| The morbidity and mortality of coronary heart disease(CAD)remain high all over the world.CAD is a complex metabolic disease involving environmental and poly-genetic factors.Although many SNPs related to the CAD risk have been identified by genome-wide association studies(GWAS),many of them still lack of the ability to explain the underlying mechanism,and research based on Chinese population is relatively scarce.Blood lipid levels and metabolic traits can act as intermediate phenotypes from genotype to clinical phenotype,which can provide strong effects in genome-wide association studies and facilitate the discovery of functional locus and provide an internal link for understanding the pathogenesis of the disease.Therefore,the purpose of this study is to carry out a genome-wide association study on blood lipid levels and metabolic groups,and to identify functional loci that affect blood lipid levels and metabolic traits in Chinese population.And the relationships between candidate SNP and severity of coronary heart disease and clinical end-point events were further analyzed.First,1443 Chinese patients with CAD were recruited and followed up.(1)The effects of serum lipid levels on the severity of coronary heart disease(SYNTAX score),death events,and the risk of major cardiovascular adverse events(MACE)were investigated.The results showed that dyslipidemia,including elevated total cholesterol(TC),low density lipoprotein cholesterol(LDLC)and lipoprotein(a)[Lp(a)],and decreased apolipoprotein(a),high density lipoprotein cholesterol(HDLC)is risk factors for the severity or clinical end-point events of CAD.(2)GWASs were carried out on the level of blood lipid traits.The associations between Lp(a)level and rs73596816,rs9355297 and rs7770628 on LPA and rs144217738 on SLC22A2 were found,as well as HDLC level and rs17231506 on CETP and triglyceride level and rs651821 on APOA5(P<2.09E-08).(3)In further analysis,rs7770628 on LPA gene were significantly correlated with the risk of high SYNTAX score[Multivariable analysis:OR(95%CI):1.29(1.01-1.64);P=0.0412].In addition,in 1028 patients with CAD,(1)genome-wide association studies for 260 metabolic traits were conducted.And 10 previously reported associations between SNP and metabolites was accurately replicated(P<0.05),and 13 other metabolic quantitative trait loci(mQTL)were found(P<4.97e-10),including 5 on previously reported loci(ACADS,ACSM5,FADS2,SLC22A4,SLC22A5),and 8 on newly discovered loci(ELF1,ASXL3,ACSM2B,FBXL14,RPS29,FOXN3,SLC10A1 and LINC00910).(2)Further analyses on mQTL and clinical traits were performed in 1443 subjects to explore the potential function.FADS2 rs 174578 was found to be related to lowering triglyceride level and RPS29 rs61980720 associated with increased BMI(P<0.001,FDR<0.01).Besides,ACADS rs9204 was nominally associated with BNP level.(3)Then,rs79602030 on FOXN3 were found to be associated with increased SYNTAX scores,and rs9929808 on ACSM5 and rs2296651 on SLC10A1 were respectively associated with death and MACE risk of CAD patients(P<0.05)Finally,the plasma tryptophan and its metabolites were determined by a newly established UPLC-MS/MS methods in 375 patients with CAD.The association between mQTLs and metabolites(ACSM5,ACSM2B and indole-3-propionic acid,SLC7A5 and urine)were successfully repeated in independent cohort.To sum up,this study is the first large-scale genome-wide study on the blood lipid traits and metabolome in Chinese population.And variants associated with blood lipid levels and metabolic traits were identified.The relationship between the candidate SNPs and the severity of CAD and the risk for clinical end-point was further investigated.This study provides reference for race-specific "genetic map" and genetic risk and precision therapy for poor prognosis of CAD. |
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