotein and high-density lipoprotein, and maintaining a healthy balance between them is essential for cellular function and organism health. Recent Advances: Cholesterol metabolism is a complex and dynamic process that involves biosynthesis, uptake, efflux, transport, and esterification. Disruptions in cholesterol metabolism are implicated in all stages of cancer, contributing to drug resistance, immune evasion, and autophagy dysfunction. These disruptions have also been linked to various types of regulated cell death, such as apoptosis, anoikis, lysosome-dependent cell death, pyroptosis, NETosis, necroptosis, entosis, ferroptosis, alkaliptosis, immunogenic cell death, and paraptosis. Critical Issues: Understanding the complex interplay between cholesterol metabolism and cell death and their impact on cancer development and progression is still a significant challenge. In addition, there is currently a lack of reliable biomarkers that can accurately reflect cholesterol metabolism dysregulation in cancer. Future Directions: To develop more specific and effective cholesterol metabolism-targeted therapies, a better understanding of the mechanisms by which cholesterol metabolism dysregulation contributes to cell death and cancer progression is needed. In addition, improving the accuracy and reliability of biomarkers will be crucial for monitoring and diagnosing cholesterol-related cancer subtypes and evaluating the effectiveness of cholesterol metabolism-targeted therapies. These efforts will require ongoing research and collaboration among multidisciplinary teams of scientists and clinicians. Antioxid. Redox Signal. 39, 102-140.

Sphingosine-1-Phosphate Receptor 4 Attenuates Neutrophilic Airway Inflammation in Experimental Asthma via Repressing Proinflammatory Macrophage Activation.

Patients with eosinophilic asthma react well to conventional treatment of asthma while individualized therapy for non-eosinophilic endotypes have yet to be developed. Dysregulated sphingosine metabolites are associated with the pathophysiology of different asthma endotypes with their receptors involved. However, whether the sphingosine-1-phosphate receptor 4 (S1PR4) contributes to disease progression of asthma remains underappreciated. In this study, we demonstrated that sphingosine metabolism was disturbed in asthma while it could not be used to distinguish between different endotypes of asthma. S1PR4, a vital receptor of bioactive sphingosine metabolites and mainly expressed in macrophages, exhibited lower expression both in patients and experimental mice with neutrophilic airway inflammation. Additionally, S1pr4 deficiency aggravated the OVA/LPS-induced pulmonary inflammation in mice along with a significant up-regulation in M1 macrophage activation. Mechanistic studies showed that S1PR4 was strongly connected to bioactive oxylipins concurrent with bounding to formyl peptide receptor 2 to influence the phosphorylation of JNK and contributed to the macrophage M1 program, which in turn secreted amounts of inflammatory cytokines associated to the inflammatory response of neutrophilic asthma. Furthermore, treating mice with S1PR4 agonist CYM50308 was characterized by less pulmonary inflammatory infiltration. Our research indicates S1PR4 a promising therapeutic target for non-eosinophilic phenotypes of asthma.

Dach1 deficiency drives alveolar epithelium apoptosis in pulmonary fibrosis via modulating C-Jun/Bim activity.

Dysregulation of type II alveolar epithelial cells (AECII) plays a vital role in the initiation and development of pulmonary fibrosis (PF). Dachshund homolog 1 (Dach1), frequently expressed in epithelial cells with stem cell potential, controls cell proliferation, apoptosis, and cell cycle in tissue development and disease process. In this study, we demonstrated that the lungs collected from PF patients and mice of Bleomycin (BLM)-treated were characterized by low expression of Dachshund homolog 1 (Dach1), especially in AECII. Dach1 deficiency in the alveolar epithelium exacerbated PF in BLM-treated mice, as evidenced by reduced pulmonary function and increased expression of fibrosis markers. Rather, treatment with lung-specific overexpression of Dach1 alleviated histopathological damage, lung compliance, and fibrosis in BLM-treated mice. Moreover, overexpression of Dach1 could inhibit epithelial apoptosis in vitro. Conversely, primary AECII with Dach1 depletion were more susceptible to apoptosis in vivo. Mechanically, Dach1 combined with C-Jun protooncogene selectively bound to the promoter of B-cell lymphoma 2 interacting mediators of cell death (Bim), by which it repressed Bim expression and alleviated epithelial apoptosis. Taken together, our data support that Dach1 in AECII contributes to the progression of PF and may be a viable target for the prevention and treatment of PF.

Club cell 10-kDa protein (CC10) as a surrogate for identifying type 2 asthma phenotypes.

Club cell 10-kDa protein (CC10) is a documented biomarker for airway obstructive diseases. Primarily produced by nonciliated club cells in the distal airway and in nasal epithelial cells, CC10 suppresses Th2 cell differentiation and Th2 cytokine production. In this study, we aimed to determine whether CC10 can also be used as an alternative biomarker for identifying Type 2 (T2) asthma.74 patients with asthma, and 24 healthy controls were enrolled in the study. T2-high asthma was defined as elevation in two or more biomarkers, such as sputum eosinophilia ≥ 3%, high blood eosinophils ≥ 300/µL, or high FeNO ≥ 30 ppb. T2-low asthma was defined as no elevation in biomarkers. Enzyme-linked immunosorbent assay (ELISA) was used to assess the CC10 levels in plasma.The plasma CC10 level in patients with T2-high asthma was lower than that of patients with T2-low asthma and healthy controls (P < 0.05). To distinguish between T2-high and T2-low phenotype in patients with asthma, a receiver-operating characteristic (ROC) analysis was performed. It showed a sensitivity of 58.1% and specificity of 78.0% when using 22.74 ng/ml of plasma CC10. Correlation analysis indicated that the plasma CC10 level was inversely correlated with sputum eosinophil, blood eosinophil, and FeNO, and positively correlated with log PD20. However, no correlation with sputum neutrophil percentages, macrophage percentages, IgE, or lung function was found.Plasma CC10 is potentially useful in predicting T2-high and T2-low asthma. Lower plasma CC10 was associated with enhanced airway hyperresponsiveness, and Type 2 inflammation.

Identification of Genetic Signature Associated With Aging in Pulmonary Fibrosis.

Background: Aging is a strong risk factor and an independent prognostic factor in idiopathic pulmonary fibrosis (IPF). In this study, we aimed to conduct a comprehensive analysis based on gene expression profiles for the role of aging in pulmonary fibrosis. Method: Four datasets (GSE21411, GSE24206, GSE47460, and GSE101286) for patients with clinical IPF and one dataset for bleomycin (BLM)-induced pulmonary fibrosis (BIPF) mouse model (GSE123293) were obtained from Gene Expression Omnibus (GEO). According to different age ranges, both patients with IPF and BIPF mice were divided into young and aged groups. The differently expressed genes (DEGs) were systemically analyzed using Gene Ontology (GO) functional, Kyoto Encyclopedia of Genes and Genomes (KEGG), and hub genes analysis. Finally, we verified the role of age and core genes associated with age in vivo. Results: Via the expression profile comparisons of aged and young patients with IPF, we identified 108 aging-associated DEGs, with 21 upregulated and 87 downregulated. The DEGs were associated with "response to glucocorticoid," "response to corticosteroid," and "rhythmic process" in GO biological process (BP). For KEGG analysis, the top three significantly enriched KEGG pathways of the DEGs included "IL-17 signaling pathway," "Mineral absorption," and "HIF-1-signaling pathway." Through the comparisons of aged and young BIPF mice, a total number of 778 aging-associated DEGs were identified, with 453 genes increased and 325 genes decreased. For GO and KEGG analysis, the DEGs were enriched in extracellular matrix (ECM) and collagen metabolism. The common DEGs of patients with IPF and BIPF mice were enriched in the BP category, including "induction of bacterial agglutination," "hyaluronan biosynthetic process," and "positive regulation of heterotypic cell-cell adhesion." We confirmed that aged BIPF mice developed more serious pulmonary fibrosis. Finally, the four aging-associated core genes (Slc2a3, Fga, Hp, and Thbs1) were verified in vivo. Conclusion: This study provides new insights into the impact of aging on pulmonary fibrosis. We also identified four aging-associated core genes (Slc2a3, Fga, Hp, and Thbs1) related to the development of pulmonary fibrosis.

Rapid detection of human heart-type fatty acid-binding protein in human plasma and blood using a colloidal gold-based lateral flow immunoassay.

The incidence of acute myocardial infarction (AMI) is currently increasing. Early detection is important for the treatment and prognosis of patients with AMI. Heart-type fatty acid-binding protein (H-FABP) may be used as an early marker of AMI due to its high sensitivity, specificity and prognostic value. Therefore, in the present study, H-FABP was used as a biomarker in a double-antibody sandwich method and colloidal gold-based lateral flow immunoassay to develop a rapid detection kit for H-FABP with a processing time of only 5 min. The sensitivity of the kit in plasma and whole blood was 1 ng/ml and this method had good specificity, exhibiting no cross-reaction with cardiac troponin I, myoglobin or creatine kinase-Mb. The kits had good shelf life and stability, as they were able to be stored at 40˚C for 30 days. A total of 12 clinical samples were collected for detection and the coincidence rate with the ELISA method was up to 91.67%. Therefore, the present study provided a simple, rapid and economical early-detection in-home testing kit.

Development and Validation of the Prognostic Index Based on Inflammation-Related Gene Analysis in Idiopathic Pulmonary Fibrosis.

Background: Historically, idiopathic pulmonary fibrosis (IPF) was considered a chronic inflammation disorder, but this conception was reassessed in the past decades. Our understanding of the role of inflammation in IPF and its association with clinical significance remained incomplete. Methods: We downloaded mRNA expression data of peripheral blood mononuclear cells (PBMCs) from the Gene Expression Omnibus (GEO) repository. Inflammation-related genes (IRGs) expressed differently between IPF and control (CTRL) were determined. In this study, we systemically analyzed the expression of differently expressed IRGs by comprehensive bioinformatic analysis, and then investigated their potential prognostic values. The related prognostic gene expressions were verified in our cohort. Results: 110 differently expressed IRGs were identified in this study, including 64 upregulated and 46 downregulated IRGs. Three IRGs (S100A12, CCR7, and TNFSF4) were identified as potential hub genes for prognosis. Those genes were subsequently subjected to the construction of the prognostic models. In the results, IPF patients categorized as high risk demonstrated a poor overall survival rate compared to patients categorized as low risk. Based on this prognostic model, the area under the curve (AUC) of the survival-dependent receiver operator characteristic (ROC) for 1-year, 2-year, and 3-year survival rates was 0.611, 0.695, and 0.681, respectively, in the GSE28042 cohort. These observations were validated in the GSE27957 cohort, confirming the good prognostic effect of this model. The expression of the three genes was validated in our cohort. We also conducted a nomogram based on the three IRGs' mRNA for quantitative IPF prognosis. Conclusion: Three IRGs (S100A12, CCR7, and TNFSF4) were identified as potential markers for the prognosis of IPF.

Association Analysis of Variants of DSCAM and BACE2 With Hirschsprung Disease Susceptibility in Han Chinese and Functional Evaluation in Zebrafish.

Hirschsprung disease (HSCR) has a higher incidence in children with Down syndrome (DS), which makes trisomy 21 a predisposing factor to HSCR. DSCAM and BACE2 are close together on the HSCR-associated critical region of chromosome 21. Common variants of DSCAM and rare variants of BACE2 were implicated to be associated with sporadic HSCR. However, the submucosal neuron defect of DS mouse model could not be rescued by normalization of Dscam. We aimed to explore the contribution of DSCAM and BACE2 to the development of the enteric nervous system (ENS) and HSCR susceptibility. We genotyped 133 tag single-nucleotide polymorphisms (SNPs) in DSCAM and BACE2 gene region in 420 HSCR patients and 1,665 controls of Han Chinese. Expression of DSCAM and BACE2 homologs was investigated in the developing gut of zebrafish. Overexpression and knockdown of the homologs were performed in zebrafish to investigate their roles in the development of ENS. Two DSCAM SNPs, rs430255 (P Addtive = 0.0052, OR = 1.36, 95% CI: 1.10-1.68) and rs2837756 (P Addtive = 0.0091, OR = 1.23, 95% CI: 1.05-1.43), showed suggestive association with HSCR risk. Common variants in BACE2 were not associated with HSCR risk. We observed dscama, dscamb, and bace2 expression in the developing gut of zebrafish. Knockdown of dscama, dscamb, and bace2 caused a reduction of enteric neurons in the hindgut of zebrafish. Overexpression of DSCAM and bace2 had no effects on neuron number in the hindgut of zebrafish. Our results suggested that common variation of DSCAM contributed to HSCR risk in Han Chinese. The dysfunction of both dscams and bace2 caused defects in enteric neuron, indicating that DSCAM and BACE2 might play functional roles in the occurrence of HSCR. These novel findings might shed new light on the pathogenesis of HSCR.

Clinical characteristics and predictors of mortality in young adults with severe COVID-19: a retrospective observational study.

BACKGROUND AND OBJECTIVE: Little is yet known whether pathogenesis of COVID-19 is different between young and elder patients. Our study aimed to investigate the clinical characteristics and provide predictors of mortality for young adults with severe COVID-19. METHODS: A total of 77 young adults with confirmed severe COVID-19 were recruited retrospectively at Tongji Hospital. Clinical characteristics, laboratory findings, treatment and outcomes were obtained from electronic medical records. The prognostic effects of variables were analyzed using logistic regression model. RESULTS: In this retrospective cohort, non-survivors showed higher incidence of dyspnea and co-existing laboratory abnormalities, compared with young survivals in severe COVID-19. Multivariate logistic regression analysis showed that lymphopenia, elevated level of d-dimer, hypersensitive cardiac troponin I (hs-CTnI) and high sensitivity C-reactive protein (hs-CRP) were independent predictors of mortality in young adults with severe COVID-19. Further analysis showed that severely young adults with two or more factors abnormalities above would be more prone to death. The similar predictive effect of above four factors had been observed in all-age patients with severe COVID-19. CONCLUSION: Lymphopenia, elevated level of d-dimer, hs-CTnI and hs-CRP predicted clinical outcomes of young adults with severe COVID-19.

Common variation of the NSD1 gene is associated with susceptibility to Hirschsprung's disease in Chinese Han population.

BACKGROUND: Hirschsprung's disease (HSCR) is the most common congenital cause of intestinal obstruction in children. Sotos syndrome (SoS) is an overgrowth disorder with constipation and sometimes accompanied by HSCR. NSD1 gene mutation is the main cause of SoS. We aimed to investigate association of NSD1 common single nucleotide polymorphisms (SNPs) with HSCR susceptibility in Chinese Han population. METHOD: We genotyped 15 SNPs encompassing NSD1 gene region in 420 HSCR patients and 1665 controls on Fludigm EP1 platform. Association analysis was performed between cases and controls. RESULT: Rs244709 was the most associated SNP with HSCR susceptibility of the sample set (PAllelic = 9.69 × 10-5, OR = 1.37, 95% CI: 1.17-1.61). Gender stratification analysis revealed that NSD1 SNPs were associated with HSCR in males, but not in females. The nonsynonymous coding SNP rs28932178 in NSD1 exon 5 represented the most significant signal in males (PAllelic = 6.43 × 10-5, OR = 1.42, 95% CI: 1.20-1.69). The associated SNPs were expression quantitative trait loci (eQTLs) of nearby genes in multiple tissues. NSD1 expression levels were higher in aganglionic colon tissues than ganglionic tissues (P = 3.00 × 10-6). CONCLUSION: NSD1 variation conferred risk to HSCR in males, indicating SoS and HSCR may share common genetic factors. IMPACT: This is the first study to reveal that NSD1 variation conferred risk to Hirschsprung's disease susceptibility in males of Chinese Han population, indicating Sotos syndrome and Hirschsprung's disease may share some common genetic background. This study indicates more attention should be paid to the symptom of constipation in patients with Sotos syndrome. Our results raise questions about the role of NSD1 in the development of enteric nervous system and the pathogenesis of Hirschsprung's disease.

Revealing the role of glycerophospholipid metabolism in asthma through plasma lipidomics.

Lipid mediators play an essential role in the pathogenesis of asthma. Many studies on the differential expression of sphingolipids and fatty acid exist, but relatively few concerned about glycerophospholipid (GP) metabolites in asthma. Here, plasma samples from 20 healthy controls and 24 asthmatic patients were collected and analyzed. High-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) revealed that 29 GPs were identified and relatively quantified as differential metabolites for discriminating asthma patients and healthy subjects, consisting of six major subclasses of GPs. Moreover, a significant relevance was found between the selected metabolites and diagnostic and prognostic indicators of asthma. Remarkably, in subgroup analyses, plasma phosphatidic acid (PA), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE) levels were higher in patients with eosinophilic asthma than non-eosinophilic asthma. Receiver-operating characteristic curve analysis revealed that the power of plasma PA and PG levels to distinguish between asthmatic patients and healthy subjects was strong (all areas under the curves > 0.9; P < 0.05). Our study characterized circulating GP metabolites in patients with asthma and explored their clinical relevance which may help to develop reliable biomarkers for early and accurate diagnosis based on lipid metabolites and provide novel insight into the role of GPs in asthma.

Pentraxin 3 promotes airway inflammation in experimental asthma.

BACKGROUND: Pentraxin 3 (PTX3) regulates multiple aspects of innate immunity and tissue inflammation. Recently, it has been reported that PTX3 deficiency enhances interleukin (IL)-17A-dominant pulmonary inflammation in an ovalbumin (OVA)-induced mouse asthma model. However, whether PTX3 treatment would provide protection against allergic airway inflammation has not been clearly elucidated. The goal of this study was to further investigate the effect of recombinant PTX3 administration on the phenotype of asthma. METHODS: C57BL/6 J mice were sensitized and challenged with OVA to induce eosinophilic asthma model, as well as sensitized with OVA plus LPS and challenged with OVA to induce neutrophilic asthma model. We evaluated effect of recombinant PTX3 on asthma phenotype through both asthma models. The bronchoalveolar lavage fluid (BALF) inflammatory cells and cytokines, airway hyperresponsiveness, and pathological alterations of the lung tissues were assessed. RESULTS: In both eosinophilic and neutrophilic asthma models, PTX3 treatment provoked airway hyperresponsiveness, concomitant with increased inflammatory cytokines IL-4, IL-17, eotaxin, and transforming growth factor (TGF)-ß1 and aggravated airway accumulation of inflammatory cells, especially eosinophils and neutrophils. In histological analysis of the lung tissue, administration of PTX3 promoted inflammatory cells infiltration, mucus production, and collagen deposition. In addition, PTX3 also significantly enhanced STAT3 phosphorylation in lung tissue. CONCLUSION: Our results show that exogenous PTX3 can exacerbate multiple asthmatic features by promoting both eosinophils and neutrophils lung infiltration and provide new evidence to better understand the complex role of PTX3 in allergic airway inflammation.

Association of Variants in PLD1, 3p24.1, and 10q11.21 Regions With Hirschsprung's Disease in Han Chinese Population.

Background and Aims: Hirschsprung's disease (HSCR) is a rare genetically heterogeneous congenital disorder. A recent study based on whole genome sequencing demonstrated that common variants at four novel loci, which contained two intronic variants on CASQ2 and PLD1, and intergenic variants located between SLC4A7 and EOMES at 3p24.1, and between LINC01518 and LOC283028 at 10q11.21, were associated with HSCR susceptibility. To validate these associations with HSCR susceptibility, we performed a case-control study in a Han Chinese sample set. Methods: We selected four previously identified single nucleotide polymorphisms (SNPs) for replication, along with tag SNPs to cover the four associated regions. In total, 61 SNPs were genotyped in 420 HSCR patients and 1,665 healthy controls from the Han Chinese population. Results: None of the 14 tag SNPs in the CASQ2 gene region, including the previously associated rs9428225, showed an association with HSCR. Among the 24 tag SNPs from the SLC4A7-EOMES region at 3p24.1, rs2642925 [odds ratio (OR) = 1.41, 95% confidence interval (95% CI) = 1.10-1.79; P Additive = 0.007] and the previously associated SNP rs9851320 showed a suggestive association (OR = 1.22, 95% CI = 1.01-1.47; P Additive = 0.042). A non-synonymous SNP, rs2287579, in PLD1 showed a suggestive association with HSCR susceptibility (OR = 1.71, 95% CI = 1.18-2.46; P Additive = 0.004). Additionally, the previously associated PLD1 SNP rs12632766 showed a suggestive significance (OR = 1.20, 95% CI = 1.01-1.42, P Additive = 0.038). In the LINC01518-LOC283028 region at 10q11.21, three SNPs meet the study-wide significance threshold. Rs17153309 was the most associated SNP (OR = 1.60, 95% CI = 1.34-1.90; P Additive = 1.13 × 10-7). The previously associated SNP rs1414027 also showed significant association (OR = 1.43, 95% CI = 1.20-1.70, P Additive = 3.92 × 10-5). Two associated SNPs at 10q11.21 (rs1414027 and rs624804) were expression quantitative trait loci in digestive tract tissues from GTEx databases. Conclusions: Our results confirmed that variants of the LINC01518-LOC283028 region were associated with HSCR in the Han Chinese population. Additionally, the susceptibility of SNPs in the LINC01518-LOC283028 region were associated with the expression levels of nearby genes. These results provide new insight into the pathogenesis of HSCR.

LncRNA HCG18 is critical for vascular smooth muscle cell proliferation and phenotypic switching.

Previous studies have shown that some specific long non-coding RNAs are dysregulated in vascular walls and abnormally expressed in vascular disease. LncRNA HLA complex group 18 (HCG18) is a member of the HLA complex group, which has been rarely investigated in human diseases. In this study, we aimed to investigate the role of HCG in vascular smooth muscle cells. HCG18 was over-expressed by adenovirus transfection and knocked down in vascular smooth muscle cells by shRNA. Cell proliferation was detected by CCK-8 assays. Flow cytometry was employed to test the impacts of HCG18 on vascular smooth muscle apoptotic cells. The expression of associated genes in protein and mRNA levels was detected by western blotting, immunofluorescence and qRT-PCR. The interactions between HCG18 and fused in sarcoma (FUS) were confirmed by RNA EMSA and RIP assays. The expression of serum HCG18 was decreased in hypertensive patients and PDGF-BB-treated vascular smooth muscle cells. HCG18 inhibited proliferation and induced apoptotic cells in vascular smooth muscle cells. In addition, we also found that HCG18 can inhibit vascular smooth muscle cell phenotypic switching from a contractile to a secretory phenotype. Finally, our results showed that HCG18 enhanced apoptotic cells by directly binding with FUS. Our findings reveal that HCG18 is involved in the regulation of proliferation, apoptosis and the expression levels of markers of the contractile and synthetic phenotype.

Common variants of NRG1 and ITGB4 confer risk of Hirschsprung disease in Han Chinese population.

BACKGROUND: Hirschsprung disease (HSCR) is a neurodevelopmental disorder with a strong genetic component. Common variants of NRG1 contributed to HSCR risk in Asians, and rare variants of ERBB2 and ITGB4 were found to be associated with HSCR. ERBB2 and ITGB4 are partners of Nrg1/ErbB pathway, which is important in HSCR pathogenesis. We aimed to investigate whether common variants in NRG1, ERBB2 and ITGB4 were associated with HSCR in Chinese Han population. METHODS: We genotype 17 single nucleotide polymorphisms (SNPs) of NRG1, ERBB2 and ITGB4 in 420 HSCR patients and 1665 controls, and performed association analysis. RESULTS: We validated associations of two NRG1 SNPs rs7835688 (PAllelic = 2.2 × 10-20, OR = 2.21, 95%CI = 1.86-2.62) and rs16879552 (PAllelic = 5.6 × 10-9, OR = 1.57, 95%CI = 1.35-1.83) with risk to HSCR. SNP rs3744000 located 5' upstream of ITGB4 showed association with HSCR (PAllelic = 2.4 × 10-3, OR = 1.27, 95%CI = 1.09-1.49). Four SNPs of ERBB2 exhibited no association. CONCLUSIONS: Our results suggested that common variation of ITGB4 and NRG1 conferred risk to HSCR in Chinese Han population, which further highlighted Nrg-1/ErbB pathway involving in the pathogenesis of HSCR.

Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility.

Biliary atresia (BA) is an idiopathic neonatal cholestatic disease. Recent genome-wide association study (GWAS) revealed that common variation of ADD3, GPC1, ARF6, and EFEMP1 gene was associated with BA susceptibility. We aimed to evaluate the association of these genes with BA in Chinese population. Twenty single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 340 BA patients and 1,665 controls. Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP (PAllele = 3.23×10-6). Meta-analysis of published data and current data indicated that rs17095355 was associated with BA susceptibility in Asians and Caucasians. Three associated SNPs were expression quantitative trait loci (eQTL) for ADD3. Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1. Haplotype harboring these two SNPs almost reached the study-wide significance (P = 0.0035). No association for ARF6 and EFEMP1 was found with BA risk in the current population. Our study validated associations of ADD3 and GPC1 SNPs with BA risk in Chinese population and provided evidence of epistatic contributions of genetic factors to BA susceptibility.

MiR-208a aggravates H2O2-induced cardiomyocyte injury by targeting APC.

Oxidative stress injury, inducing cardiomyocyte injury, is the major denominator of many cardiovascular diseases. In present study, we aimed to explore the molecular mechanism of microRNA-208a (miR-208a) in oxidative stress-induced cardiomyocyte injury. In this study, hydrogen peroxide (H2O2)-induced injury in H9c2 and AC16 cardiomyocytes was used as a model of myocardial injury. The pro-apoptosis potential and mechanism of miR-208a for oxidative injury were evaluated by MTT, flow cytometry, qRT-PCR and Western blot assays. Intracellular reactive oxygen species and detection of lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD) were performed to analyze the effect of miR-208a on H2O2-induced injury in H9c2 cardiomyocytes. The association between miR-208a and activated protein C (APC) was confirmed by luciferase reporter and RIP assays. We foundthatmiR-208a mimic aggravated H2O2-induced apoptosis and oxidative injury in cardiomyocytes, while miR-208a inhibitor hadan inverse effect. APC was a target gene of miR-208a and miR-208a negatively regulated the expression of APC. APC reduced H2O2-induced injury in H9c2 cardiomyocytes. Knockdown of APC attenuated the inhibitiveeffect of miR-208a inhibitor on H2O2-induced injuryin H9c2 cardiomyocytes. We concluded thatmiR-208a could aggravate H2O2-induced injury in H9c2 cardiomyocytes by targeting APC. A new signaling pathway miR-208a/APC was first observed in myocardial injury.