Healthy lifestyle, DNA methylation age acceleration, and incident risk of coronary heart disease
Authors: Si Jiahui , Chen Lu , Yu Canqing , Guo Yu , Sun Dianjianyi , Pang Yuanjie , Millwood Iona Y. , Walters Robin G. , Yang Ling , Chen Yiping , Du Huaidong , Feng Shixian , Yang Xiaoming , Avery Daniel , Chen Junshi , Chen Zhengming , Liang Liming , Li Liming , Lv Jun ,   the China Kadoorie Biobank Collaborative Group, Chen Junshi , Chen Zhengming , Collins Rory , Li Liming , Peto Richard , Avery Daniel , Boxall Ruth , Bennett Derrick , Chang Yumei , Chen Yiping , Chen Zhengming , Clarke Robert , Du Huaidong , Gilbert Simon , Hacker Alex , Holmes Michael , Iona Andri , Kartsonaki Christiana , Kerosi Rene , Kong Ling , Kurmi Om , Lancaster Garry , Lewington Sarah , Lin Kuang , McDonnell John , Mei Winnie , Millwood Iona , Nie Qunhua , Radhakrishnan Jayakrishnan , Rafiq Sajjad , Ryder Paul , Sansome Sam , Schmidt Dan , Sherliker Paul , Sohoni Rajani , Turnbull Iain , Walters Robin , Wang Jenny , Wang Lin , Yang Ling , Yang Xiaoming , Bian Zheng , Chen Ge , Guo Yu , Hou Can , Lv Jun , Pei Pei , Qu Shuzhen , Tan Yunlong , Yu Canqing , Pang Zengchang , Gao Ruqin , Wang Shaojie , Liu Yongmei , Du Ranran , Zang Yajing , Cheng Liang , Tian Xiaocao , Zhang Hua , Lv Silu , Wang Junzheng , Hou Wei , Yin Jiyuan , Jiang Ge , Zhou Xue , Yang Liqiu , He Hui , Yu Bo , Li Yanjie , Mu Huaiyi , Xu Qinai , Dou Meiling , Ren Jiaojiao , Wang Shanqing , Hu Ximin , Wang Hongmei , Chen Jinyan , Fu Yan , Fu Zhenwang , Wang Xiaohuan , Weng Min , Zheng Xiangyang , Li Yilei , Li Huimei , Wang Yanjun , Wu Ming , Zhou Jinyi , Tao Ran , Yang Jie , Ni Chuanming , Zhang Jun , Hu Yihe , Lu Yan , Ma Liangcai , Tang Aiyu , Zhang Shuo , Jin Jianrong , Liu Jingchao , Tang Zhenzhu , Chen Naying , Huang Ying , Li Mingqiang , Meng Jinhuai , Pan Rong , Jiang Qilian , Zhang Weiyuan , Liu Yun , Wei Liuping , Zhou Liyuan , Chen Ningyu , Guan Hairong , Wu Xianping , Zhang Ningmei , Chen Xiaofang , Tang Xuefeng , Luo Guojin , Li Jianguo , Chen Xiaofang , Zhong Xunfu , Liu Jiaqiu , Sun Qiang , Ge Pengfei , Ren Xiaolan , Dong Caixia , Zhang Hui , Mao Enke , Wang Xiaoping , Wang Tao , zhang Xi , Zhang Ding , Zhou Gang , Feng Shixian , Chang Liang , Fan Lei , Gao Yulian , He Tianyou , Sun Huarong , He Pan , Hu Chen , Lv Qiannan , Zhang Xukui , Yu Min , Hu Ruying , Wang Hao , Qian Yijian , Wang Chunmei , Xie Kaixue , Chen Lingli , Zhang Yidan , Pan Dongxia , Huang Yuelong , Chen Biyun , Yin Li , Jin Donghui , Liu Huilin , Fu Zhongxi , Xu Qiaohua , Xu Xin , Zhang Hao , Xiong Youping , Long Huajun , Li Xianzhi , Zhang Libo , Qiu Zhe 
Published: March 2023

Abstract
Background
DNA methylation clocks emerged as a tool to determine biological aging and have been related to mortality and age-related diseases. Little is known about the association of DNA methylation age (DNAm age) with coronary heart disease (CHD), especially in the Asian population.

Results
Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip for 491 incident CHD cases and 489 controls in the prospective China Kadoorie Biobank. We calculated the methylation age using a prediction model developed among Chinese. The correlation between chronological age and DNAm age was 0.90. DNA methylation age acceleration (Δage) was defined as the residual of regressing DNA methylation age on the chronological age. After adjustment for multiple risk factors of CHD and cell type proportion, compared with participants in the bottom quartile of Δage, the OR (95% CI) for CHD was 1.84 (1.17, 2.89) for participants in the top quartile. One SD increment in Δage was associated with 30% increased risk of CHD (OR = 1.30; 95% CI 1.09, 1.56; Ptrend = 0.003). The average number of cigarette equivalents consumed per day and waist-to-hip ratio were positively associated with Δage; red meat consumption was negatively associated with Δage, characterized by accelerated aging in those who never or rarely consumed red meat (all P < 0.05). Further mediation analysis revealed that 10%, 5% and 18% of the CHD risk related to smoking, waist-to-hip ratio and never or rarely red meat consumption was mediated through methylation aging, respectively (all P for mediation effect < 0.05).

Conclusions
We first identified the association between DNAm age acceleration and incident CHD in the Asian population, and provided evidence that unfavorable lifestyle-induced epigenetic aging may play an important part in the underlying pathway to CHD.