Degree of methylation of ZAC1 (PLAGL1) is associated with prenatal and post-natal growth in healthy infants of the EDEN mother child cohort

Abstract

The ZAC1 gene, mapped to the 6q24 region, is part of a network of co-regulated imprinted genes involved in the control of embryonic growth. Loss of methylation at the ZAC1 differentially methylated region (DMR) is associated with transient neonatal diabetes mellitus, a developmental disorder involving growth retardation and diabetes in the first weeks of post-natal life. We assessed whether the degree of methylation of the ZAC1 DMR in leukocytes DNA extracted from cord blood is associated with fetal, birth and post-natal anthropometric measures or with C-peptide concentrations in cord serum. We also searched for an influence of dietary intake and maternal parameters on ZAC1 DMR methylation. We found positive correlations between the ZAC1 DMR methylation index (MI) and estimated fetal weight (EFW) at 32 weeks of gestation, weight at birth and weight at one year of age (respectively, r = 0.15, 0.09, 0.14; P values = 0.01, 0.15, 0.03). However, there were no significant correlations between the ZAC1 DMR MI and cord blood C-peptide levels. Maternal intakes of alcohol and of vitamins B2 were positively correlated with ZAC1 DMR methylation (respectively, r = 0.2 and 0.14; P = 0.004 and 0.04). The influence of ZAC1 seems to start in the second half of pregnancy and continue at least until the first year of life. The maternal environment also appears to contribute to the regulation of DNA methylation.

Keywords: C-peptide; ZAC1/HYMAIimprinted locus; fetal development; imprinting disorders; insulin secretion in vivo; metabolism disorders; nutrition and epigenetic regulation; pathophysiology and metabolism; transient neonatal diabetes mellitus.

Figure 1. Distribution of the ZAC1 DMR methylation index, scored as a percentage (n = 254).

Figure 2. Mean anthropometric z-scores by tertiles of the ZAC1 DMR methylation index (n = 251). Mean values adjusted for gender and study center with standard errors are presented, global P values for Anova tests are shown for each variable.