| Major adverse cardiovascular events?MACE?is a composite clinical efficacy endpoint,including cardiovascular death,myocardial infarction,stroke?CT or MR scan confirmed?and repeated revascularization.As a standard treatment procedure for patients suffering from acute coronary syndrome?ACS?and those undergoing percutaneous coronary intervention?PCI?with stenting,dual antiplatelet therapy?DAPT?with clopidogrel in addition to aspirin,significantly reduces the risk of major adverse cardiac events in patients.However,the pharmacodynamic response to DAPT varies substantially among patients.Although a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events,these genotypes account for only a small fraction of the variation and evidence is insufficient.Therefore,it's very important to identify new genetic variants associated with major adverse cardiovascular events and reveal the underlying mechanisms of major adverse cardiovascular events by large-scale sequencing data.We evaluated the associations of genetic variants and major adverse cardiovascular events in 1961 patients with ACS undergoing PCI,all patients in this study were allocated to dual antiplatelet therapy for up to 12 months and have the follow-up duration of 18 months.A two-stage association study was performed,including high-depth whole exome sequencing of168 patients in the discovery cohort and high-depth targeted sequencing of 1793 patients in the replication cohort.The discovery study identified 6268 SNPs and 408 genes associated with the occurrence of major adverse cardiovascular events?P<0.05?.The replication study identified3325 SNPs associated with the occurrence of major adverse cardiovascular events?P<0.05?.A total of 177 SNPs were replicated and correlated with major adverse cardiovascular events in both the discovery cohort and the replication cohort.Then,we combined whole exome and targeted sequencing to investigate the genetic factors underlying the major adverse cardiovascular events,the main results were as following:Firstly,we discovered and confirmed six new genotypes associated with major adverse cardiovascular events in patients with ACS.Of which,rs17064642 at MYOM2 increased the risk of major adverse cardiovascular events?hazard ratio[HR]2.76;P=2.95×10-9?and reached genome-wide significance.The other five suggestive variants were KRTAP10-4?rs201441480?,WDR24?rs11640115?,ECHS1?rs140410716?,AGAP3?rs75750968?and NECAB1?rs74569896?.Notably,the expressions of MYOM2 and ECHS1 are down-regulated in both animal models and patients with phenotypes related to major adverse cardiovascular events.Secondly,we confirmed that age,hypertension and creatinine were significantly associated with the occurrence of major adverse cardiovascular events.In addition,when the p-value threshold was loosened,27 potential gene polymorphisms were further identified associated with major adverse cardiovascular events in this study(P<10-4),and candidate gene sets affecting major adverse cardiovascular events were further supplemented for further verification in more samples or larger population.Importantly,this study combined clinical factors and identified 27 significant genetic polymorphisms to develop the first superior classifier for predicting major adverse cardiovascular events and achieved high predictive accuracy?0.809?.Large-scale genome sequencing of patients with acute coronary syndrome not only enables us to find pathogenic genes related to major adverse cardiovascular events,but also provides a solid data base for subsequent functional genomics studies,such as transcriptome,proteomics and metabolomics.Our findings shed light on the pathogenesis of cardiovascular outcomes and may help clinician to make decision on the therapeutic intervention for ACS patients. |
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