背景:Corin蛋白及其编码基因变体与妊娠高血压疾病(HDP)有关,但潜在的机制尚不清楚。作为将固定基因组与动态环境联系起来的中介,CORIN基因的DNA甲基化可能将corin与HDP联系起来,但尚未进行研究。本研究旨在检测中国孕妇中CORIN启动子是否甲基化和HDP。
方法:基于中国孕妇队列,我们设计了一项巢式病例对照研究,包括196例HDP患者和200例健康对照.在20孕周之前使用外周血通过焦磷酸测序定量CORIN启动子中的DNA甲基化水平。通过单CpG关联分析系统地检查了CORIN启动子中DNA甲基化与HDP之间的关联,其次是基于基因的分析。多重测试由错误发现率(FDR)方法控制。
结果:单CpG关联分析发现,在测定的5个CpG位点中,一个CpG位点的高甲基化(Chr4:47839945)与HDP显著相关(OR=1.94,原始P=0.020),但对于多重检验校正(FDR-P=0.100),显著性并不存在.基于基因的关联分析发现5个CpG位点的DNA甲基化与HDP共同相关(原始P=0.003)。除了HDP,CORIN启动子甲基化也与妊娠期动态血压显著相关(P<0.05)。
结论:中国妇女妊娠早期CORIN启动子甲基化与妊娠晚期HDP风险相关。然而,需要进一步的证据来确定CORIN启动子甲基化与HDP之间的因果关系。
Corin protein and its coding gene variants have been associated with hypertensive disorders of pregnancy (HDP), but the underlying mechanisms are unclear. As a mediator linking fixed genome with the dynamic environment, DNA methylation at the CORIN gene may link corin with HDP but not has been studied. This
study aimed to examine whether CORIN promoter methylation and HDP in Chinese pregnant women.
Based on a cohort of Chinese pregnant women, we designed a nested case-control
study including 196 cases with HDP and 200 healthy controls. DNA methylation levels in the CORIN promoter were quantified by pyrosequencing using peripheral blood before 20 gestational weeks. The association between DNA methylation in CORIN promoter and HDP was systemically examined by single CpG association analysis, followed by gene-based analysis. Multiple testing was controlled by the false discovery rate (FDR) method.
The single CpG association analysis found that, among the 5 CpG sites assayed, hypermethylation at one CpG site (Chr4:47839945) was significantly associated with HDP (OR = 1.94, raw P = 0.020), but the significance did not survive for multiple testing correction (FDR-P = 0.100). The gene-based association analysis found that DNA methylation of the 5 CpG sites was jointly associated with HDP (raw P = 0.003). In addition to HDP, CORIN promoter methylation was also significantly associated with dynamic blood pressure during pregnancy (raw P < 0.05).
Hypermethylation in CORIN promoter at early pregnancy was associated with the risk of HDP during late pregnancy in Chinese women. However, further evidence is required to establish the causality between CORIN promoter methylation and HDP.