克隆性造血不定潜能、DNA 甲基化与冠状动脉疾病风险。
Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease.
机构信息
Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
出版信息
Nat Commun. 2022 Sep 12;13(1):5350. doi: 10.1038/s41467-022-33093-3.
Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.
年龄相关的全基因组 DNA 甲基化（DNAm）模式在血液中的变化已有充分的记录。具有不确定潜能的克隆性造血（CHIP）的特征是造血干细胞（HSCs）中与年龄相关的白血病突变的获得和扩增，与血液癌和冠状动脉疾病（CAD）有关。表观遗传调节剂 DNMT3A 和 TET2 是最常突变的 CHIP 基因。在这里，我们展示了在 582 名心血管健康研究（CHS）参与者中进行的 CHIP 全基因组关联研究的结果，并在 2655 名社区动脉粥样硬化风险研究（ARIC）参与者中进行了复制。我们表明，DNMT3A 和 TET2 CHIP 具有不同的、方向相反的全基因组 DNAm 关联模式，与它们的调节作用一致，尽管两者都促进 HSCs 的自我更新。孟德尔随机化分析表明，与这两个主要的 CHIP 基因相关的 DNAm 改变的一部分可能会增加 CAD 的风险。
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