Impact of placental and peripheral blood DNA methylation on celiac disease susceptibility

Objectives: Several studies suggest that the first immunogenic insult in celiac disease (CeD) could occur during fetal development. The placenta is a key organ that could link the environment with the genome and future outcomes, including CeD. Our objective is to determine the involvement of placental DNA methylation (DNAm) as potential mediator of the genetic susceptibility to CeD. Methods: We used Summary-data-based Mendelian Randomization to infer what part of the susceptibility to CeD acts through DNAm in placenta or peripheral blood. We interrogated whether DNAm of the CpGs identified correlated with the expression of adjacent genes in the same tissues, and repeated the procedure only in cases and controls carrying the HLA-DQ2 risk haplotype. Results: We identified 248 and 215 CpGs associated with CeD in placenta and blood, respectively. Among the former, the DNAm of seven CpGs correlated with the placental expression of ZFP57. In contrast, in the latter group, the most represented gene was RNF5, with DNAm of 11 CpGs correlating with its expression in blood. In HLA-DQ2 positive individuals, we observed a decrease of placental CpGs associated with CeD, with a remarkable exception in chromosome 2, close to AHSA2. In blood, we identified 44 CpGs associated with CeD in the HLA region, with HLA-DPA1 showing the largest number of DNAm-expression associations. Conclusions: Our results suggest that placenta does not seem to be a crucial effector in CeD, and show potentially causal relationships between blood DNAm and CeD, with independent signals in the HLA, and particularly in the HLA-DPA1 gene.