Journal of Shandong University (Health Sciences) ›› 2026, Vol. 64 ›› Issue (6): 86-93.doi: 10.6040/j.issn.1671-7554.0.2025.0928

• Public Health and Preventive Medicine • Previous Articles    

Genetic evidence on the association of metformin targets with risk of fetal congenital nervous system malformations

JI Hanbing1,2, WU Yutong1,2, WU Sijia1,2, HUANG Xin3, LI Hongkai1,2, CHEN Hao1,2   

  1. 1. Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China;
    2. Institute for Medical Research, Cheeloo College of Medical, Shandong University, Jinan 250012, Shandong, China;
    3. China National Center for Biotechnology Development, Beijing 100039, China
  • Published:2026-06-29

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Abstract: Objective To systematically and separately evaluate whether genetic perturbations of the five established targets of metformin are causally associated with the risk of fetal congenital nervous system malformations(CNSM). Methods This study employed a drug-target Mendelian randomization approach. Summary data for five target genes(PRKAB1, GPD1, ETFDH, SLC47A1, and ACACB)were utilized, with their quantitative trait loci at transcriptomic and proteomic levels serving as instrumental variables. Causal inference was estimated using various methods, including inversevariance weighted. Key findings were then validated through colocalization analysis. Results Among the five targets examined, only metformins core pharmacodynamic target, PRKAB1, and its downstream target, ACACB, showed a significant causal association with a reduced risk of CNSM. This protective effect was validated at both transcriptomic level(OR=0.897, 95%CI: 0.808-0.997, P=0.043)and proteomic level(OR=0.709, 95%CI: 0.521-0.964, P=0.028). Analysis of the other three targets revealed no significant signals. Colocalization analysis supported the possibility that PRKAB1 and CNSM may share a common causal variant(PP.H4=0.654). Conclusion Among the multiple metformin-related pathways, the pathway mediated by its core target PRKAB1 may play a protective role in the development of the fetal nervous system. This finding provides novel, pathway-specific genetic evidence supporting the safety of metformin use during pregnancy.

Key words: Gestational diabetes mellitus, Metformin, PRKAB1, Congenital neural system malformations, Drug-target Mendelian randomization

CLC Number: 

  • R715.3
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