EPAS1 involves in the hypoxic response and is suggested to be responsible for 
the genetic adaptation of high-altitude hypoxia in Tibetans. However, the 
detailed molecular mechanism remains unknown. In this study, a single nucleotide 
polymorphism rs56721780:G>C and an insertion/deletion (indel) polymorphism -742 
indel in the promoter region showed divergence between Tibetans and non-Tibetan 
lowlanders. rs56721780:G>C regulated the transcription of EPAS1 by IKAROS family 
zinc finger 1 (IKZF1), which was identified as a new transcriptional repressor 
for EPAS1 gene. It demonstrated that the C allele of rs56721780:G>C decreased 
the binding of IKZF1, leading to the attenuated transcriptional repression of 
EPAS1 gene. The insertion at -742 indel provided a new binding site for Sp1 and 
was related to the activation of EPAS1 promoter. Further functional analysis 
revealed that lysyl oxidase (LOX) gene, which was reported to be responsible for 
extracellular matrix protein cross-linking of amnion previously, was a direct 
target of EPAS1. The CC genotype at rs56721780:G>C and the insertion genotype at 
-742 indel were found associated with higher EPAS1 and LOX expression levels in 
amnion, as well as higher birth weight of Tibetan newborns, suggesting that 
EPAS1 gene might play important roles in the development of amnion, fetus growth 
and high-altitude adaptation of Tibetans.