Epigenome-wide study for the offspring exposed to maternal HBV infection during pregnancy, a pilot study

Background & aim: Hepatitis B virus (HBV) can be transmitted to infants, and is related to infants' later disease risk. Epigenetic change (such as DNA methylation) may be mechanism underlying the relationship. In this study, we aimed to investigate whether prenatal HBV infection could alter DNA methylation status in newborns. Method: We selected 12 neonates with intrauterine HBV infection whose mothers were HBsAg-positive during pregnancy, relative to 12 HBV-free neonates with HBsAg-negative mothers. The pattern of genome-wide DNA methylation in the umbilical cord blood was investigated by Illumina Infinium Human Methylation 450K BeadChip. Result: The average level of global methylation in infected neonates exposed to maternal HBV infection was not significantly different from controls. However, after adjusting for multiple comparisons, we found differential significance in the cases group compared to the controls for 663 CpG sites, associated with 534 genes. Among these sites, 53.85% (357/663) had decreased methylation (Delta M < 0) and 46.15% (306/663) had increased methylation (Delta M > 0). The average percentage change (Delta beta) in methylation ranged from -46% to 36%. Validated by pyrosequencing, we identified 4 significantly differentially methylated CpG sites in the KLHL35 gene and additional CpGs for the CPT1B gene. These genes play a role in the development of hepatocellular and colorectal carcinoma and fatty acid oxidation, suggesting the candidature of these genes in HBV related disease. Conclusion: Prenatal HBV exposure, even without malformation or preterm birth, may alter the epigenome profile in newborns. We identified a set of genes with differentially methylated CpG sites presented in the cord blood of HBV-infected newborns with HBsAg-positive mothers, demonstrating that DNA methylation status at birth can be used as a biomarker of prenatal exposure. These DNA methylation differences suggest a possible role for epigenetic processes in neonatal development in response to prenatal HBV exposure.