ABSTRACT

Methylation levels at the hypoxia-inducible factor 3α gene (HIF3A) in blood have been linked to body mass index (BMI) in adults. Despite evidence implicating HIF3A in angiogenesis and metabolism, no studies have examined links between HIF3A methylation in early life and cardiovascular health. Here, we investigated the relationship between HIF3A methylation in blood at birth and 12 months of age with cardiovascular measures at 4 years. We also examined influences of prenatal exposures, birth outcomes, and genetic variation. Methylation of two HIF3A promoter regions in cord blood was measured using Sequenom EpiTYPER mass-spectrometry. The first promoter region was also measured in 12-month blood. Four-year cardiovascular measures included blood pressure, pulse wave velocity, and aortic and carotid intima-media thickness. Associations were tested using partial correlation tests and linear regression modelling. Methylation of the first HIF3A promoter in cord and 12-month blood was not associated with four-year measures. There was modest evidence of an association between DNA methylation at the second HIF3A promoter in cord blood and four-year systolic blood pressure (n = 353, r = 0.12, p = 0.03). In sex-stratified analysis, methylation of the second promoter was modestly associated with systolic and diastolic blood pressure (r = 0.16, p = 0.03 for both) in males only. In conclusion, HIF3A methylation at birth shows some evidence of an association with later blood pressure in childhood. Further work should determine whether this relationship persists into later childhood, and should assess potential functional links between HIF3A methylation and cardiovascular health more generally.

摘要

血液中缺氧诱导因子3α基因（HIF3A）的甲基化水平已与成年人的体重指数（BMI）相关。尽管有证据表明HIF3A参与血管生成和代谢，但尚无研究检查HIF3A甲基化与早期心血管疾病之间的联系。在这里，我们调查了出生时和12个月大时血液中HIF3A甲基化与4岁时的心血管测量之间的关系。我们还检查了产前暴露，出生结局和遗传变异的影响。两个HIF3A的甲基化使用Sequenom EpiTYPER质谱仪测量脐带血中的启动子区域。在12个月的血液中也测量了第一启动子区域。四年的心血管测量包括血压，脉搏波速度以及主动脉和颈动脉内膜中层厚度。使用偏相关检验和线性回归模型对关联进行检验。脐带血和12个月血液中第一个HIF3A启动子的甲基化与四年措施无关。有少量证据表明第二个HIF3A的DNA甲基化之间存在关联脐血和四年收缩压中的启动子（n = 353，r = 0.12，p = 0.03）。在按性别分层的分析中，仅在男性中，第二个启动子的甲基化与收缩压和舒张压适度相关（r = 0.16，p和0.03）。总之，出生时的HIF3A甲基化显示出一些证据表明其与儿童期以后的血压相关。进一步的工作应确定这种关系是否持续到儿童晚期，并应更广泛地评估HIF3A甲基化与心血管健康之间的潜在功能联系。