Genome-Wide Analysis of DNA Methylation and Acute Coronary Syndrome

Jun Li; Xiaoyan Zhu; Kuai Yu; Haijing Jiang; Yizhi Zhang; Siyun Deng; Longxian Cheng; Xuezhen Liu; Jia Zhong; Xiaomin Zhang; Meian He; Weihong Chen; Jing Yuan; Ming Gao; Yansen Bai; Xu Han; Bing Liu; Xiaoting Luo; Wenhua Mei; Xiaosheng He; Shunchang Sun; Liyun Zhang; Hesong Zeng; Huizhen Sun; Chuanyao Liu; Yanjun Guo; Bing Zhang; Zhihong Zhang; Jinyan Huang; An Pan; Yu Yuan; Francesca Angileri; Bingxia Ming; Fang Zheng; Qiutang Zeng; Xiaobo Mao; Yudong Peng; Yi Mao; Ping He; Qing K Wang; Lu Qi; Frank B Hu; Liming Liang; Tangchun Wu

doi:10.1161/CIRCRESAHA.116.310324

Genome-Wide Analysis of DNA Methylation and Acute Coronary Syndrome

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

Authors

Jun Li¹, Xiaoyan Zhu¹, Kuai Yu¹, Haijing Jiang¹, Yizhi Zhang¹, Siyun Deng¹, Longxian Cheng¹, Xuezhen Liu¹, Jia Zhong¹, Xiaomin Zhang¹, Meian He¹, Weihong Chen¹, Jing Yuan¹, Ming Gao¹, Yansen Bai¹, Xu Han¹, Bing Liu¹, Xiaoting Luo¹, Wenhua Mei¹, Xiaosheng He¹, Shunchang Sun¹, Liyun Zhang¹, Hesong Zeng¹, Huizhen Sun¹, Chuanyao Liu¹, Yanjun Guo¹, Bing Zhang¹, Zhihong Zhang¹, Jinyan Huang¹, An Pan¹, Yu Yuan¹, Francesca Angileri¹, Bingxia Ming¹, Fang Zheng¹, Qiutang Zeng¹, Xiaobo Mao¹, Yudong Peng¹, Yi Mao¹, Ping He¹, Qing K Wang¹, Lu Qi¹, Frank B Hu¹, Liming Liang¹, Tangchun Wu²

Affiliations

¹ 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.).
² 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.). wut@mails.tjmu.edu.cn lliang@hsph.harvard.edu.

PMID: 28348007
DOI: 10.1161/CIRCRESAHA.116.310324

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 P<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 IL6R, FASLG, and CCL18; P<5.9×10^-4), 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 (P_enrichment≤1×10^-5).

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.

Keywords: DNA methylation; acute coronary syndrome; coronary artery disease; epigenomics; gene expression regulation; leukocytes; smoking.

MeSH terms

Acute Coronary Syndrome / blood*
Acute Coronary Syndrome / epidemiology
Acute Coronary Syndrome / genetics*
Aged
Case-Control Studies
China / epidemiology
DNA Methylation / physiology*
Epigenesis, Genetic / physiology*
Female
Genome-Wide Association Study / methods*
Humans
Male
Middle Aged