Department of Epidemiology and Prevention, IRCCS NEUROMED, Pozzilli, IS, Italy.
Department of Medicine and Surgery, University of Insubria, Varese, Italy.
Clin Epigenetics. 2019 May 10;11(1):74. doi: 10.1186/s13148-019-0665-6.
Zinc finger and BTB domain-containing protein 12 (ZBTB12) is a predicted transcription factor with potential role in hematopoietic development. Recent evidence linked low methylation level of ZBTB12 exon1 to myocardial infarction (MI) risk. However, the role of ZBTB12 in the pathogenesis of MI and cardiovascular disease in general is not yet clarified. We investigated the relation between ZBTB12 methylation and several blood parameters related to cardio-cerebrovascular risk in an Italian family-based cohort.
ZBTB12 methylation was analyzed on white blood cells from the Moli-family cohort using the Sequenom EpiTYPER MassARRAY (Agena). A total of 13 CpG Sequenom units were analyzed in the small CpG island located in the only translated ZBTB12 exon. Principal component analysis (PCA) was performed to identify groups of CpG units with similar methylation estimates. Linear mixed effect regressions showed a positive association between methylation of ZBTB12 Factor 2 (including CpG units 8, 9-10, 16, 21) and TNF-ɑ stimulated procoagulant activity, a measure of procoagulant and inflammatory potential of blood cells. In addition, we also found a negative association between methylation of ZBTB12 Factor 1 (mainly characterized by CpG units 1, 3-4, 5, 11, and 26) and white blood cell and granulocyte counts. An in silico prediction analysis identified granulopoiesis- and hematopoiesis-specific transcription factors to potentially bind DNA sequences encompassing CpG1, CpG3-4, and CpG11.
ZBTB12 hypomethylation is linked to shorter TNF-ɑ stimulated whole blood coagulation time and increased WBC and granulocyte counts, further elucidating the possible link between ZBTB12 methylation and cardiovascular disease risk.
锌指和 BTB 结构域蛋白 12（ZBTB12）是一种预测的转录因子，可能在造血发育中发挥作用。最近的证据表明，ZBTB12 外显子 1 的低甲基化水平与心肌梗死（MI）风险相关。然而，ZBTB12 在 MI 发病机制和一般心血管疾病中的作用尚不清楚。我们在一个意大利基于家族的队列中研究了 ZBTB12 甲基化与几个与心脑血管风险相关的血液参数之间的关系。
使用 Sequenom EpiTYPER MassARRAY（Agena）在 Moli 家族队列的白细胞上分析了 ZBTB12 甲基化。在唯一翻译的 ZBTB12 外显子中，分析了位于小 CpG 岛上的 13 个 CpG Sequenom 单位。进行主成分分析（PCA）以识别具有相似甲基化估计值的 CpG 单位组。线性混合效应回归显示 ZBTB12 因子 2（包括 CpG 单位 8、9-10、16、21）的甲基化与 TNF-ɑ 刺激的促凝活性呈正相关，促凝活性是血细胞促凝和炎症潜能的指标。此外，我们还发现 ZBTB12 因子 1（主要由 CpG 单位 1、3-4、5、11 和 26 组成）的甲基化与白细胞和粒细胞计数呈负相关。计算机预测分析鉴定了粒细胞生成和造血特异性转录因子，以潜在地结合包含 CpG1、CpG3-4 和 CpG11 的 DNA 序列。
ZBTB12 低甲基化与 TNF-ɑ 刺激全血凝固时间缩短以及白细胞和粒细胞计数增加有关，进一步阐明了 ZBTB12 甲基化与心血管疾病风险之间的可能联系。
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