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Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis.
Clinical Epigenetics ( IF 5.7 ) Pub Date : 2020-04-30 , DOI: 10.1186/s13148-020-00852-2
Edwina H Yeung 1 , Weihua Guan 2 , Xuehuo Zeng 3 , Lucas A Salas 4 , Sunni L Mumford 1 , Paula de Prado Bert 5, 6, 7 , Evelien R van Meel 8, 9 , Anni Malmberg 10 , Jordi Sunyer 5, 6, 7, 11 , Liesbeth Duijts 8, 9 , Janine F Felix 8, 9 , Darina Czamara 12 , Esa Hämäläinen 13 , Elisabeth B Binder 12, 14 , Katri Räikkönen 10 , Jari Lahti 10 , Stephanie J London 15 , Robert M Silver 16 , Enrique F Schisterman 1
Affiliation  

BACKGROUND 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. RESULTS 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. CONCLUSIONS 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. TRIAL REGISTRATION Clinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363.

中文翻译:

脐带血DNA甲基化反映的是脐带血C反应蛋白水平,而不是母亲水平:一项纵向研究和荟萃分析。

背景技术已经提出产前炎症是几种不良妊娠结局中的重要介导因素。C反应蛋白(CRP)是一种在血液中容易测量的炎症细胞因子。由于其作为系统性炎症的生物标记物的可靠性,因此具有临床价值,并且可以指示细胞损伤和疾病严重性。成年后CRP水平升高与DNA甲基化改变有关。然而,尚无研究前瞻性研究脐带血中具有合理的表观基因组范围覆盖的母体CRP水平与新生儿DNA甲基化之间的关系。重要的是,怀孕期间接触炎症的时机也可能导致不同的影响。从而,我们的目标是评估在多个妊娠期间和分娩时脐带血中测得的CRP水平的这种前瞻性关联,该关联可在一个队列中使用(即,阿司匹林在妊娠和生殖试验中的作用),并进行荟萃分析并从妊娠和儿童表观遗传学联盟(PACE)的其他三个队列中获得妊娠某一时刻的可用数据。其次,评估了孕期母亲随机给予低剂量阿司匹林对甲基化的影响。结果无论孕周如何,孕妇的CRP水平均与新生儿的DNA甲基化无关(例如,在EAGeR的358名新生儿中,CRP在大约8、20和36周时出现)。荟萃分析中也没有关联(所有p> 0。5)从所有参与的PACE队列中获得更大的样本量(n = 1603),并具有早孕期(小于18周)的可用CRP数据。阿司匹林的随机化与DNA甲基化无关。另一方面,在EAGeR试验中,新生儿CRP水平与DNA甲基化显着相关,当在脐带血中同时测量CRP和甲基化时,鉴定出33种CpG(FDR校正p <0.05)。与CRP相关性最高的前7个CpG位于炎症和血管相关基因中。结论在每个孕期测量的孕妇CRP水平与脐血DNA甲基化无关。相反,DNA甲基化与脐带血,尤其是主要与血管生成和炎症途径相关的基因区域中测得的CRP水平相关。
更新日期:2020-04-30
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