二甲双胍靶点对胎儿神经系统畸形影响的遗传学证据

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

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。

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.

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

Key words

Gestational diabetes mellitus / Metformin / PRKAB1 / Congenital neural system malformations / Drug-target Mendelian randomization

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基金资助

国家自然科学基金专项项目(T2341018)

国家自然科学基金青年科学基金项目(82404378)

山东省青年科技人才托举工程(SDAST2024QTB020)