外显子组测序确定了早发性冠状动脉粥样硬化疾病高残留风险的易感基因。

Exome Sequencing Identified Susceptible Genes for High Residual Risks in Early-Onset Coronary Atherosclerotic Disease.

作者信息

Wu Runda, Su Ya, Liao Jianquan, Shen Juan, Ma Yuanji, Gao Wei, Dong Zheng, Dai Yuxiang, Yao Kang, Ge Junbo

机构信息

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.

Shanghai Institute of Cardiovascular Disease, Shanghai, P.R. China.

出版信息

Clin Cardiol. 2024 Dec;47(12):e70066. doi: 10.1002/clc.70066.

DOI:10.1002/clc.70066

PMID:39673281

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11645474/

Abstract

AIMS

Despite the tremendous improvement in therapeutic medication and intervention for coronary atherosclerotic disease (CAD), residual risks remain. Exome sequencing enables identification of rare variants and susceptibility genes for residual risks of early-onset coronary atherosclerotic disease (EOCAD) with well-controlled conventional risk factors.

METHODS

We performed whole-exome sequencing of subjects who had no conventional risk factors, defined as higher body mass index, smoking, hypertension and dyslipidemia, screened from 1950 patients with EOCAD (age ≤ 45 years, at least 50% stenosis of coronary artery by angiography), and selected control subjects from 1006 elder (age ≥ 65 years) with < 30% coronary stenosis. Gene-based association analysis and clinical phenotypic comparison were conducted.

RESULTS

Subjects without defined conventional risk factors accounted for 4.72% of young patients. Totally, 6 genes might be associated with residual risk of EOCAD, namely CABP1 (OR = 22.19, p = 0.02), HLA-E (OR = 22.19, p = 0.02), TOE1 (OR = 33.6, p = 0.002), HPSE2 (OR = 11.1, p = 0.04), CHST14 (OR = 22.19, p = 0.02) as well as KLHL8 (OR = 22.19, p = 0.02). Phenotypic analysis displayed the levels of low-density lipoprotein cholesterol in carriers of mutations from CABP1, HLA-E, TOE1, and HPSE2 were significantly elevated compared to noncarriers. Notably, extracellular matrix-associated CHST14 and fibrinogen-associated KLHL8 both displayed possible correlation with increased neutrophil proportion and decreased monocyte percentage (both p < 0.05), exerting potential effects on the residual inflammatory risks of EOCAD.

CONCLUSION

The study identified six genes related to dyslipidemia and inflammation pathways with potential association with residual risk of EOCAD, which will contribute to precision-based prevention in these patients.

TRIAL REGISTRATION

The GRAND study was registered at www.

CLINICALTRIALS

gov on July 14, 2015, and the registry number is NCT02496858.

摘要

目的

尽管冠状动脉粥样硬化性疾病（CAD）的治疗药物和干预措施有了巨大改进，但仍存在残余风险。外显子组测序能够识别具有良好控制的传统风险因素的早发性冠状动脉粥样硬化疾病（EOCAD）残余风险的罕见变异和易感基因。

方法

我们对从1950例EOCAD患者（年龄≤45岁，血管造影显示冠状动脉至少50%狭窄）中筛选出的无传统风险因素（定义为较高体重指数、吸烟、高血压和血脂异常）的受试者进行了全外显子组测序，并从1006例老年（年龄≥65岁）冠状动脉狭窄<30%的患者中选取了对照受试者。进行了基于基因的关联分析和临床表型比较。

结果

无明确传统风险因素的受试者占年轻患者的4.72%。共有6个基因可能与EOCAD的残余风险相关，即CABP1（OR = 22.19，p = 0.02）、HLA-E（OR = 22.19，p = 0.02）、TOE1（OR = 33.6，p = 0.002）、HPSE2（OR = 11.1，p = 0.04）、CHST14（OR = 22.19，p = 0.02）以及KLHL8（OR = 22.19，p = 0.02）。表型分析显示，与非携带者相比，CABP1、HLA-E、TOE1和HPSE2突变携带者的低密度脂蛋白胆固醇水平显著升高。值得注意的是，细胞外基质相关的CHST14和纤维蛋白原相关的KLHL8均显示与中性粒细胞比例增加和单核细胞百分比降低可能相关（均p < 0.05），对EOCAD的残余炎症风险产生潜在影响。