Abstract
Background: Genetic areas of FOXP3 TSDR, HLA-Gupstream of CpG island 96, CpG41 and CpG73 islands of theHLA‐DRB1 and HLA-DQB1 genes respectively, previously
documented to display immune modulatory properties, were subjected to
epigenetic/genetic analysis to assess their influence in IgE-mediated
food allergy (FA) development in children.
Methods: 64 orally challenged and IgE- tested food allergic
subjects together with 44 controls were recruited. Targeted
pyrosequencing analysis, to detect DNA methylation status and genetic
variations was utilized and experimental results obtained were analysed
by statistical software platform and correlated to clinical data. Also,
transcription factor (TF) binding sites at study areas were unmasked by
the JASPAR prediction database.
Results: Parents’ smoking was significantly correlated with
aberrant methylation patterns, regardless food allergic or control
status. HLA-G promoter
region showed a trend for hypomethylation in food allergic subjects,
with one of the CG sites displaying significantly decreased methylation
values. Rs1233333, residing within HLA-G promoter region
preserved a protective role towards DNA methylation. Variable
methylation patterns were recorded for CpG41 of the HLA‐DRB1 gene
and hypermethylation of the region was significantly correlated with the
presence of (Single Nucleotide Polymorphisms) SNPs. TFs’ recognition
sites, located at studied genetic areas and exerting pivotal regulatory
biological roles, are potentially affected from divergent DNA
methylation status.
Conclusions: We propose that HLA-G expression is triggered by
food derived allergens, providing a TregFoxP3-/HLA-G+subpopulation generation and direct immune-tolerance. Furthermore, clear
evidence is provided for the underlying co-operation of genetic
polymorphisms with epigenetic events, mainly at CpG41 island ofHLA-DRB1 gene, which need an extended investigation and
elucidation.
Keywords: FOXP3 TSDR methylation, HLA-G promoter
region, HLADQB1/HLADR B1 CpG islands, SNP detection, epigenetic
background, genetic/epigenetic interplay