全基因组分析 DNA 甲基化与急性冠状动脉综合征

Genome-Wide Analysis of DNA Methylation and Acute Coronary Syndrome.

机构信息

From the Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (J.L., X. Zhu, K.Y., H.J., Y.Z., S.D., X. Liu, X. Zhang, M.H., W.C., J.Y., Y.B., X. Han, B.L., X. He, H.S., C.L., Y.G., B.Z., Z.Z., A.P., Y.Y., F.A., T.W.); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (J.L., L.Q., F.B.H.); Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (L.C., Q.Z., X.M., Y.P., Y.M.); Environmental Health Science, Columbia University Mailman School of Public Health, New York, NY (J.Z.); Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (M.G., B.M., F.Z.); Department of Cardiology, People's Hospital of Zhuhai, Guangdong, China (X. Luo, W.M.); Department of Cardiology, Bao'an Hospital, Shenzhen, Guangdong, China (S.S.); Department of Cardiology, Wuhan Central Hospital, Wuhan, Hubei, China (L.Z., P.H.); Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (H.Z.); Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA (J.H., L.L.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, China (Q.K.W.).

出版信息

Circ Res. 2017 May 26;120(11):1754-1767. doi: 10.1161/CIRCRESAHA.116.310324. Epub 2017 Mar 27.

DOI:10.1161/CIRCRESAHA.116.310324

PMID:28348007

Abstract

RATIONALE

Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development; however, whether epigenetic modulation contributes to the regulation of blood immune cells in this disease has not been investigated.

OBJECTIVE

We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS.

METHODS AND RESULTS

We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in 6 purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 cytosine-phosphoguanine sites (discovery: false discovery rate <0.005; replication: Bonferroni corrected <0.05). The association of methylation levels at these cytosine-phosphoguanine sites with ACS was further validated in at least 1 of the 6 leukocyte subsets, with predominant contributions from CD8 T cells, CD4 T cells, and B cells. Blood methylation of 26 replicated cytosine-phosphoguanine sites showed significant correlation with expressions of annotated genes (including , , and ; <5.9×10), and differential gene expression in case versus controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis, and T-cell-mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated cytosine-phosphoguanine sites associated with smoking and low-density lipoprotein cholesterol (≤1×10).

CONCLUSIONS

Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS.

摘要

背景

急性冠状动脉综合征（ACS）是全球范围内导致死亡的主要原因。免疫功能在 ACS 的发展中起着至关重要的作用；然而，表观遗传调节是否有助于调节这种疾病中的血液免疫细胞尚未得到研究。

目的

我们对循环免疫细胞进行了全基因组甲基化分析，以鉴定 ACS 中差异甲基化的基因。

方法和结果

我们使用 HumanMethylation450 阵列检查了 102 例 ACS 患者和 101 例对照者的全血全基因组甲基化情况，并在 100 例患者和 102 例对照者中进行了外部复制。对于复制的基因座，我们进一步分析了它们与 6 种纯化白细胞亚群中的 ACS 的相关性，与注释基因表达的相关性，以及与心血管特征/危险因素的相关性。我们发现了 ACS 与血液中 47 个胞嘧啶-磷酸鸟嘌呤位点甲基化之间的新的、可重复的关联（发现：错误发现率<0.005；复制：Bonferroni 校正<0.05）。这些胞嘧啶-磷酸鸟嘌呤位点的甲基化水平与 ACS 的相关性在至少 1 种白细胞亚群中得到了进一步验证，其中 CD8 T 细胞、CD4 T 细胞和 B 细胞的贡献较大。26 个复制的胞嘧啶-磷酸鸟嘌呤位点的血液甲基化与注释基因的表达呈显著相关（包括、和；<5.9×10），病例与对照之间的差异基因表达证实了观察到的差异甲基化。复制的基因座表明它们在与 ACS 相关的功能中起作用，包括趋化作用、冠状动脉血栓形成和 T 细胞介导的细胞毒性。使用纯化的 T 细胞和 B 细胞中的 ACS 相关甲基化位点进行的功能分析揭示了与动脉粥样硬化信号和适应性免疫反应相关的重要途径。此外，我们观察到与吸烟和低密度脂蛋白胆固醇（≤1×10）相关的复制胞嘧啶-磷酸鸟嘌呤位点有显著富集。