Somatic and Germline Variants and Coronary Heart Disease in a Chinese Population

Zhao，Kun1; Shen，Xuxiang1; Liu，Hongwei1; Lin，Zhennan1; Li，Jianxin1; Chen，Shufeng1; Liu，Fangchao1; Huang，Keyong1; Cao，Jie1; Liu，Xiaoqing2; Shen，Chong3; Yu，Ling4; Zhao，Yingxin5; Zhao，Liancheng1; Li，Ying1; Hu，Dongsheng6,7; Huang，Jiangfeng1; Lu，Xiangfeng1; Gu，Dongfeng1,8

2024

10.1001/jamacardio.2023.5095

JAMA Cardiology   影响因子和分区

2380-6583

2380-6591

Importance: The genetic basis of coronary heart disease (CHD) has expanded from a germline to somatic genome, including clonal hematopoiesis of indeterminate potential (CHIP). How CHIP confers CHD risk in East Asian individuals, especially those with small clones (variant allele fraction [VAF] 0.5%-2%) and different genetic backgrounds, was completely unknown. Objective: To investigate the CHIP profile in a general Chinese cohort by deep sequencing and further explore the association between CHIP and incident CHD considering germline predisposition. Design, Setting, and Participants: This cohort study used data from 3 prospective cohorts in the project Prediction for Atherosclerotic Cardiovascular Disease Risk in China. Participants without cardiovascular disease or cancer at baseline were enrolled in 2001 and 2008 and had a median follow-up of 12.17 years extending into 2021. Exposures: CHIP mutations were detected by targeted sequencing (mean depth, 916×). A predefined CHD polygenic risk score (PRS) comprising 531 variants was used to evaluate germline predisposition. Main Outcomes and Measures: The main outcome was first incident CHD. Results: Among 6181 participants, the median (IQR) age was 53.83 years (45.35-62.39 years); 3082 participants (49.9%) were female, and 3099 (50.1%) were male. A total of 1100 individuals (17.80%) harbored 1372 CHIP mutations at baseline. CHIP was independently associated with incident CHD (hazard ratio [HR], 1.42; 95% CI, 1.18-1.72; P = 2.82 × 10) and presented a risk gradient with increasing VAF (P = 3.98 × 10 for trend). Notably, individuals with small clones, nearly half of CHIP carriers, also demonstrated a higher CHD risk compared with non-CHIP carriers (HR, 1.33; 95% CI, 1.02-1.74; P =.03) and were 4 years younger than those with VAF of 2% or greater (median age, 58.52 vs 62.70 years). Heightened CHD risk was not observed among CHIP carriers with low PRS (HR, 1.02; 95% CI, 0.64-1.64; P =.92), while high PRS and CHIP jointly contributed a 2.23-fold increase in risk (95% CI, 1.51-3.29; P = 6.29 × 10) compared with non-CHIP carriers with low PRS. Interestingly, the diversity in CHIP-related CHD risk within each PRS group was substantially diminished when removing variants in the inflammatory pathway from the PRS. Conclusions: This study revealed that elevated CHD risk attributed to CHIP was nonnegligible even for small clones. Inflammation genes involved in CHD could aggravate or abrogate CHIP-related CHD risk.

SCI

英语

其他

2-s2.0-85182777145

Scopus

1.Key Laboratory of Cardiovascular Epidemiology,Department of Epidemiology,State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences,Peking Union Medical College,Beijing,China
2.Division of Epidemiology,Guangdong Provincial People's Hospital and Cardiovascular Institute,Guangzhou,China
3.Department of Epidemiology and Biostatistics,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,China
4.Department of Cardiology,Fujian Provincial Hospital,Fuzhou,China
5.Cardio-Cerebrovascular Control and Research Center,Institute of Basic Medicine,Shandong Academy of Medical Sciences,Jinan,China
6.Department of Epidemiology and Health Statistics,College of Public Health,Zhengzhou University,Zhengzhou,China
7.Department of Biostatistics and Epidemiology,School of Public Health,Shenzhen University Health Science Center,Shenzhen,China
8.School of Public Health and Emergency Management,School of Medicine,Southern University of Science and Technology,Shenzhen,China

Zhao，Kun,Shen，Xuxiang,Liu，Hongwei,et al. Somatic and Germline Variants and Coronary Heart Disease in a Chinese Population[J]. JAMA Cardiology,2024.

Zhao，Kun.,Shen，Xuxiang.,Liu，Hongwei.,Lin，Zhennan.,Li，Jianxin.,...&Gu，Dongfeng.(2024).Somatic and Germline Variants and Coronary Heart Disease in a Chinese Population.JAMA Cardiology.

Zhao，Kun,et al."Somatic and Germline Variants and Coronary Heart Disease in a Chinese Population".JAMA Cardiology (2024).