BACKGROUND & AIMS The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene–smoking interactions) that affect risk for Crohn’s disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD. METHODS We used 55 immunochip-wide data sets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10−/− and Nod2−/− mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription PCR. RESULTS We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P<5.0×10−5; heterogeneity Cochrane Q test P>.05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of IL10-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine, compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wildtype mice exposed to smoke. CONCLUSION In an analysis of 55 immunochip-wide data sets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene–smoking interactions were confirmed in mice with disruption of Il10 and Nod2—variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants.
MicroRNA (miRNA) is a small non-coding molecule that is involved in gene regulation and RNA silencing by complementary on their targets. Experimental methods for target prediction can be time-consuming and expensive. Thus, the application of the computational approach is implicated to enlighten these complications with experimental studies. However, there is still a need for an optimized approach in miRNA biology. Therefore, machine learning (ML) would initiate a new era of research in miRNA biology towards potential diseases biomarker. In this article, we described the application of ML approaches in miRNA discovery and target prediction with functions and future prospective. The implementation of a new era of computational methodologies in this direction would initiate further advanced levels of discoveries in miRNA.
Background: Familial atrial septal defect (ASD) has previously been attributed primarily to mutations in cardiac transcription factors. Here, we report a large, multi-generational family (78 members) with ASD combined with a late-onset dilated cardiomyopathy and further characterize the consequences of mutant α-actin. Methods: We combined a genome-wide linkage analysis with cell biology, microscopy, and molecular biology tools to characterize a novel ACTC1 (cardiac α-actin) mutation identified in association with ASD and late-onset dilated cardiomyopathy in a large, multi-generational family. Results: Using a genome-wide linkage analysis, the ASD disease locus was mapped to chromosome 15q14 harboring the ACTC1 gene. In 15 affected family members, a heterozygous, nonsynonymous, and fully penetrant mutation (p. Gly247Asp) was identified in exon 5 of ACTC1 that was absent in all healthy family members (n=63). In silico tools predicted deleterious consequences of this variant that was found absent in control databases. Ultrastructural analysis of myocardial tissue of one of the mutation carriers showed sarcomeric disarray, myofibrillar degeneration, and increased apoptosis, while cardiac proteomics revealed a significant increase in extracellular matrix proteins. Consistently, structural defects and increased apoptosis were also observed in neonatal rat ventricular cardiomyocytes overexpressing the mutant, but not native human ACTC1. Molecular dynamics studies and additional mechanistic analyses in cardiomyocytes confirmed actin polymerization/turnover defects, thereby affecting contractility. Conclusions: A combined phenotype of ASD and late-onset heart failure was caused by a heterozygous, nonsynonymous ACTC1 mutation. Mechanistically, we found a shared molecular mechanism of defective actin signaling and polymerization in both cardiac development and contractile function. Detection of ACTC1 mutations in patients with ASD may thus have further clinical implications with regard to monitoring for (late-onset) dilated cardiomyopathy.
BACKGROUNDObjective-To prospectively measure and evaluate various CT linear indices namely Cella Media index (CMI), Frontal Horn Index (FHI), Evan's Index (EI) and Ventricular/Biparietal (V/BP) Ratio in children with clinically suspected hydrocephalus caused by various aetiologies. MATERIALS AND METHODSAxial CT scans of 53 symptomatic children were studied prospectively with proper consent. Out of these 53 patients, 31 were males and 22 were females. All patients had 2-phase examination (pre-and post-contrast studies) of the brain using the department's Siemens 128 slice somatom definition as multi-detector spiral CT. Predicated on the measurements various linear indices, notably Cella Media Index, Frontal Horn Index, Evan's index and V/BP Ratio were calculated. RESULTSIn our study, meningitis was found to be the most common cause of hydrocephalus in children followed by HIE, aqueductal stenosis and intracranial tumours. Of these 53 cases, 32 had communicating and 21 had non-communicating hydrocephalus. We can grade hydrocephalus based on measured linear indices as mild, moderate and severe. CONCLUSIONOur study proved that combination of various indices measured together, rather than single index is better in grading hydrocephalus. CT is a valuable tool in differentiating communicating from non-communicating hydrocephalus depending on the level of obstruction. CT is also useful in determining the aetiology of hydrocephalus in children.
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