Five Common Functional Polymorphisms in microRNAs and Susceptibility to Breast Cancer: An Updated Meta-Analysis.

AIMS: microRNAs (miRNA) play a key role in the pathogenesis of breast cancer (BC) as regulators of tumor-associated genes, and understanding their polymorphisms is critical to the control of breast carcinogenesis. Thus, the present study explored the association between five common functional polymorphisms in miRNAs (i.e., miRNA-196a2C>T, rs11614913; miRNA-146aG>C, rs2910164; miRNA-423C>A, rs6505162; miRNA-608G>C, rs4919510; miRNA-27aC>T, rs895819) and the risk of BC. MATERIALS AND METHODS: Meta-analyses were performed on 31 studies, including 14,677 BC patients and 16,143 cancer-free controls. Fourteen studies with 6147 cases and 5820 controls were analyzed for rs2910164, seventeen studies with 7021 cases and 8186 controls were analyzed for rs11614913, seven studies with 1891 (3390) cases and 2239 (5485) controls were analyzed for rs6505162 and rs4919510, respectively, and nine studies with 4499 cases and 5434 controls were analyzed for rs895819. Odds ratios (ORs) and 95% confidence intervals (CIs) were adopted to estimate BC risk. Subgroup analyses were performed for ethnicity. Because there was one study with mixed ethnicities, 16 studies were used in the analysis of Caucasian groups, and 16 studies were used for the Asian group. RESULT: Meta-analysis showed that rs895819 correlated with reduced BC risk in three genotypic models: allele (Caucasian: OR = 0.89, 95% CI = 0.82-0.97, p = 0.008; Total: OR = 0.93, 95% CI = 0.87-0.99, p = 0.03), recessive (Caucasian: OR = 0.85, 95% CI = 0.77-0.94, p = 0.002; Total: OR = 0.92, 95% CI = 0.85-0.99, p = 0.04), and dominant (Total: OR = 0.87, 95% CI = 0.77-0.99, p = 0.04). Of note, a significant publication bias for rs895819 was observed in the dominant model. Unexpectedly, the other four polymorphisms were not associated with BC risk in any of the models. CONCLUSIONS: The present study indicates that only the rs895819 polymorphism was associated with BC risk.

Impact of matrix metalloproteinase 9 rs3918242 genetic variant on lipid-lowering efficacy of simvastatin therapy in Chinese patients with coronary heart disease.

BACKGROUND: Genetic variation of matrix metalloproteinase 9 (MMP-9) gene polymorphism has been suggested to modulate coronary heart diseases (CHD), yet the underlying mechanisms are not well understood. METHODS: We investigated the association of MMP9 rs3918242 single nucleotide polymorphism with inflammation and lipid-lowering efficacy after simvastatin treatment in Chinese patients with CHD. Fasting serum lipid profile and plasma inflammatory mediators were determined at baseline in 264 patients with CHD and 186 healthy control subjects, and after HMG-CoA reductase inhibitor simvastatin treatment (20 mg/day) for 12 weeks in CHD subjects. RESULTS: We found that plasma MMP-9, TNF-α and IL-10 levels were significantly elevated in patients with CHD compared to control subjects before treatment. The plasma MMP9 in CHD patients carrying rs3918242 CC, CT and TT genotypes were comparable. Interestingly, CHD patients carrying TT genotype had significantly higher level of triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) than those carrying CC genotype (P <0.05). Simvastatin treatment significantly reduced LDL-C, TG and plasma inflammatory mediator levels in CHD patients. The reduction of LDL-C upon simvastatin therapy was significantly greater in patients carrying TT genotype than those carrying CC genotype (P <0.05). CONCLUSIONS: MMP9 rs3918242 TT genotype is associated with elevated serum TG and LDL-C, and enhanced LDL-C-lowering response upon simvastatin treatment in Chinese patients with CHD. CLINICAL TRIAL REGISTRATION: This study was retrospectively registered at Chinese Clinical Trial Registry (Registration number: ChiCTR-ROC-17010971 ) on March 23rd 2017.

Inhibition of microRNA-25 by tumor necrosis factor α is critical in the modulation of vascular smooth muscle cell proliferation.

Atherosclerosis and coronary heart disease are characterized by a hyperplastic neointima and inflammation involving cytokines, such as tumor necrosis factor­α (TNF­α). TNF­α is pleiotropic and mediates inflammation and proliferation in various cell types, such as vascular smooth muscle cells (VSMCs). The molecular mechanism for the pleiotropic effects of TNF­α has not previously been fully elucidated. The current study identified that the expression of microRNA­25 (miR­25), a small noncoding RNA, was reduced in response to TNF­α signaling in VSMCs. Restored miR­25 expression inhibited cell proliferation and Ki­67 expression. The present study indicated that cyclin­dependent kinase 6 (CDK6) was the direct target gene of miR­25 using mRNA and protein expression analysis, and luciferase assays. It was also observed that restored CDK6 expression in the miR­25 mimic­treated VSMCs partly reduced miR­25­mediated VSMC proliferation. In conclusion, miR­25 is suggested to be important in TNF­α­induced abnormal proliferation of VSMCs.

Interaction network analysis revealed biomarkers in myocardial infarction.

Myocardial infarction (MI) is a serious heart disease. The cardiac cells of patients with MI will die due to lack of blood for a long time. In this study, we aimed to find new targets for MI diagnosis and therapy. We downloaded GSE22229 including 12 blood samples from healthy persons and GSE29111 from Gene Expression Omnibus including 36 blood samples from MI patients. Then we identified differentially expressed genes (DEGs) in patients with MI compared to normal controls with p value < 0.05 and |logFC| > 1. Furthermore, interaction network and sub-network of these of these DEGs were constructed by NetBox. Linker genes were screened in the Global Network database. The degree of linker genes were calculated by igraph package in R language. Gene ontology and kyoto encyclopedia of genes and genomes pathway analysis were performed for DEGs and network modules. A total of 246 DEGs were identified in MI, which were enriched in the immune response. In the interaction network, LCK, CD247, CD3D, FYN, HLA-DRA, IL2, CD8A CD3E, CD4, CD3G had high degree, among which CD3E, CD4, CD3G were DEGs while others were linker genes screened from Global Network database. Genes in the sub-network were also enriched in the immune response pathway. The genes with high degree may be biomarkers for MI diagnosis and therapy.

Bioinformatics analysis of time series gene expression in left ventricle (LV) with acute myocardial infarction (AMI).

This study is to investigate the key genes and their possible function in acute myocardial infarction (AMI). The data of GSE4648 downloaded from the Gene Expression Omnibus (GEO) database include 6 time points (15 min, 60 min, 4h, 12h, 24h and 48 h) of 12 left ventricle (LV) samples, 12 surviving LV free wall (FW) samples, 12 inter-ventricular septum (IVS) samples after AMI operation and corresponding sham-operated samples. The data of each sample were analyzed with Affy and Bioconductor packages, and differentially expressed genes (DEGs) were screened out using BETR package with false discovery rate (FDR)<0.01. Then, functional enrichment analysis for DEGs was conducted with Database for Annotation, Visualization and Integrated Discovery (DAVID). Totally 194 DEGs were identified in LV, and only the gene tubulin beta 2a (Tubb2a) and natriuretic peptide B (Nppb) were respectively up-regulated in surviving FW tissue and IVS tissue. The biological process response to wounding and inflammatory response were significantly enriched, as well as leukocyte transendothelial migration pathway. Besides, the expression pattern analysis showed the DEGs mostly up-regulated at 4h after AMI, and these genes were mainly associated with immunity. Additionally, in transcriptional regulatory network, early growth response 1 (Egr1), activating transcription factor 3 (Atf3), Atf4, Myc and Fos were considered as the key transcription factors related to immune response. The key transcription factors and potential target genes might provide new information for the development of AMI, and leukocyte transendothelial migration pathway might play a vital role in AMI.