Presenting Author:

Rachel Kadakia, M.D.

Principal Investigator:

Jami Josefson, M.D.

Department:

Pediatrics

Keywords:

Epigenetics, Neonatal Adiposity, Cord Blood

Location:

Ryan Family Atrium, Robert H. Lurie Medical Research Center

C85 - Clinical

Cord Blood DNAJA4 Hypermethylation is Associated with Increased Neonatal Leptin

Increasing adiposity at birth may be a predictor of obesity in childhood and adulthood, even in children without traditional risk factors such as gestational diabetes. The predisposition towards obesity may begin in-utero, hypothesized to be due to the effects of the intrauterine environment on fetal programming of genes and organ development related to adiposity. Epigenetic changes to neonatal DNA may represent one important mechanism by which this programming occurs. In this study, we aimed to identify epigenetic changes in novel genes that are associated with neonatal adiposity. We performed a cross-sectional epigenome-wide association study in a cohort of 114 healthy, full-term infants born to healthy mothers with normal glucose tolerance according to the International Association of Diabetes and Pregnancy Study Groups criteria. Cord blood was assayed for leptin and epigenome-wide DNA methylation profiles were obtained via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariate linear regression models were used to analyze the epigenome-wide associations between methylation levels of each CpG site and log transformed leptin levels. Regional analysis was then applied to the regression coefficient to identify any differentially methylated regions among gene promoters. We found that every 1% increase in methylation in the promoter region of the DNAJA4 gene was associated with a 7.3% increase in neonatal cord blood leptin levels (FDR=0.011). In addition, leptin levels were positively correlated with measures of neonatal adiposity including birth weight (r=0.45, p<0.001), fat mass (r=0.47, p<0.001), and percent body fat (r=0.44, p<0.001) when adjusted for maternal age at delivery, maternal race, gestational age, and neonatal sex. This suggests that cord blood leptin levels are a surrogate marker of adipose tissue quantity. DNAJA4 encodes for a heat shock protein and prior studies have demonstrated that DNAJA4 hypomethylation is associated with intrauterine growth retardation and hypermethylation with tissue and tumoral growth. We speculate that cord blood DNAJA4 promoter region hypermethylation alters gene expression leading to increased adipocyte leptin production and adipose tissue growth. This DNAJA4 hypermethylation signature in cord blood may be a contributor to neonatal adiposity.