Birth Outcomes and IGF2 Methylation in P3 Promoter Region in Tibetan and Han Chinese Maternal-newborn Pairs in Hypo-baric Hypoxia High-altitude Area

Background: The relationship between Insulin-like growth factor 2 (IGF2) methylation in the P3 promoter region and birth outcomes in a hypobaric-hypoxia environment has never been investigated. This study examined the association and compared birth outcomes and IGF2 methylation in this region by ethnicity and altitude. Methods: Four hundred and six (406) mother and newborn pairs in the Tibetan Plateau were enrolled in a birth cohort study. Data were collected through interviews using structural questionnaires or extracted from medical records. Pyrosequencing was performed for IGF2 methylation in the P3 promoter region in maternal peripheral and umbilical cord blood. Birth outcomes and IGF2 methylation were compared among three groups: Han in high altitude (HHA, n=164, 2000-3500m), Tibetan in high altitude (THA, n=42, 2000-3500m), and Tibetan in ultra-high altitude (TUHA, n=200, 3500m and higher). Results: TUHA seemed to have a higher prevalence of macrosomia (7.5%) than both THA (0.0.%) and HHA (2.4%) and a lower IGF2 methylation level in maternal blood than THA (P=0.008). No difference in the IGF2 methylation levels was found between THA and HHA. The IGF2 methylation levels in maternal peripheral blood were associated with a reduced risk of macrosomia (RR= 0.726, 95% CL [0.528,0.998], P=0.049) among all mother and newborn pairs. Conclusions: Increased altitude appears to be associated with decreased maternal IGF2 methylation levels in the P3 promoter region, and maternal IGF2 methylation levels in this region was associated with reduced risk of macrosomia in newborns in the hypobaric hypoxic Tibetan Plateau environment. Keywords Macrosomia; IGF2; DNA methylation; high altitude; Tibet Plateau