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

Expert Rev Endocrinol Metab. 2019 Jul;14(4):233-241. doi: 10.1080/17446651.2019.1620103. Epub 2019 May 27.


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-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.

Keywords: HLA-G; diabetes; epigenetics; inflammation; network medicine; polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 3' Untranslated Regions
  • Coronary Disease / genetics*
  • Coronary Disease / immunology
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / immunology
  • Epigenesis, Genetic*
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • HLA-G Antigens / genetics*
  • Humans
  • Polymorphism, Genetic


  • 3' Untranslated Regions
  • HLA-G Antigens