The Effect Of Gene Variation And Plasma Metabolome Associated With Blood Coagulation On Bleeding Risk In Patients With Coronary Heart Disease Received PCI

In patients with coronary heart disease,antiplatelet medications constitute a cornerstone of treatment and are used to prevent thrombotic complications as myocardial infarction(MI),stroke,and death.The use of antiplatelet medication has increased markedly over the past decade.The risk of bleeding is caused by different predisposing factors,e.g.age,renal failure and previous bleeding,and the bleeding risk is further exacerbated due to antiplatelet drugs used widely.Natural coagulation and hemostasis of the human systems mainly depend on the structure and function of the complete blood vessel wall,natural coagulation factor activity,and effective platelet quality and quantity.Coagulation dysfunction could be a potential risk factor for increased bleeding risk.Human genetic factors and plasma metabolome could cause imbalances in the homeostasis of the coagulation system through potentially unknown mechanisms.Although many studies have identified single nucleotide polymorphism sites related to the metabolism of antiplatelet drugs such as clopidogrel and aspirin,few have directly studied the relationship between single nucleotide polymorphisms and the coagulation system and bleeding.Use the coagulation system as an intermediate phenotype from genotype to clinical phenotype,which may provide a powerful effect in genome-wide association studies.Clarifying the size and direction of their interaction is helpful for researchers to find functional biomarkers affecting bleeding risks in patients with coronary heart disease,which provide a theoretical basis for functional study.In addition,the coagulation system is a complex network regulated by endogenous molecules.By constructing the association between plasma metabolites and the coagulation system,the candidate functional metabolites revealed the deep-seated mechanism that caused individual differences in coagulation function could be found,which will provide a more powerful insights for the optimal strength of antiplatelet.First,in a cohort included 841 Chinese patients with coronary heart disease:1)we analyzed the association between the seven coagulation parameters(APTT,TT,INR,PTA,FIB,D-DI and PT)and bleeding risks in patients with coronary heart disease.After adjusting for multiple confounding factors,it was found that the prolongation of TT significantly increased the risk of bleeding.Considering the complexity of the bleeding event,we divided the seven coagulation index into three levels:low,medium,and high levels according to the quartile.Through constructing a cox regression model to compare the impact of the three different levels on bleeding risk,we found that the risk of bleeding could not be modified by patient's baseline coagulation index.2)In order to find candidate SNP loci that independently affect the coagulation function of patients,we carried out genome-wide association analysis and linkage disequilibrium analysis for these 7 coagulation indexes,and found the significant correlation of 22,5,7,5 SNP with the levels of TT,D-DI,PT,and INR separately(P<2E10-8).3)Considering the significantly association between the levels of TT and bleeding risk,we further explored whether the SNP sites related to TT level can affect the occurrence of bleeding events,and found that rs363405(P=0.0403)on the SLC18A2 gene and rs10930412 on the MYO3B gene are associated to bleeding events(P=0.0163).After adjusting for confounding factors,rs10930412 still shows an independent association with bleeding risk(P=0.0313),which suggesting that this site may further affect the bleeding event through affecting the TT variation.Therefore,functional SNP associated with dysfunction of blood coagulation is of great significance for guiding clinical precise medication.In addition,1040 patients and 367 patients were included to two independent cohorts to conduct a widely targeted metabolomic study.In cohort 1,a multivariable linear model adjusted confounding factors was used to find plasma metabolites associated with seven blood coagulation indicators(P<0.05),then we verify these metabolites in the same way in cohort 2(P<0.05).In order to reduce the false positive rate,we used meta-analysis to verify the candidate metabolites by combine the effect of the two cohorts(P<0.0003),finally,the metabolites that independently affected the blood coagulation could be selected.We found that 2 metabolites with FIB levels,and 1 metabolite with TT showed a strong correlation in two independent cohorts.Among them,threonine(estimate=-0.241;P=0.0002)and serine(estimate=-0.258;P=0.0002),which belong to amino acids,both show strong correlation with FIB levels.In addition,2-hydroxybutyric acid,which belongs to lipids,is independently related to TT.These three special metabolites can be used clinically as new biomarkers for patients with dysfunction of blood coagulation.Therefore,when selecting anticoagulant drugs or antiplatelet drugs,the plasma levels of these three metabolites should be considered to avoid serious complications such as bleeding events.In summary,this study comprehensively analyze the association between gene mutation related to coagulation function and bleeding events in Chinese patients with coronary heart disease by using the coagulation system as a "bridge".Secondly,on the basis of this study,we further carried out widely targeted metabolomics analysis to found endogenous metabolites that regulate the homeostasis of the coagulation system.In summary,a combination of genomics and metabolomics could identify functional gene mutation and metabolites responsible for dysfuntion of hemostasis and bleeding.Finally,this study provides a theoretical basis for balancing the risk of bleeding and ischemia in patients with coronary heart disease who take DAPT after PCI.