二甲双胍靶点对胎儿神经系统畸形影响的遗传学证据

doi:10.6040/j.issn.1671-7554.0.2025.0928

摘要/Abstract

摘要： 目的系统、分离评估二甲双胍5个已知相关靶点的遗传扰动,探讨是否分别与胎儿先天性神经系统畸形(congenital nervous system malformations, CNSM)的风险存在因果关联。方法采用药物靶向孟德尔随机化方法,选取PRKAB1、GPD1、ETFDH、SLC47A1和ACACB 5个靶点的转录组学及蛋白质组学汇总数据,以其数量性状基因座为遗传工具变量,采用逆方差加权等多种方法进行因果推断,并辅以共定位分析验证关键结果。结果在5个被检靶点中,仅二甲双胍的核心药效靶点PRKAB1及其下游靶点ACACB显示出与CNSM风险降低的显著因果关联,该保护效应在转录(OR=0.897, 95%CI: 0.808~0.997, P=0.043)和蛋白(OR=0.709, 95%CI: 0.521~0.964, P=0.028)两个层面均得到验证。其他3个靶点的分析未见显著信号。共定位分析支持PRKAB1与CNSM可能共享因果变异(PP.H4=0.654)。结论在二甲双胍的多个相关通路中,其通过核心靶点PRKAB1介导的通路可能对胎儿神经系统发育具有保护作用,为二甲双胍的孕期安全性提供了新的、具有通路特异性的遗传学证据支撑。

关键词: 妊娠期糖尿病, 二甲双胍, PRKAB1, 先天性神经系统畸形, 药物靶向孟德尔随机化

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

中图分类号:

R715.3

吉寒冰,吴雨桐,吴思佳,黄鑫,李洪凯,陈昊. 二甲双胍靶点对胎儿神经系统畸形影响的遗传学证据[J]. 山东大学学报 (医学版), 2026, 64(6): 86-93.

JI Hanbing, WU Yutong, WU Sijia, HUANG Xin, LI Hongkai, CHEN Hao. Genetic evidence on the association of metformin targets with risk of fetal congenital nervous system malformations[J]. Journal of Shandong University (Health Sciences), 2026, 64(6): 86-93.

参考文献

[1] ElSayed NA, McCoy RG, Aleppo G, et al. 15. Management of diabetes in pregnancy: standards of care in diabetes: 2025[J]. Diabetes Care, 2025, 48(s1): 306-320.
[2] He BT, Lam HS, Qiu X, et al. Association and mediation pathways of maternal hyperglycaemia and liability to gestational diabetes with neonatal outcomes: a two-sample Mendelian randomization study[J]. Diabetes Obes Metab, 2025, 27(2): 529-538.
[3] Sweeting A, Enticott J, Immanuel J, et al. Relationship between early-pregnancy glycemia and adverse outcomes: findings from the TOBOGM study[J]. Diabetes Care, 2024, 47(12): 2085-2092.
[4] Hivert MF, Backman H, Benhalima K, et al. Pathophysiology from preconception, during pregnancy, and beyond[J]. Lancet, 2024, 404(10448): 158-174.
[5] Venkatesh KK, Lynch CD, Powe CE, et al. Risk of adverse pregnancy outcomes among pregnant individuals with gestational diabetes by race and ethnicity in the United States, 2014-2020[J]. JAMA, 2022, 327(14): 1356-1367.
[6] Juan J, Yang HX. Prevalence, prevention, and lifestyle intervention of gestational diabetes mellitus in China[J]. Int J Environ Res Public Health, 2020, 17(24): 9517. doi:10.3390/ijerph17249517
[7] 中华医学会糖尿病学分会. 中国糖尿病防治指南(2024版)[J]. 中华糖尿病杂志, 2025, 17(1): 16-139. doi:10.3760/cma.j.cn115791-20241203-00705
[8] Paschou SA, Shalit A, Gerontiti E, et al. Efficacy and safety of metformin during pregnancy: an update[J]. Endocrine, 2024, 83(2): 259-269.
[9] He K, Guo Q, Ge J, et al. The efficacy and safety of metformin alone or as an add-on therapy to insulin in pregnancy with GDM or T2DM: a systematic review and meta-analysis of 21 randomized controlled trials[J]. J Clin Pharm Ther, 2022, 47(2): 168-177.
[10] Li F, Liu LG, Hu Y, et al. Efficacy and safety of metformin compared to insulin in gestational diabetes: a systemic review and meta-analysis of Chinese randomized controlled trials[J]. Int J Clin Pharm, 2022, 44(5): 1102-1113.
[11] Roy A, Sahoo J. Long-term effects of metformin use in gestational diabetes mellitus on offspring health[J]. World J Diabetes, 2021, 12(11): 1812-1817.
[12] Malek R, Davis SN. Is metformin safe in pregnancy: a focus on offspring outcomes[J]. Expert Opin Drug Saf, 2025, 24(1): 5-8.
[13] 肖建中. 二甲双胍的作用机制新进展[J]. 中华糖尿病杂志, 2024, 16(7): 735-739. XIAO Jianzhong. Update on the mechanisms of action of metformin[J]. Chinese Journal of Diabetes Mellitus, 2024, 16(7): 735-739.
[14] Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential[J]. Nat Rev Endocrinol, 2023, 19(8): 460-476.
[15] Sun MW, Lee JY, de Bakker PIW, et al. Haplotype structures and large-scale association testing of the 5' AMP-activated protein kinase genes PRKAA2, PRKAB1, and PRKAB2 with type 2 diabetes[J]. Diabetes, 2006, 55(3): 849-855.
[16] Muraleedharan R, Dasgupta B. AMPK in the brain: its roles in glucose and neural metabolism[J]. FEBS J, 2022, 289(8): 2247-2262.
[17] Rosso P, Fioramonti M, Fracassi A, et al. AMPK in the central nervous system: physiological roles and patholo-gical implications[J]. Res Rep Biol, 2016, 7: 1-13. doi:10.2147/RRB.S90858
[18] Knox C, Wilson M, Klinger CM, et al. DrugBank 6.0: the DrugBank knowledgebase for 2024[J]. Nucleic Acids Res, 2024, 52(1): 1265-1275.
[19] Ardissino M, Slob EAW, Reddy RK, et al. Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations[J]. Eur J Prev Cardiol, 2024, 31(8): 955-965.
[20] Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement[J]. JAMA, 2021, 326(16): 1614-1621.
[21] Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase[J]. Nature, 2014, 510(7506): 542-546.
[22] Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action[J]. J Clin Invest, 2001, 108(8): 1167-1174.
[23] Xu JX, Zhu QL, Bi YM, et al. New evidence: Metformin unsuitable as routine adjuvant for breast cancer: a drug-target Mendelian randomization analysis[J]. BMC Cancer, 2024, 24(1): 691. doi:10.1186/s12885-024-12453-w
[24] Chen PX, Cao YM, Chen SR, et al. Association of SLC22A1, SLC22A2, SLC47A1, and SLC47A2 polymorphisms with metformin efficacy in type 2 diabetic patients[J]. Biomedicines, 2022, 10(10): 2546. doi:10.3390/biomedicines10102546
[25] Võsa U, Claringbould A, Westra HJ, et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression[J]. Nat Genet, 2021, 53(9): 1300-1310.
[26] GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues[J]. Science, 2020, 369(6509): 1318-1330.
[27] Sun BB, Chiou J, Traylor M, et al. Plasma proteomic associations with genetics and health in the UK Biobank[J]. Nature, 2023, 622(7982): 329-338.
[28] Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population[J]. Nature, 2023, 613(7944): 508-518.
[29] Zuber V, Grinberg NF, Gill D, et al. Combining evidence from Mendelian randomization and colocalization: review and comparison of approaches[J]. Am J Hum Genet, 2022, 109(5): 767-782.
[30] 唐蕾, 白宇, 李玲, 等. 妊娠高血糖患者孕期应用二甲双胍的临床探索[J]. 中华糖尿病杂志, 2019, 11(9): 603-609. TANG Lei, BAI Yu, LI Ling, et al. Clinical experience of metformin in treating patients with hyperglycemia in pregnancy[J]. Chinese Journal of Diabetes Mellitus, 2019, 11(9): 603-609.
[31] Mason T, Alesi S, Fernando M, et al. Metformin in gestational diabetes: physiological actions and clinical applications[J]. Nat Rev Endocrinol, 2025, 21(2): 77-91.
[32] Yu YH, Platt RW, Reynier P, et al. Metformin and risk of adverse pregnancy outcomes among pregnant women with gestational diabetes in the United Kingdom: a population-based cohort study[J]. Diabetes Obes Metab, 2025, 27(2): 976-986.
[33] Given JE, Loane M, Garne E, et al. Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study[J]. BMJ, 2018, 361: k2477. doi:10.1136/bmj.k2477
[34] Panchaud A, Rousson V, Vial T, et al. Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information ser-vices[J]. BrJClinPharmacol, 2018, 84(3): 568-578.

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