Genetic and epigenetic-sensitive regulatory network in immune response: a putative link between HLA-G and diabetes.

INTRODUCTION: Human leukocyte antigen-G (HLA-G) gene encodes for a tolerogenic molecule constitutively expressed in human pancreas and upregulated upon inflammatory signals. The 14 bp INS/DEL polymorphism in the 3'UTR of HLA-G may influence the susceptibility for diabetes and coronary heart diseases (CHD), thus suggesting a novel candidate gene. DNA hypomethylation at HLA-G promoter may be a putative useful clinical biomarker for CHD onset. Upregulation of soluble HLA-G isoform (sHLA-G) was detected in prediabetic and diabetic subjects, suggesting a putative role in metabolic dysfunctions. AREAS COVERED: We conducted a scoping literature review of genetic and epigenetic-sensitive mechanisms regulating HLA-G in diabetes. English-language manuscripts published between 1997 and 2019, were identified through PubMed, Google Scholar, and Web of Science database searches. After selecting 14 original articles representing case-control studies, we summarized and critically evaluated their main findings. EXPERT COMMENTARY: Although epigenetic modifications are involved in the onset of hyperglycemic conditions evolving into diabetes and CHD, it is still difficult to obtain simple and useful clinical biomarkers. Inflammatory-induced KDM6A/INF-ß/HLA-G axis might be a part of the epigenetic network leading to overexpression of HLA-G at pancreatic level. Network medicine may show whether HLA-G is involved in diabetes and CHD.

Interplay between genetics and epigenetics in modulating the risk of venous thromboembolism: A new challenge for personalized therapy.

Although venous thromboembolism (VTE) shows a polygenic nature, the crossroad between genome and environment is not fully understood. Genetics explains only a part of VTE hereditability and not defined molecular causes are found in approximately 50% of thrombotic patients. Thus, a major understanding of molecular mechanisms may clarify the missing hereditability. Concerning epigenetics, a particular histone modification (citrullination) plays a key role in increasing the rate of venous occlusive events by inducing neutrophil apoptosis and expulsion of neutrophil extra-cellular traps (NETs), which may be useful biomarkers of active disease. Moreover, an over-expression of miR-320a/b, miR-582, miR-195, miR-424-5p, and miR-532, or a down-regulation of miR495, miR-136-5p and miR-26a may improve the accuracy of VTE diagnosis. No clinical studies have focused on DNA methylation in VTE. Nowadays, no validated epigenetics biomarkers are routinely used for diagnosis and prevention of VTE. In the era of personalized therapy, several clinical trials are investigating the putative role of statins, a class of lipid-lowering epigenetic-based drugs, as additional therapeutic agents in VTE. Furthermore, single nucleotide polymorphisms (SNPs) in CYP2C9, VKORC1, and MIR133 genes can help physicians to predict individual warfarin dose requirement. Consequently, a comprehensive understanding of the mechanisms involved in the control of blood clot development is crucial to design novel therapeutic strategies. This review summarizes the current clinical concepts both in genetic and epigenetic VTE framework. Furthermore, we discuss the contribution of the innovative network medicine paradigm into advancing our knowledge about molecular underpinnings needed to support novel VTE diagnostic and therapeutic options.

Effect of nitric oxide reduction on arterial thrombosis.

OBJECTIVES: Nitric oxide (NO) represents the most powerful endogenous molecule with vasodilator action mainly produced by endothelial nitric oxide synthase (eNOS) enzyme. Polymorphisms and epigenetic-sensitive mechanisms can modulate the expression of eNOS gene, leading to the endothelial dysfunction. This review updates on the mechanistic role of NO in the regulation of platelet activation, as well as the impact of eNOS genetic and epigenetic modifications on arterial thrombosis onset. DESIGN: A systematic search was addressed to examination of PubMed databases with the following terms: nitric oxide; arterial thrombosis; endothelial dysfunction; DNA variations; epigenetic modifications; personalized therapy; network medicine. RESULTS: G894T, -786T/C, and 4b/4a variable number tandem repeat (VNTR), are the main classes of polymorphisms harbored in eNOS gene associated to increased arterial thrombosis risk. DNA methylation, histone/non-histone modifications, and microRNA (miRNAs) can modulate eNOS gene expression. Investigators largely focused on the role of miRNAs in modulating NO production in arterial thrombosis development. In detail, miR-195, and miR-582 are inversely correlated both to eNOS and NO levels, thus suggesting novel biomarkers. CONCLUSION: We are far from incorporating omics pathogenic data from bench to arterial thrombosis bedside. Network medicine is an emerging paradigm that ideally overcomes the current shortcomings of the reductionist approach. Despite several clinical limitations, the network-based analysis of the interactome might reveal the key nodes underlying the perturbations of the arterial thrombosis, thus advancing personalized therapy.

Novel epigenetic-sensitive clinical challenges both in type 1 and type 2 diabetes.

BACKGROUND: Epigenetics modulated tissue-specific gene expression during the onset of type 1 and type 2 diabetes and their complications. METHODS: We searched the PubMed recent studies about the main epigenetic tags involved in type 1 and type 2 diabetes onset and their clinical complications. PubMed studies about the epigenetic tags involved in type 1 and 2 diabetes onset was searched. RESULTS: The epigenetic methylation maps of cord blood samples highlighted differences in the methylation status of CpG sites within the MHC genes between carriers of diabetes type 1 DR3-DQ2 and DR4-DQ8 risk haplotypes. ß cell-derived unmethylated INS DNA showed the decline of ß-cell mass preserving insulin secretion. Differentially methylated regions in pancreatic islets from type 2 diabetes covered PDX1, TCF7L2, and ADCY5 promoters during islet dysfunction. The recruitment of SET7 and SUV39H1 histone methyltransferases and LSD-1 lysine-specific demethylase-1 at NF-kß-p65 promoter in vascular cells was involved in coronary heart disease. Neutrophil extracellular trap, activated by protein arginine deiminase-4, impaired wound healing from diabetic foot ulcers. MiR-199a-3p over-expression induced coagulative cascade, swelling and pain by a down-regulation of SERPIN-E2 in diabetic peripheral neuropathy. A DNA hypo-methylation and histone hyper-acetylation at MIOX promoter led an overexpression of ROS, fibronectin, HIF-1α, and NOX-4 associated with diabetic tubulopathy. A hypo-methylation of H3K4 at SOD2 promoter by LSD-1 increased ROS causing diabetic retinopathy. CONCLUSIONS: Epigenetics played a relevant role in prevention, diagnosis, and treatment of diabetes.