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

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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.

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