Congenital long QT syndrome (LQTS) is a hereditary disorder that leads to sudden cardiac death secondary to fatal cardiac arrhythmias. Although many genes for LQTS have been described, the etiology remains unknown in 30%-40% of cases. In the present study, a large Chinese family (four generations, 49 individuals) with autosomal-dominant LQTS was clinically evaluated. Genome-wide linkage analysis was performed by using polymorphic microsatellite markers to map the genetic locus, and positional candidate genes were screened by sequencing for mutations. The expression pattern and functional characteristics of the mutated protein were investigated by western blotting and patch-clamp electrophysiology. The genetic locus of the LQTS-associated gene was mapped to chromosome 11q23.3-24.3. A heterozygous mutation (Kir3.4-Gly387Arg) was identified in the G protein-coupled, inwardly rectifying potassium channel subunit Kir3.4, encoded by the KCNJ5 gene. The Kir3.4-Gly387Arg mutation was present in all nine affected family members and absent in 528 ethnically matched controls. Western blotting of human cardiac tissue demonstrated significant Kir3.4 expression levels in the cardiac ventricles. Heterologous expression studies with Kir3.4-Gly387Arg revealed a loss-of-function electrophysiological phenotype resulting from reduced plasma membrane expression. Our findings suggest a role for Kir3.4 in the etiology of LQTS.
Ablation around the PV ostia diminishes left atrial response to VS and decreases the atrial VW. The attenuated vagal response after ablation may contribute to the suppression of AF.
Growing evidence has indicated that lysyl oxidase (LOX) G473A polymorphism (rs1800449) is associated with cancer risk among Asians. However, results of single center and small sample study lack enough power. We first investigated the effect of LOX G473A polymorphism on cancer risk among Asians by a meta-analysis, and then further validated this association by a case-control study of colorectal cancer (CRC) with LOX G473A polymorphism in a Chinese population. STATA 12.0 software was used for the meta-analysis. The relationships were evaluated by calculating the pooled odds ratios (ORs) and their 95 % confidence intervals (CIs). In a case-control study comprising 577 CRC patients and 696 controls, LOX G473A polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Logistic regression was used to evaluate genetic associations with the occurrence of CRC. The results of our meta-analysis, including seven case-control studies with a total of 2,377 cancer patients and 2,499 controls, suggested that LOX G473A polymorphism might be associated with an increased risk of cancer among Asians. In addition, results of a case-control study indicated that individuals with the AA or AG genotype had a significantly increased susceptibility to CRC occurrence, compared with individuals who had GG genotype. Overall, this meta-analysis and case-control study of CRC observed convincing association of LOX G473A polymorphism with cancer risk in Asians; our study would contribute to complete elucidation of carcinogenesis.
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Up to date, HCC pathogenesis has not been fully understood. The aim of the present study was to identify crucial genes and pathways associated with HCC by bioinformatics methods. The differentially expressed genes (DEGs) between 14 HCC tissues and corresponding non-cancerous tissues were identified using limma package. Gene Ontology (GO) and KEGG pathway enrichment analysis of DEGs were performed by clusterProfiler package. The protein–protein interaction (PPI) network of DEGs was constructed and visualized by STRING database and Cytoscape software, respectively. The crucial genes in PPI network were identified using a Cytoscape plugin, CytoNCA. Furthermore, the effect of the expression level of the crucial genes on HCC patient survival was analyzed by an interactive web-portal, UALCAN. A total of 870 DEGs including 237 up-regulated and 633 down-regulated genes were identified in HCC tissues. KEGG pathway analysis revealed that DEGs were mainly enriched in complement and coagulation cascades pathway, chemical carcinogenesis pathway, retinol metabolism pathway, fatty acid degradation pathway, and valine, leucine and isoleucine degradation pathway. PPI network analysis showed that CDK1, CCNB1, CCNB2, MAD2L1, ACACB, IGF1, TOP2A, and EHHADH were crucial genes. Survival analysis suggested that the high expression of CDK1, CCNB1, CCNB2, MAD2L1, and TOP2A significantly decreased the survival probability of HCC patients. In conclusion, the identification of the above crucial genes and pathways will not only contribute to elucidating the pathogenesis of HCC, but also provide prognostic markers and therapeutic targets for HCC.
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