DNA methylation mediates the effect of BMI on insulin-treated gestational diabetes mellitus
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摘要:
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212 991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6 348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。 -
关键词:
- 胰岛素-妊娠期糖尿病 /
- BMI /
- 因果推断检验 /
- 中介效应
Abstract: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 212 991 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 6 348 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. -
表 1 44例I-GDM病例与64例对照的基线特征(x±s)
Table 1. Baseline characteristics of 44 I-GDM cases and 64 controls (x±s)
变量 对照(64例) 病例(44例) t/χ2值 P值 孕龄(岁) 30.09±5.09 31.16±4.58 -1.11 0.268 胎龄(周) 39.41±1.28 38.95±1.43 1.72 0.088 胎儿出生体重(g) 3 360.94±535.72 3 559.89±500.99 -1.95 0.054 血液pH值 7.30±0.09 7.27±0.08 2.02 0.046 BMI(kg/m2) 25.25±5.63 28.23±6.13 -2.60 0.011 孕妇身高(cm) 165.73±8.74 166.82±6.69 -0.69 0.489 怀孕前孕妇体重(kg) 71.19±16.15 80.07±17.79 -2.69 0.008 出生后孕妇体重(kg) 84.90±16.21 93.14±17.92 -2.44 0.016 出生方式a[n(%)] 0.36 0.547 剖腹产 15(24.6) 8(19.5) 顺产 46(71.9) 33(75.0) 胎儿性别[n(%)] 0.05 0.816 男 32(50.0) 23(52.3) 女 32(50.0) 21(47.7) 孕妇是否吸烟a[n(%)] 0.01 0.941 是 5(10.9) 5(11.4) 否 41(64.1) 39(88.6) 注：a存在数据缺失。 
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表 2 候选CpG位点信息及CIT分析结果
Table 2. Candidate CpG site information and CIT analysis results
CpG位点 染色体 位置 基因 参考基因区 CIT检验条件的P值 Y~X Y~M|X M~X|Y X⊥Y|M cg00542041 chr1 1272559 DVL1 Body 0.010 0.024 0.035 0.033 cg08589721 chr1 1370722 VWA1 TSS200 0.010 0.044 0.002 0.045 cg25775742 chr1 2337977 PEX10 Body 0.010 0.019 0.034 0.024 cg15819225 chr1 3583333 TP73 5’UTR 0.010 0.016 0.041 0.041 cg26824326 chr1 9664366 TMEM201 Body, 3’UTR 0.010 0.048 0.004 0.030 cg15110463 chr1 27113560 PIGV TSS1500 0.010 0.040 0.026 0.033
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表 3 BMI与I-GDM的中介效应分析
Table 3. Mediation analysis between BMI and I-GDM
CpG位点 染色体 位置 基因 CME DE TE 中介比例 效应值 95% CI P值 cg00542041 chr1 1272559 DVL1 0.001 3 (0.000 0~0.005 2) 0.026 0.004 4 0.005 8 22.3% cg08589721 chr1 1370722 VWA1 0.001 5 (0.000 0~0.006 1) 0.043 0.004 1 0.005 6 26.1% cg25775742 chr1 2337977 PEX10 0.001 4 (0.000 0~0.005 3) 0.020 0.004 3 0.005 8 24.1% cg15819225 chr1 3583333 TP73 0.001 3 (0.000 0~0.005 7) 0.018 0.004 2 0.005 6 23.8% cg26824326 chr1 9664366 TMEM201 0.001 4 (0.000 0~0.005 9) 0.048 0.004 0 0.005 4 25.2% cg15110463 chr1 27113560 PIGV 0.001 3 (0.000 0~0.005 3) 0.043 0.004 5 0.005 9 21.5%
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