Open Access

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

Wenxiu Jian, Pin Sun, Xuejun Wang, Pinhua Wang, Jiangzuo Zhaxi, Yangrui Zhang, Shulin Wang, Dexiong Zhao, Yuemei Fan, Liehong Wang, Wen Peng

January 10, 2023



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.


Macrosomia; IGF2; DNA methylation; high altitude; Tibet Plateau

Copyright© 2022 by the author(s). Licensee Global Clinical and Translational Research Institute, Inc., Bethesda, MD. This is an open-access article distributed under the terms and conditions of the Creative Commons Attribution License (CCBY4.0,, which permits unrestricted use, distribution, and reproduction in any medium provided the original work is properly cited.

How to cite this article: Jian W, Sun P, Wang X, Wang P, Zhaxi J, Zhang Y, Wang S, Zhao D, Fan Y, Wang L, Peng W. Birth outcomes and IGF2 methylation in P3 promoter region in Tibetan and Han Chinese Maternal-Newborn Pairs in hypobaric hypoxia high-altitude area. Glob Clin Transl Res. 2023; 5(1): 1-11. DOI:10.36316/gcatr.05.0047


1.       Mortola JP, Frappell PB, Aguero L, Armstrong K. Birth weight and altitude: a study in Peruvian communities. J Pediatr. 2000;136(3):324-9.

2.         Giussani DA, Salinas CE, Villena M, Blanco CE. The role of oxygen in prenatal growth: studies in the chick embryo. The Journal of Physiology. 2007;585(3):911-7.

3.         Moore LG, Charles SM, Julian CG. Humans at high altitude: hypoxia and fetal growth. Respir Physiol Neurobiol. 2011;178(1):181-90.

4.         Soria R, Julian CG, Vargas E, Moore LG, Giussani DA. Graduated effects of high-altitude hypoxia and highland ancestry on birth size. Pediatr Res. 2013;74(6):633-8.

5.         Beall CM. Tibetan and Andean contrasts in adaptation to high-altitude hypoxia. Adv Exp Med Biol. 2000;475:63-74.

6.         Reik W, Constância M, Fowden A, Anderson N, Dean W, Ferguson-Smith A, et al. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J Physiol. 2003;547(Pt 1):35-44.

7.         Shao W-J, Tao L-Y, Gao C, Xie J-Y, Zhao R-Q. Alterations in methylation and expression levels of imprinted genes H19 and Igf2 in the fetuses of diabetic mice. Comp Med. 2008;58(4):341-6.

8.         Tabano S, Colapietro P, Cetin I, Grati FR, Zanutto S, Mandò C, et al. Epigenetic modulation of the IGF2/H19 imprinted domain in human embryonic and extra-embryonic compart-ments and its possible role in fetal growth restriction. Epigenetics. 2010;5(4):313-24.

9.         Tobi EW, Heijmans BT, Kremer D, Putter H, Delemarre-van de Waal HA, Finken MJ, et al. DNA methylation of IGF2, GNASAS, INSIGF and LEP and being born small for gestational age. Epigenetics. 2011;6(2):171-6.

10.      Liu FD, Xue G, Wang G. Relationship between methylation status of IGF2 in parturient women and neonates and birth outcomes of neonates. Maternal Child Health Care of China. 2011.

11.      Montoya-Williams D, Quinlan J, Clukay C, Rodney NC, Kertes DA, Mulligan CJ. Associations between maternal prenatal stress, methylation changes in IGF1 and IGF2, and birth weight. J Dev Orig Health Dis. 2018;9(2):215-22.

12.      Rotwein P. The complex genetics of human insulin-like growth factor 2 are not reflected in public databases. J Biol Chem. 2018;293(12):4324-33.

13.      Yamaguchi Y, Tayama C, Tomikawa J, Akaishi R, Kamura H, Matsuoka K, et al. Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2. Clin Epigenetics. 2019;11(1):113.

14.      Engström W, Shokrai A, Otte K, Granérus M, Gessbo A, Bierke P, et al. Transcriptional regulation and biological significance of the insulin like growth factor II gene. Cell Prolif. 1998;31(5-6):173-89.

15.      Ji M, Wang X, Wu W, Guan Y, Liu J, Wang J, et al. ART manipulation after controlled ovarian stimulation may not increase the risk of abnormal expression and DNA methylation at some CpG sites of H19,IGF2 and SNRPN in foetuses: a pilot study. Reprod Biol Endocrinol. 2018; 16(1):63.

16.      Watanabe H, Higashimoto K, Miyake N, Morita S, Horii T, Kimura M, et al. DNA methylation analysis of multiple imprinted DMRs in Sotos syndrome reveals IGF2-DMR0 as a DNA methylation-dependent, P0 promoter-specific enhan-cer. Faseb j. 2020;34(1):960-73.

17.      Cui D, Yang W, Shao P, Li J, Wang P, Leng J, et al. Interactions between Prepregnancy Overweight and Passive Smoking for Macrosomia and Large for Gestational Age in Chinese Pregnant Women. Obes Facts. 2021;14(5):520-30.

18.      Ye J, Torloni MR, Ota E, Jayaratne K, Pileggi-Castro C, Ortiz-Panozo E, et al. Searching for the definition of macrosomia through an outcome-based approach in low- and middle-income countries: a secondary analysis of the WHO Global Survey in Africa, Asia and Latin America. BMC Pregnancy Childbirth. 2015;15:324.

19.      Zong XN, Li H, Zhang YQ, Wu HH. Reference values and growth curves of weight/length, body mass index, and ponderal index of Chinese newborns of different gestational ages. Zhonghua Er Ke Za Zhi. 2021;59(3):181-8.

20.      Zhang Z, Du H, Bai L, Yang C, Li Q, Li X, et al. Whole genome bisulfite sequencing reveals unique adaptations to high-altitude environments in Tibetan chickens. PLoS One. 2018;13(3):e0193597.

21.      Bouwland-Both MI, van Mil NH, Stolk L, Eilers PH, Verbiest MM, Heijmans BT, et al. DNA methylation of IGF2DMR and H19 is associated with fetal and infant growth: the generation R study. PLoS One. 2013;8(12):e81731.

22.      Liu Y, Murphy SK, Murtha AP, Fuemmeler BF, Schildkraut J, Huang Z, et al. Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements. Epigenetics. 2012;7(7):735-46.

23.      St-Pierre J, Hivert MF, Perron P, Poirier P, Guay SP, Brisson D, et al. IGF2 DNA methylation is a modulator of newborn's fetal growth and development. Epigenetics. 2012;7(10): 1125-32.

24.      Bouwland-Both MI, Van M, Lisette S, Eilers P, Verbiest M, Heijmans BT, et al. DNA Methylation of IGF2DMR and H19 Is Associated with Fetal and Infant Growth: The Generation R Study. Plos One. 2013;8(12):1389-92.

25.      St-Pierre, Hivert, M.-F., Perron, ChicoutimiHospital, Poirier, et al. IGF2 DNA methylation is a modulator of newborn's fetal growth and development. Epigenetics: official journal of the DNA Methylation Society. 2012.

26.      Haggarty P, Hoad G, Horgan GW, Campbell DM. DNA methyltransferase candidate polymorphisms, imprinting methylation, and birth outcome. PLoS One. 2013;8(7): e68896.

27.      Burris HH, Braun JM, Byun HM, Tarantini L, Mercado A, Wright RJ, et al. Association between birth weight and DNA methylation of IGF2, glucocorticoid receptor and repetitive elements LINE-1 and Alu. Epigenomics. 2013;5(3):271-81.

28.      Su R, Wang C, Feng H, Lin L, Liu X, Wei Y, et al. Alteration in Expression and Methylation of IGF2/H19 in Placenta and Umbilical Cord Blood Are Associated with Macrosomia Exposed to Intrauterine Hyperglycemia. PLoS One. 2016; 11(2):e0148399.

29.      Qiao J, Wang Y, Li X, Jiang F, Zhang Y, Ma J, et al. A Lancet Commission on 70 years of women's reproductive, maternal, newborn, child, and adolescent health in China. The Lancet. 2021;397(10293):2497-536.

30.      Wang W, Liu F, Zhang Z, Zhang Y, Fan X, Liu R, et al. The Growth Pattern of Tibetan Infants at High Altitudes: a Cohort Study in Rural Tibet region. Sci Rep. 2016;6:34506.

31.      Moucheraud C, Gyal L, Gyaltsen K, Tsering L, Narasimhan S, Gipson J. Maternal Health Behaviors and Outcomes in a Nomadic Tibetan Population. Matern Child Health J. 2018; 22(2):264-73.