Using Differential Threshold Effects of Individual and Combined Periconceptional Methyl Donor Status on Maternal Genomic LINE-1 and Imprinted H19 DNA Methylation to Predict Birth Weight Variance in the Taiwan Pregnancy-Newborn Epigenetics (TPNE) Cohort Study

BACKGROUND: Few studies have comprehensively examined the effect of methyl donor status on maternal DNA methylation and birth outcomes. OBJECTIVES: This study examined associations between periconceptional methyl donor status and genome-wide and specific imprinted gene methylation and fetal growth indices in the Taiwan Pregnancy-Newborn Epigenetics cohort. METHODS: Plasma folate, choline (free form), and betaine concentrations of the participants enrolled at 7-10 weeks of gestation were analyzed. DNA methylation at regulatory sequences of the imprinted H19 gene and genomic long interspersed nuclear element 1 (LINE-1) were measured in maternal lymphocytes using bisulfite/high-resolution melt polymerase chain reaction. Associations with birth weight (BW) were estimated through multiple regressions from 112 mother-newborn pairs. RESULTS: A nonlinear "L-shaped" relation and an inverse association between maternal plasma folate in T1 (mean +/- SE: 17.6 +/- 5.1 nmol/L) and lymphocytic LINE-1 methylation (beta: -0.49, P = 0.027) were characterized. After adjusting for LINE-1 methylation, individual maternal folate concentrations were positively associated with BW variance (beta = 0.24, P = 0.035), and the association was more pronounced in mothers with choline in T1 (mean +/- SE: 5.4 +/- 0.6 mumol/L; beta: 0.40, P = 0.039). Choline status of the mothers in T2 (mean +/- SE: 7.2 +/- 0.6 mumol/L) was inversely associated with LINE-1 methylation (beta: -0.43, P = 0.035), and a positive association was evident between T1 choline and H19 methylation (beta: 0.48, P = 0.011). After adjusting for epigenetic modification, maternal choline status predicted a positive association with BW (beta: 0.56, P = 0.005), but the effect was limited to mothers with high betaine concentrations in T3 (mean +/- SE: 36.4 +/- 8.8 mumol/L), depending on folate status. CONCLUSIONS: Our data highlight the differential threshold effects of periconceptional folate, choline, and betaine status on genomic LINE-1 and H19 DNA methylation and how their interplay has a long-term effect on BW variance.