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 3ʹUTR 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-β/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.