Maternal glycemia in pregnancy is longitudinally associated with blood DNAm variation at the FSD1L gene from birth to 5 years of age.

IF 5.7 2区 医学 Q1 Medicine
Amélie Taschereau, Kathrine Thibeault, Catherine Allard, Diana Juvinao-Quintero, Patrice Perron, Sharon M Lutz, Luigi Bouchard, Marie-France Hivert
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引用次数: 0

Abstract

Background: In utero exposure to maternal hyperglycemia has been associated with an increased risk for the development of chronic diseases in later life. These predispositions may be programmed by fetal DNA methylation (DNAm) changes that persist postnatally. However, although some studies have associated fetal exposure to gestational hyperglycemia with DNAm variations at birth, and metabolic phenotypes in childhood, no study has yet examined how maternal hyperglycemia during pregnancy may be associated with offspring DNAm from birth to five years of age.

Hypothesis: Maternal hyperglycemia is associated with variation in offspring DNAm from birth to 5 years of age.

Methods: We estimated maternal hyperglycemia using the area under the curve for glucose (AUCglu) following an oral glucose tolerance test conducted at 24-30 weeks of pregnancy. We quantified DNAm levels in cord blood (n = 440) and peripheral blood at five years of age (n = 293) using the Infinium MethylationEPIC BeadChip (Illumina). Our total sample included 539 unique dyads (mother-child) with 194 dyads having DNAm at both time-points. We first regressed DNAm M-values against the cell types and child age for each time-point separately to account for the difference by time of measurement for these variables. We then used a random intercept model from the linear mixed model (LMM) framework to assess the longitudinal association between maternal AUCglu and the repeated measures of residuals of DNAm. We adjusted for the following covariates as fixed effects in the random intercept model: maternal age, gravidity, smoking status, child sex, maternal body mass index (BMI) (measured at first trimester of pregnancy), and a binary variable for time-point.

Results: In utero exposure to higher maternal AUCglu was associated with lower offspring blood DNAm levels at cg00967989 located in FSD1L gene (β = - 0.0267, P = 2.13 × 10-8) in adjusted linear regression mixed models. Our study also reports other CpG sites for which DNAm levels were suggestively associated (P < 1.0 × 10-5) with in utero exposure to gestational hyperglycemia. Two of these (cg12140144 and cg07946633) were found in the promotor region of PRDM16 gene (β: - 0.0251, P = 4.37 × 10-07 and β: - 0.0206, P = 2.24 × 10-06, respectively).

Conclusion: Maternal hyperglycemia is associated with offspring DNAm longitudinally assessed from birth to 5 years of age.

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从出生到 5 岁期间,孕妇的血糖与 FSD1L 基因的血液 DNAm 变异纵向相关。
背景:胎儿在子宫内暴露于母体高血糖与日后罹患慢性疾病的风险增加有关。胎儿 DNA 甲基化(DNAm)的变化可能会导致这些易感性在出生后持续存在。然而,尽管一些研究将胎儿暴露于妊娠期高血糖与出生时的 DNAm 变异以及儿童期的代谢表型联系起来,但还没有研究探讨孕期母体高血糖如何与出生至 5 岁的后代 DNAm 相关:假设:母体高血糖与后代从出生到 5 岁 DNAm 的变化有关:方法:我们利用妊娠24-30周时进行的口服葡萄糖耐量试验的葡萄糖曲线下面积(AUCglu)来估计母体的高血糖情况。我们使用Infinium MethylationEPIC BeadChip(Illumina)芯片对脐带血(n = 440)和五岁时外周血(n = 293)中的DNAm水平进行了量化。我们的总样本包括 539 个独特的双亲(母子),其中 194 个双亲在两个时间点都有 DNAm。我们首先将每个时间点的 DNAm M 值分别与细胞类型和儿童年龄进行回归,以考虑这些变量在测量时间上的差异。然后,我们使用线性混合模型(LMM)框架中的随机截距模型来评估母体 AUCglu 与 DNAm 的重复测量残差之间的纵向联系。在随机截距模型中,我们将以下协变量作为固定效应进行了调整:母体年龄、孕期、吸烟状况、儿童性别、母体体重指数(BMI)(在妊娠头三个月测量),以及时间点的二进制变量:结果:在调整后的线性回归混合模型中,母体较高的 AUCglu 与位于 FSD1L 基因 cg00967989 处较低的子代血液 DNAm 水平相关(β = - 0.0267,P = 2.13 × 10-8)。我们的研究还报告了 DNAm 水平与子宫内妊娠高血糖相关的其他 CpG 位点(P -5)。其中两个 CpG 位点(cg12140144 和 cg07946633)位于 PRDM16 基因的启动子区域(分别为 β:- 0.0251,P = 4.37 × 10-07 和 β:- 0.0206,P = 2.24 × 10-06):结论:从出生到 5 岁的纵向评估发现,母亲的高血糖与后代的 DNAm 有关。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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