| Coronary artery disease(CAD),one of the leading causes of morbidity and mortality worldwide,is a complex disease interacted by genetic and environmental factors.Genome-wide association analyses have identified a large number of loci influencing CAD,but these identified loci still could not account for a considerable proportion of disease variation.Additionally,comprehensive metabolome,the sum of endogenous metabolites of the organism,is the downstream product of the interaction between environmental factors and genometranscriptome-proteome,and epigenetic modification served as a bridge connecting the external environment and internal genetic variation.Combination of the both aspects may provide a deeper understanding and supplement for the occurrence and development of CAD.Hence,this study intends to apply widely-targeted metabolomic and lipidomic studies in a large scale follow-up cohort of Chinese patients with CAD to discover and verify the influence and predictive value of plasma metabolites and lipid species on disease progression and severity,and to determine the key disturbed metabolic pathways.Moreover,genome-wide surveys of DNA methylation may uncover epigenetic factors influencing lipid metabolism.Further analysis of the mediation effect between the candidate loci associated with lipid traits and the clinical prognosis,to explore the potential role of DNA methylation in the disease progression and prognosis.First,among 942 Chinese patients with CAD,patients were further stratified into three subgroups [stable coronary heart disease(SCAD),unstable angina pectoris(UA),and myocardial infarction(MI)] on the basis of a detailed diagnosis performed by cardiologists.We compared SCAD vs.UA and UA vs.MI to identify comprehensive metabolomic characteristics of plasma from stable arterial plaques to unstable plaques and further myocardial ischemia events following plaque rupture,respectively.Consequently,a total of 72 and 88metabolites/lipid species were identified to be significantly altered(P<0.05).The disturbed pathways included the glycerophospholipid metabolism,and cysteine and methionine metabolism.Furthermore,diagnostic models incorporating metabolic and lipidomic characteristics with traditional risk factors were constructed.The combined model that incorporated 11 independent metabolite/lipid molecules and four traditional risk factors for distinguishing the two subtypes of unstable angina pectoris and myocardial infarction(Cstatistic=0.823,95%CI: 0.783-0.863)represented better discrimination compared with the prediction model involving risk factors alone(C-statistic=0.758,95%CI: 0.712-0.810).In addition,in a cohort with 953 CAD patients,epigenome-wide association analyses were conducted based on four traditional lipid traits,including high-density lipoprotein(HDL-C),low-density lipoprotein(LDL-C),total cholesterol(TC),and total triglyceride(TG).A total of49 Cp G loci were found to be significantly associated with lipid levels(P<6.88E-08).To be noticed,cg17901584 on DHCR24 and cg15128785 on SREBF2 are significantly correlated with LDL-C and TC(P<6.88E-08).Besides,cg06500161 on ABCG1 was significantly negatively correlated with HDL-C and positively correlated with TG(P<6.88E-08),cg00574958 on CPT1 A was significantly negatively associated with TG,cg15659943 on ABCA1 was negatively correlated with HDL-C(Estimate:-0.11±0.02,FDR=0.0023),while positively correlated with TG(Estimate:0.06±0.011,FDR=0.024).The pathway enrichment analysis showed that the genes annotated for Cp G sites were mostly enriched in lipid-related pathways,especially in the cholesterol reversal pathway.Finally,exploratory studies of biological function have indicated that these lipid-associated Cp G sites are enriched in enhancers or active transcription regions in blood cells and hematopoietic stem cells.By integration of gene expression data,a number of Cp G sites showed negative association with gene expression,as cg06500161 was negatively correlated with ABCG1 expression,cg00574958 was negatively correlated with CPT1 A,and cg17901584 was negatively correlated with DHCR24.Mediation analyses showed that DNA methylation of multiple Cp G sites in combination explain at least 19% of the association of HDL-C with the risk of disease severity and 76% of the association of HDL-C with the risk of clinical end events.In summary,this study provides an effective predictive marker and model for the severity and progression of CAD,and provides specific gene targets and molecular markers of lipid metabolism for revealing the association between epigenetic variation,plasma lipid level,and poor clinical prognosis. |
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