1. Introduction
The World Health Organization (WHO) and most countries recommend a
healthy diet plus a folic acid supplement of 400 µg/d from preconception
until the end of the first trimester of pregnancy to seek neural-tube
defects prevention (WHO, 2012). Alternatively, human studies,
inconsistent annotations were observed associations between maternal
folic acid intake along with folate levels during pregnancy and risk of
childhood wheeze, asthma, and respiratory symptoms (Veeranki et al.,
2014; Roy et al., 2018; Vereen et al., 2018). The inconsistent
annotations of maternal folate can be partly explained by vary maternal
folate levels and susceptibility of modified DNA methylation regarding
risk of respiratory symptoms.
As potential biological mechanism, maternal folate intake can modify
inflammation and immune susceptibility of offspring with some epigenetic
role involving DNA methylation (Montrose et al., 2017). Folate as methyl
donors change DNA methylation that is a covalent addition of a methyl
group to a cytosine residue at the CpG site in the DNA sequence. In
vitro experiments have suggested that epigenetic modifications also
contribute to the pathogenic mechanism underlying 17q21locus ,
which is a potential gene related to asthma and harbors the adjacent
genes GSDMB (Gasdermin B)/ORMDL3 (Orosomucoid-like 3) andIKZF3 (IKAROS family zinc finger 3). Recent studies have
suggested that GSDMB/ORMDL3 and IKZF3 have a role in IL-6 and IL-8
levels (Wu et al., 2018), viral respiratory infections (Bouzigon et al.,
2008), and childhood asthma (Breslow et al., 2010). In a Swedish study,
differential DNA methylation among CpG including GSDMB/ORMDL3 andIKZF3 was associated with a risk of childhood asthma and RNA
expression (Acevedo et al., 2015). However, no study evaluates whether
the difference in DNA methylation in GSDMB /ORMDL3 andIKZF3 modifies the association between maternal folate level and
childhood wheeze.
Participants of this study are from part of the Hokkaido Birth Cohort
Study on Environment and Children’s Health. The current study evaluates
the associations between maternal folate levels during pregnancy and
childhood wheeze and whether DNA methylation of GSDMB, ORMDL3, and IKZF3
changes the association.