Elevated methylation of cyclin dependent kinase inhibitor 2B contributes to the risk of coronary heart disease in women

Chen,Xiaomin; Jiang,Danjie; Xu,Limin; Han,Liyuan; Hu,Haochang; Huang,Yi; Lu,Deyi; Ji,Huihui; Li,Bin; Yang,Yong; Zhou,Cong; Xu,Xuting; Wu,Nan; Xu,Xiaofeng; Xu,Yan; Shen,Yusheng; Li,Jiyi; Duan,Shiwei

doi:10.3892/etm.2018.6920

Elevated methylation of cyclin dependent kinase inhibitor 2B contributes to the risk of coronary heart disease in women

Authors:
- Xiaomin Chen
- Danjie Jiang
- Limin Xu
- Liyuan Han
- Haochang Hu
- Yi Huang
- Deyi Lu
- Huihui Ji
- Bin Li
- Yong Yang
- Cong Zhou
- Xuting Xu
- Nan Wu
- Xiaofeng Xu
- Yan Xu
- Yusheng Shen
- Jiyi Li
- Shiwei Duan
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Affiliations: Key Laboratory of Ningbo First Hospital and Cardiovascular Center of Ningbo First Hospital, Ningbo University, Ningbo, Zhejiang 315010, P.R. China, Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China, Richard and Loan Hill Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, USA
Published online on: November 2, 2018 https://doi.org/10.3892/etm.2018.6920
Pages: 205-213
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cyclin dependent kinase inhibitor 2B (CDKN2B) encodes a cyclin‑dependent kinase inhibitor that may enhance the formation of atherosclerotic plaques. The aim of the present study was to investigate the contribution of CDKN2B promoter methylation on the risk of coronary heart disease (CHD). The present results indicated a significant association between increased CDKN2B methylation and the risk of CHD (adjusted P=0.043). A breakdown analysis according to sex demonstrated that CDKN2B methylation was significantly associated with the risk of CHD in women (adjusted P=0.010), but not in men. A further breakdown analysis by age indicated a significant association of CHD in the women >60 years (P=0.024). Luciferase reporter gene assay results indicated that the CDKN2B promoter fragment significantly enhanced luciferase activity (P<0.001). In addition, CDKN2B transcription was significantly enhanced following treatment with 5‑aza‑2'‑deoxycytidine methylation inhibitor in human aortic endothelial cells (HAEC) and human primary coronary artery smooth muscle cells (HPCASMC; P<0.05 and P<0.01), but not in 293 cells. Notably, estrogen treatment reduced CDKN2B methylation of several CpGs and significantly increased CDKN2B gene expression levels in HAEC, HPCASMC and 293 cells (P<0.05 and P<0.01). Additionally, treatment of HAEC and HPCASMC with simvastatin and γ‑carboxy‑L‑glutamic acid reduced CDKN2B promoter methylation and increased CDKN2B transcription concomitantly. The present study suggests that CDKN2B promoter methylation may be associated with sex dimorphism in the pathogenesis of CHD.

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