Maternal Adiposity and DNA Methylation of TfR2 and HJV Genes in Early Pregnancy: Mediating Role of Inflammation and Consequences for Iron Status

Background: Growing evidence shows that obesity influences iron status during pregnancy; however, it is unknown whether maternal obesity is associated with epigenetic changes in transferrin receptor 2 (TfR2) and hemojuvelin (HJV). Objectives: This study aimed to explore the association between adiposity and DNA methylation in TfR2 and HJV in early pregnancy and the mediating effect of inflammation on this association. Methods: This cross-sectional study used data from a double-blind randomized controlled trial in singleton pregnant women with normal weight (BMI: 18.5-24.9 kg/m2) and obesity (BMI: ≥30.0 kg/m2). Maternal BMI, fat mass, visceral fat, iron/inflammatory markers and DNA methylation of TfR2 and HJV were measured at 12 gestational weeks. Two primer sets were designed [TfR2 zone 1 and 2 (TfR2z1, TfR2z2); HJV zone 1 and 2 (HJVz1, HJVz2)]. An inflammation score was calculated using proinflammatory cytokines. Results: A total of 65 pregnant females were included, 34 with normal weight, and 31 with obesity. Compared with those of normal-weight women, those with obesity showed: lower percentage of DNA methylation in TfR2z1 cytosine-phosphate-guanine (CpG) sites 5, 6, 8-10 and the average in this zone (average CpG methylation 5.80% compared with 6.92%, P = 0.004); lower percentage of DNA methylation in TfR2z2 CpG sites 5 and 6 (12.5% compared with 14.7%, P = 0.035; 17.8% compared with 20.1%, P = 0.031); higher percentage methylation of DNA in HJVz1 CpG site 3 (HJVz1 CpG 3 45.3% compared with 43.4%, P = 0.010) and HJVz2 CpG site 2 and the average (HJVz2 CpG 2 43.2% compared with 37.9%, P < 0.001, average 65.9% compared with 61.6%, P < 0.001). Adjusting for covariates, TfR2z1 was negatively and HJVz2 positively associated with all adiposity measures (TfR2z1, BMI β = -0.288, P = 0.030; HJVz2 β = 0.459, P < 0.001). Inflammation showed a mediating effect on the association between all adiposity measures and DNA methylation of HJVz1 (P = 0.019). Conclusions: Maternal adiposity is associated with epigenetic changes in the iron metabolism genes TfR2 and HJV in early pregnancy, part of which are inflammation-mediated changes in HJV.