Key message
Epigenetic combined with genetic background of immune-related genetic loci, mainly HLA-G promoter region and CpG41 island ofHLA-DRB1 highlighted their potential to FA appearance.HLA-G hypomethylation and consequent generation of HLA-G positive/FOXP3 negative Tregs emerge as an immediate modulator of the immune cells’ phenotype urging an early desensitization process. Also, rs1233333 residing withinHLA-G gene’s promoter region, shows significant results in safeguarding the area from DNA methylation spreading. Methylation levels of HLA-DRB1 CpG island 41 and co-occurrence of SNPs pronounce their cooperation and their modulatory role towards FA development. Finally, aberrant background methylation patterns at HLA-G gene’s promoter region andFOXP3 TSDR are attributed to parents’ smoking habit.
Introduction
IgE-mediated food allergy (FA) development during childhood appears as a complex disorder, implicating immune dysfunction and influenced by genetic variants, epigenetic modifications, parental habits and environmental contributors or combinations thereof1-5. Among factors mediating gene-environment interactions is the epigenetic remodelling of genome, a critical mechanism for immune system adaptation to environmental exposures6.
FOXP3-expressing Tregs hold a leading role in the immune system homeostasis and effectively protect against allergies7. High levels ofFOXP3 methylation inhibiting gene’s expression, have been attributed to extensive exposure to air pollutants, an effect pronounced in asthmatic compared to non-asthmatic children8.
Other immune related genes, encompassed in the major histocompatibility complex (MHC) system, modulate adaptive immune responses. The human leukocyte antigen-G (HLA-G ) is a MHC class I gene, epigenetically regulated by methylation9 and has been recognized as an important mediator of immune tolerance at the fetal–maternal interface of human placenta10,11. In healthy adults, thymus generates a proportion of 1-3% HLA-G-positive/FOXP3-negative CD4+ and CD8+ T-cells,12 with regulatory properties (Tregs) 1314 and increased frequency at sites of inflammation.
MHC class II cluster includes HLA-DQ and HLA -DRgenes, whose expression is limited to the professional antigen-presenting cells. Cell-processed antigens’ presentation by MHC class II to CD4+ T lymphocytes, stimulates the antigen-specific hypersensitivity type I allergic reaction. GWAS studies and review analysis have provided convincing evidence that HLA-DRand HLA-DQ genes’ polymorphic regions harbor significant genetic and epigenetic risk for FA15,16.
The present study aimed to accomplish deeper insights for the genetic/epigenetic and environmental associations influencing the predisposition to FA development.
Methods