Maternal Dietary Glycemic Index and Glycemic Load in Pregnancy and Offspring Cord Blood DNA Methylation

<strong>Abstract</strong> <strong>Objective</strong>: Suboptimal nutrition in pregnancy is associated with worse offspring cardiometabolic health. DNA methylation may be an underlying mechanism. We meta-analyzed epigenome-wide association studies (EWASs) of maternal dietary glycemic index and load with cord blood DNA methylation. <strong>Research Design and Methods</strong>: We calculated maternal glycemic index and load from food frequency questionnaires, and ran EWASs on cord blood DNA methylation in 2003 mother-offspring pairs from three cohorts. Analyses were additionally stratified by maternal BMI categories. We looked-up the findings in EWASs of maternal glycemic traits and BMI, and in EWASs of birthweight and child BMI. We examined associations with gene expression in child blood in the online Human Early Life Exposome eQTM catalogue and in 223 adipose tissue samples. <strong>Results</strong>: Maternal glycemic index and load were associated with cord blood DNA methylation at 41 cytosine-phosphate-guanine sites (CpGs, P&lt;1.17x10^-7), mostly in mothers with overweight/obesity. We did not observe overlap with CpGs associated with maternal glycemic traits, BMI or child birthweight or BMI. Only DNA methylation at cg24458009 and cg23347399 was associated with expression of <em>PCED1B</em> and <em>PCDHG</em>, respectively, in child blood, and DNA methylation at cg27193519 was associated with expression of <em>TFAP4</em>, <em>ZNF500</em>, <em>PPL</em> and <em>ANKS3</em> in child subcutaneous adipose tissue. <strong>Conclusions</strong>: We observed multiple associations of maternal glycemic index and load during pregnancy with cord blood DNA methylation, mostly in mothers with overweight/obesity; some of these CpGs were associated with gene expression. Additional studies are required to further explore functionality, uncover causality, and study pathways to offspring health.**摘要** **研究目的**：妊娠期营养摄入不佳与子代心血管代谢健康状况较差相关，DNA甲基化可能是其潜在介导机制。本研究针对母亲膳食血糖指数（glycemic index, GI）与血糖负荷（glycemic load, GL）和脐血DNA甲基化的关联，开展了表观全基因组关联研究（Epigenome-wide Association Study, EWAS）的荟萃分析。 **研究设计与方法**：本研究通过食物频率问卷计算母亲的膳食血糖指数与血糖负荷，并对来自三项队列的2003对母婴对的脐血DNA甲基化数据开展EWAS分析。此外，我们按母亲的体质量指数（body mass index, BMI）分层进行亚组分析。我们进一步在母亲血糖性状与BMI的EWAS、以及子代出生体质量与儿童BMI的EWAS中验证了本研究发现。同时，我们依托在线人类早期生命暴露组表达数量性状甲基化（expression quantitative trait methylation, eQTM）目录，以及223例脂肪组织样本，分析了上述关联位点与儿童血液基因表达的相关性。 **研究结果**：母亲膳食血糖指数与血糖负荷与41个胞嘧啶-磷酸-鸟嘌呤位点（cytosine-phosphate-guanine site, CpG位点）的脐血DNA甲基化水平存在显著关联（P<1.17×10⁻⁷），上述关联主要见于体质量超重/肥胖的母亲亚组。本研究未观察到这些CpG位点与母亲血糖性状、BMI，或子代出生体质量、儿童BMI相关的CpG位点存在重叠。仅cg24458009位点的DNA甲基化与儿童血液中*PCED1B*基因的表达相关，cg23347399位点与*PCDHG*基因的表达相关；此外，cg27193519位点的DNA甲基化与儿童皮下脂肪组织中*TFAP4*、*ZNF500*、*PPL*及*ANKS3*基因的表达相关。 **研究结论**：本研究发现，妊娠期母亲的膳食血糖指数与血糖负荷与脐血DNA甲基化存在多处显著关联，上述关联主要见于体质量超重/肥胖的母亲群体；其中部分CpG位点与基因表达存在相关性。未来仍需开展更多研究以进一步探索其功能、明确因果关系，并阐明其对子代健康的作用通路。