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

ABSTRACT

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.

KEYWORDS:

• HLA-G
• polymorphism
• epigenetics
• diabetes
• inflammation
• network medicine

Article highlights

• HLA-G exerts peculiar tolerogenic and anti-inflammatory activities.

• DNA polymorphisms may regulate HLA-G gene in diabetes and its cardiovascular complications.

• Soluble HLA-G isoform (sHLA-G) may be a putative useful clinical biomarker in diabetes and its cardiovascular complications.

• No study investigated the role of epigenetic sensors regulating HLA-G gene in hyperglycemic conditions.

• We speculate that KDM6A/INF-β/HLA-G axis might induce a tolerogenic milieu upon inflammation at pancreatic level.

• Network medicine is a molecular-bioinformatic approach that might aid to confirm or not HLA-G as candidate gene in diabetes.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by “Ricerca Corrente 2018” from Italian Ministry of Health (PI Prof Napoli).