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

IF 2.4 3区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Clinical Cardiology Pub Date : 2024-12-14 DOI:10.1002/clc.70066

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

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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 NCT 02496858.

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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。

目的：尽管冠状动脉粥样硬化疾病（CAD）的治疗药物和干预措施有了巨大的进步，但残留的风险仍然存在。外显子组测序能够识别具有良好控制的常规危险因素的早发性冠状动脉粥样硬化疾病（EOCAD）剩余风险的罕见变异和易感基因。方法：我们从1950例EOCAD患者（年龄≤45岁，冠状动脉造影至少50%狭窄）和1006例老年人（年龄≥65岁）中筛选无常规危险因素（定义为较高体重指数、吸烟、高血压和血脂异常）的受试者进行全外显子组测序。结果：未定义常规危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残留风险相关，分别是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）和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都显示出可能与中性粒细胞比例增加和单核细胞百分比下降相关（均为p）。结论：该研究确定了6个与血脂异常和炎症途径相关的基因，它们与EOCAD的残留风险有潜在的关联，这将有助于这些患者的精准预防。试验注册：GRAND研究于2015年7月14日在www.Clinicaltrials: gov注册，注册号为NCT02496858。

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来源期刊

Clinical Cardiology 医学-心血管系统

CiteScore

5.10

自引率

3.70%

发文量

189

审稿时长

4-8 weeks

期刊介绍： Clinical Cardiology provides a fully Gold Open Access forum for the publication of original clinical research, as well as brief reviews of diagnostic and therapeutic issues in cardiovascular medicine and cardiovascular surgery. The journal includes Clinical Investigations, Reviews, free standing editorials and commentaries, and bonus online-only content. The journal also publishes supplements, Expert Panel Discussions, sponsored clinical Reviews, Trial Designs, and Quality and Outcomes.