Introduction: The complex genetic diversity among human populations results from an assortment of factors acting at various sequential levels, including mutations, population migrations, genetic drift, and selection. Although there are a plethora of DNA sequence variations identified through genome-wide association studies (GWAS), the challenge remains to explain the mechanisms underlying interindividual phenotypic disparity accounting for disease susceptibility. Single nucleotide polymorphisms (SNPs) present in the sites for DNA methylation, transcription factor (TF) binding, or miRNA targets can alter the gene expression. The systematic review aimed to evaluate the complex crosstalk among SNPs, miRNAs, DNA methylation, and TFs for complex multifactorial disease risk. Methods: PubMed and Scopus databases were used from inception until May 15, 2019. Initially, screening of articles involved studies assessing the interaction of SNPs with TFs, DNA methylation, or miRNAs resulting in allele-specific gene expression in complex multifactorial diseases. We also included the studies which provided experimental validation of the interaction of SNPs with each of these factors. The results from various studies on multifactorial diseases were assessed. Results: A total of 11 articles for SNPs interacting with DNA methylation, 30 articles for SNPs interacting with TFs, and 11 articles for SNPs in miRNA binding sites were selected. The interactions of SNPs with epigenetic factors were found to be implicated in different types of cancers, autoimmune diseases, cardiovascular diseases, diabetes, and asthma. Conclusion: The systematic review provides evidence for the interplay between genetic and epigenetic risk factors through allele-specific gene expression in various complex multifactorial diseases.
Folate metabolism genes are pivotal to critical biological processes and are related to several conditions, including developmental, cognitive, and cardiovascular anomalies. A systematic catalog of genetic polymorphisms in protein coding regions, regulatory transcription factor binding sites, and miRNA binding sites associated with folate pathway genes may contribute to personalized medicine. We performed a comprehensive computational survey of single nucleotide polymorphisms (SNPs) of folate pathway genes to highlight functional polymorphisms in the coding region, transcription factor binding sites, and miRNAs binding sites. Folate pathway genes were searched through PubMed and Kyoto Encyclopedia of Genes and Genomes pathway databases. SNPs were identified and characterized using the University of California, Santa Cruz genome browser and SNPnexus tool. Functional characterization of nonsynonymous SNPs (nsSNPS) was performed using bioinformatics tools, and common deleterious nsSNPs were identified. We identified 48 genes of folate pathway containing 287 SNPs in the coding regions. Out of these SNPs, rs5742905, rs45511401, and rs1801133 were predicted to be deleterious through four different bioinformatics tools. Three-dimensional structures of two proteins with and without deleterious nsSNPs were predicted by SWISSPDB viewer and SuperPose. Besides, a total of 237 SNPs was identified in transcription factor binding sites using the Genomatix software suite and six miRNA target site SNPs using miRNASNP. This systematic and extensive in silico analysis of functional SNPs of folate pathway may provide a foundation for future targeted mechanistic, structure-function, and genetic epidemiological studies.
Immunomodulatory and analgesic effects of dexamethasone are clinically well established, and this synthetic corticosteroid acts as an agonist of glucocorticoid receptors. Early results of the RECOVERY Trial from the United Kingdom and others suggest certain benefits of dexamethasone against COVID-19 chronic patients. The efforts have been acknowledged by World Health Organization with an interim guideline to use in patients with a severe and critical illness. The inherent genetic variations in genes such as CYP3A5, NR3C1, NR3C2, etc., involved in the pharmacokinetic and pharmacodynamic processes may influence dexamethasone’s effects as an anti-inflammatory drug. Besides, the drug may influence transcriptome or metabolic changes in the individuals. In the present review, we summarize the reported genetic variations that impact dexamethasone response and discuss dexamethasone-induced changes in transcriptome and metabolome that may influence potential treatment outcome against COVID-19.
Coronary artery disease (CAD) and ischemic stroke are the two most predominant forms of cardiovascular diseases (CVDs) caused by genetic, epigenetic and environmental risk factors. Although studies on the impact of ‘epigenetics’ in CVDs is not new, its effects are increasingly being realized as a key regulatory determinant that may drive predisposition, pathophysiology and therapeutic outcome. The most widely studied epigenetic risk factors are regulated by DNA methylation and miRNA expression. To keep pace with growing developments and discoveries, a comprehensive review was performed using Pubmed, Science Direct and Scopus databases to highlight the role of DNA methylation and miRNAs in CAD and stroke subjects. Network analysis was performed using ClueGO software and miRTargetLink database. We identified 32 studies of DNA methylation on CAD and stroke, of which, 6 studies showed differences in global DNA methylation, 10 studies reported the genome-wide difference in DNA methylation and 16 studies demonstrated altered DNA methylation at 14 candidate loci. The network analysis showed positive regulation of nitric oxide biosynthetic process, homocysteine metabolic process and negative regulation of lipid storage. About, 155 miRNAs were associated with CAD, stroke and related phenotypes in 83 studies. Interestingly, mir-223 hypomethylation and altered expression were associated with cerebral infarction and stroke. The target prediction for 18 common miRNAs between CAD and stroke showed strong interaction with SP3 and SP1 genes. This systematic review addresses the present knowledge on DNA methylation and miRNAs in CAD and stroke, whose abnormal regulation has been implicated in etiology or progression of the diseases.
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