Rahimabad, Parnian Kheirkhah, Arshad, Syed, Holloway, John, Mukherjee, Nadini, Hedman, Anna M., Gruzieva, Olena, Andolf, Ellika, Kere, Juha, Pershagen, Göran, Almqvist, Catarina, Jiang, Yu, Chen, Su and Karmaus, Wilfried (2021) Association of maternal DNA methylation and offspring birthweight. Reproductive Sciences, 28 (1), 218-227. (doi:10.1007/s43032-020-00281-9).
Abstract
This study aims to evaluate the association of maternal DNA methylation (DNAm) during pregnancy and offspring birthweight.One hundred twenty-two newborn-mother dyads from the Isle of Wight (IOW) cohort were studied to identify differentiallymethylated cytosine-phosphate-guanine sites (CpGs) in maternal blood associated with offspring birthweight. Peripheral bloodsamples were drawn from mothers at 22–38 weeks of pregnancy for epigenome-wide DNAm assessment using the IlluminaInfinium HumanMethylation450K array. Candidate CpGs were identified using a course of 100 repetitions of a training andtesting process with robust regressions. CpGs were considered informative if they showed statistical significance in at least 80%of training and testing samples. Linear mixed models adjusting for covariates were applied to further assess the selected CpGs.The Swedish Born Into Life cohort was used to replicate our findings (n= 33). Eight candidate CpGs corresponding to the genesLMF1,KIF9,KLHL18,DAB1,VAX2,CD207,SCT,SCYL2,DEPDC4,NECAP1,andSFRS3in mothers were identified asstatistically significantly associated with their children’s birthweight in the IOW cohort and confirmed by linear mixed modelsafter adjusting for covariates. Of these, in the replication cohort, three CpGs (cg01816814, cg23153661, and cg17722033 withpvalues = 0.06, 0.175, and 0.166, respectively) associated with four genes (LMF1,VAX2,CD207,andNECAP1)weremargin-ally significant. Biological pathway analyses of three of the genes revealed cellular processes such as endocytosis (possiblysustaining an adequate maternal-fetal interface) and metabolic processes such as regulation of lipoprotein lipase activity (in-volved in providing substrates for the developing fetus). Our results contribute to an epigenetic understanding of maternalinvolvement in offspring birthweight. Measuring DNAm levels of maternal CpGs may in the future serve as a diagnostic toolrecognizing mothers at risk for pregnancies ending with altered birthweights
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