Genomic And Metabolomic Signatures Of Inflammatory Markers And Their Impact On Disease Severity In Coronary Artery Disease Populations

Coronary artery disease(CAD)is a metabolic disease with substantial worldwide morbidity and death and is one of the leading causes of the global disease burden.The underlying pathology of CAD is coronary atherosclerosis,which involves an inflammatory response.Numerous studies have demonstrated that systemic immune inflammatory markers(SII,NLR,etc.)and markers reflecting low-grade inflammation(hs-CRP and INFLA,etc.)are predictive of coronary heart disease development and progression.However,the genetic and metabolic factors that regulate the inflammatory markers in Chinese patients with CAD still unknown.To address this,we conducted a genome-wide association study and gene-based association test on systemic immune inflammatory markers(SII,NLR)and markers of low-grade inflammation(hs-CRP and INFLA)in a large population of Chinese CAD patients,to identify genetic regulators affecting inflammation and immune responses.Additionally,we explored the relationship of metabolomics and lipidomics to four inflammatory markers in patients with CAD to obtain further insights into inflammation-associated metabolism during disease progression.Finally,we investigated the relationship between inflammatory markers,metabolic signatures,and disease severity.The main points are as follows:(1)Initially,genome-wide association studies were conducted in the discovery and validation groups,respectively,on low-grade inflammatory markers(hs-CRP and INFLA)and systemic immune inflammatory indicators(SII and NLR).The method of Meta-analysis was utilized to combine the results of both groups.One locus associated with SII(rs62577104,P=2.40E-08)and one locus associated with hs-CRP(rs118108109,P=1.80E-08)were identified after LD analysis.Further gene-based association test found that SLMAP and DNAH12 were nominally associated with multiple inflammatory indicators and also associated with SYNTAX Score,LVEF,or BNP,suggesting that these two genes may affect inflammatory response in coronary heart disease and participate in disease progression.(2)Secondly,We identified 49 metabolites associated with both SII and NLR values and status,of which 18 were solely associated with NLR,20 solely with SII,and 11 with both SII and NLR.Moreover,we found a total of 31 metabolites and lipids were associated with both INFLA and hs-GRP levels and status,of which 11 were associated with hs-CRP alone,16 with INFLA alone,and 5 with both hs-CRP and INFLA.Using a combination of metabolites,our model can be used to predict a high or low inflammatory status.The pathway enrichment analysis revealed that glycerophospholipid metabolic pathways(P<0.05,Impact=0.23)and arginine and proline metabolic pathways(P<0.05,Impact=0.22)are the key altered metabolic pathways for both general systemic immune and low-grade inflammation states.(3)Finally,we identified 27 metabolites and lipids that are correlated with BNP or LVEF and associated with SII or NLR levels and status.(FDR<0.05).In addition,One-sample Mendelian randomization analysis identified 18 causal "metaboliteinflammation markers" relationships,and further mediation analysis uncover the relationship between these 18 causal "metabolite-inflammation markers" and disease severity.In summary,this study enhances our comprehension of the molecular mechanisms implicated in the dysregulation of inflammatory responses observed in patients with CAD.These novel findings are anticipated to offer promising targets for intervention,ultimately mitigating the risk of adverse outcomes and facilitating the development of predictive and therapeutic tools for CAD from the perspective of inflammatory response.