High Maternal Glycine Levels Increase the Risk of Developing Atrial Septal Defect in the Offspring

Ya-Nan Qiao; Wei-Cheng Chen; Yu-Ling Chen; Jie Xiang; Yu-Fan Ke; Li Cao; Lei Li; Jing Cao; Rui Zhao; Jian-Yuan Zhao

doi:10.1016/j.jacbts.2025.05.006

High Maternal Glycine Levels Increase the Risk of Developing Atrial Septal Defect in the Offspring

JACC Basic Transl Sci. 2025 Jun 24;10(7):101311. doi: 10.1016/j.jacbts.2025.05.006. Online ahead of print.

Authors

Ya-Nan Qiao¹, Wei-Cheng Chen², Yu-Ling Chen³, Jie Xiang³, Yu-Fan Ke³, Li Cao², Lei Li⁴, Jing Cao⁴, Rui Zhao⁵, Jian-Yuan Zhao⁶

Affiliations

¹ Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
² National Health Commission (NHC) Key Laboratory of Neonatal Diseases, School of Life Sciences, Children's Hospital of Fudan University, Obstetrics and Gynecology Hospital of Fudan University, Fudan University, Shanghai, China.
³ Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
⁵ Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: zr_gre@hotmail.com.
⁶ Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; International Human Phenome Institutes (Shanghai), Shanghai, China. Electronic address: zhaojianyuan1508@xinhuamed.com.cn.

PMID: 40561639
DOI: 10.1016/j.jacbts.2025.05.006

Abstract

Amino acid imbalance is linked to increased congenital heart disease risk. Here, we found women carrying rs2545801 C/C genotypes exhibited increased glycine levels and increased risk for atrial septal defects (ASDs) in their offspring. Elevated maternal glycine levels during the first trimester were correlated with a higher ASD risk in the offspring. Additionally, feeding pregnant mice with high-glycine chow increased ASD risk in their offspring. Mechanistically, elevated maternal glycine led to increased lysine-glycylation of lysine-688 within the TEK receptor tyrosine kinase and inhibited TEK-PI3K-AKT/FOXO1 signaling in cardiac endothelial cells. These findings indicate that lysine-glycylation exerts teratogenic effects and may be a target for ASD intervention.

Keywords: TEK; atrial septal defects; glycine; maternal single-nucleotide variation; pregnancy serum.