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.