Gene polymorphisms associated so far with BMI can explain only 1.18-1.45% of observed variation in BMI.Recent studies suggest that epigenetic modifications (DNA methylation) could contribute to explain part of the missing heritability, and two epigenetic genome-wide analysis studies (EWAS) have reported that HIF3A methylation was associated with BMI or BMI change.We therefore assessed whether the HIF3A methylation is associated with obesity and other obesity-related phenotypes in Chinese children.The subjects included 110 severe obese cases aged 7-17y and 110 normal-weight controls matched by age and gender for measurement of blood DNA methylation levels at the HIF3A gene locus using the Sequenoms MassARRAY system.We observed significantly higher methylation levels in obese children than in controls at positions 46801642 and 46801699 in HIF3A gene (P<0.05), and found positive associations between methylation and ALT levels adjusted by gender, age and BMI at the position 46801699 (r=0.200, P =0.016).These results suggest that HIF3A DNA methylation is associated with childhood obesity,and has a BMI-independent association with ALT.The results provide evidence for identifying epigenetic factors of elivated ALT and may be useful for risk assessment and personalized medicine of liver diseases such as NAFLD.