DNA甲基化介导BMI对胰岛素-妊娠期糖尿病的中介效应

DNA methylation mediates the effect of BMI on insulin-treated gestational diabetes mellitus

目的探索DNA甲基化是否为BMI和胰岛素-妊娠期糖尿病(insulin-treated gestational diabetes mellitus,I-GDM)之间的中介变量,并估计其中介效应。方法研究资料来自基因表达数据库(gene expression omnibus,GEO),检索号为GSE88929,由产科医生收集44例I-GDM病例和64例对照,共纳入212991个胞嘧啶-磷酸-鸟嘌呤双核苷酸(cytosine-phosphate-guanine pairs of nucleotides,CpG)位点。采用因果推断检验(causal inference test,CIT)筛选出潜在的中介CpG位点。调整孕龄、胎儿性别和胎龄三个混杂因素,进一步通过CpG位点估计BMI对I-GDM的中介效应。结果CIT过程第一步结果表明BMI与I-GDM有关联(OR=1.057,95%CI:1.014~1.105,P=0.010);第二步调整BMI,采用伪发现率(false discorery rate,FDR)方法进行多重检验校正,共筛选出与I-GDM相关联的6348个CpG位点纳入下一步分析;第三步调整I-GDM后,确定529个CpG位点分别与BMI有关联;第四步分别调整6个CpG位点后,BMI与I-GDM相互独立。因此,CIT检验出6个CpG位点(cg00542041、cg08589721、cg25775742、cg15819225、cg26824326、cg15110463)作为BMI与I-GDM的中介变量。进一步采用中介分析因果推断模型,证实上述6个CpG存在中介效应。结论本研究发现6个DNA甲基化CpG位点在BMI和I-GDM之间发挥了中介作用,均可能作为I-GDM发病机制中新的生物标记物,为研究BMI和I-GDM之间复杂的生物学机制提供了参考依据。

Objective To explore the mediate role of DNA methylation between body mass index(BMI)and insulin-treated gestational diabetes mellitus(I-GDM)and further estimate its mediation effect.Methods Based on Gene Expression Omnibus(GEO)data repository(accession number GSE88929),obstetricians collected 44 I-GDM and 64 controls,which included a total of 212991 cytosine-phosphate-guanine pairs of nucleotides(CpG)sites.A causal inference test(CIT)was used to select potential mediator of CpG sites.Furthermore,after adjusting for confounding factors including maternal age,fetal sex,and gestational age,we estimated the mediation effect of BMI on I-GDM by CpG sites.Results In CIT process,step 1 results showed that BMI was associated with I-GDM(OR=1.057,95%CI:1.014-1.105,P=0.010).Step 2 results indicated that 6348 CpG after adopting FDR correction were associated with I-GDM conditional on BMI.Step 3 results manifested that 529 CpG were associated with BMI adjusting for I-GDM.Step 4 results showed that I-GDM was independent of BMI after adjusting 6 CpG.Therefore,CIT detected 6 CpG sites(cg00542041,cg08589721,cg25775742,cg15819225,cg26824326,cg15110463)as mediators between BMI and I-GDM.The above 6 CpG showed significant mediation effects by a causal inference model of mediation analysis.Conclusion Our research identified 6 DNA methylation CpG sites,which represent a potential mediation relationship between BMI and I-GDM.These findings suggest that the 6 CpG may serve as novel biomarkers and provide an essential reference for studying the complex biological mechanism between BMI and I-GDM.