Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Dr, MSC 7004, Bethesda, MD, 20817, USA.
Division of Biostatistics, School of Public Health, University of Minnesota, A460 Mayo Building, MMC 303, 420 Delaware St. SE, Minneapolis, MN, 55455, USA.
Clin Epigenetics. 2020 Apr 30;12(1):60. doi: 10.1186/s13148-020-00852-2.
Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed.
Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (< 18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p < 0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes.
Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways.
Clinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363.
产前炎症被认为是多种不良妊娠结局的重要中介因素。C 反应蛋白（CRP）是一种在血液中容易测量的炎症细胞因子。由于其作为全身炎症生物标志物的可靠性，CRP 具有临床价值，并且可以指示细胞损伤和疾病严重程度。成年期 CRP 水平升高与 DNA 甲基化改变有关。然而，尚无研究前瞻性地调查妊娠期间 CRP 水平与新生儿脐带血中通过微阵列测量的 DNA 甲基化之间的关系，并且合理的全基因组范围内的 DNA 甲基化也没有。重要的是，怀孕期间炎症暴露的时间也可能导致不同的影响。因此，我们的目的是评估在一个队列（即妊娠和生殖中的阿司匹林作用试验）中测量的多个妊娠期间和分娩时脐带血中的 CRP 水平与现有数据的荟萃分析之间的这种前瞻性关联来自妊娠和儿童表观遗传学联盟（PACE）的三个其他队列中的一个时间点。其次，评估母亲在妊娠前随机分配低剂量阿司匹林对甲基化的影响。
无论测量的妊娠龄如何（即在 EAGeR 中，358 名新生儿中约 8、20 和 36 周的 CRP），母体 CRP 水平与新生儿 DNA 甲基化均无关。荟萃分析也没有关联（所有 p>0.5），样本量更大（n = 1603），所有参与 PACE 队列的研究均有来自妊娠早期（<18 周妊娠）的 CRP 数据。随机分配给阿司匹林与 DNA 甲基化无关。另一方面，在 EAGeR 试验中，新生儿 CRP 水平与 DNA 甲基化显著相关，当同时在脐带血中测量 CRP 和甲基化时，鉴定出 33 个 CpG（经 FDR 校正的 p <0.05）。与 CRP 强相关的前 7 个 CpG 位于炎症和血管相关基因中。
每个三个月测量的母体 CRP 水平与脐带血 DNA 甲基化无关。相反，DNA 甲基化与脐带血中 CRP 水平相关，特别是在主要与血管生成和炎症途径相关的基因区域。
Clinicaltrials.gov，NCT00467363，注册于 2007 年 4 月 30 日，http://www.clinicaltrials.gov/ct2/show/NCT00467363。
