{"title":"Association between Human Blood Proteome and the Risk of Myocardial Infarction.","authors":"Linghuan Wang, Weiwei Zhang, Zhiyi Fang, Tingting Lu, Zhenghui Gu, Ting Sun, Dong Han, Yabin Wang, Feng Cao","doi":"10.31083/j.rcm2506199","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety.</p><p><strong>Methods: </strong>From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions.</p><p><strong>Results: </strong>Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13-1.18; <i>p</i> = 1.29 <math><mo>×</mo></math> <math><msup><mi>10</mi> <mrow><mo>-</mo> <mn>31</mn></mrow> </msup> </math> ), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13-1.20; <i>p</i> = 4.73 <math><mo>×</mo></math> <math><msup><mi>10</mi> <mrow><mo>-</mo> <mn>24</mn></mrow> </msup> </math> ), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90-0.96; <i>p</i> = 1.08 <math><mo>×</mo></math> <math><msup><mi>10</mi> <mrow><mo>-</mo> <mn>5</mn></mrow> </msup> </math> ), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90-0.94; <i>p</i> = 8.05 <math><mo>×</mo></math> <math><msup><mi>10</mi> <mrow><mo>-</mo> <mn>13</mn></mrow> </msup> </math> ), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03-1.07; <i>p</i> = 1.41 <math><mo>×</mo></math> <math><msup><mi>10</mi> <mrow><mo>-</mo> <mn>5</mn></mrow> </msup> </math> ). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects.</p><p><strong>Conclusions: </strong>Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.</p>","PeriodicalId":20989,"journal":{"name":"Reviews in cardiovascular medicine","volume":"25 6","pages":"199"},"PeriodicalIF":1.9000,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11270110/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reviews in cardiovascular medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.31083/j.rcm2506199","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Background: The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety.
Methods: From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions.
Results: Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13-1.18; p = 1.29 ), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13-1.20; p = 4.73 ), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90-0.96; p = 1.08 ), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90-0.94; p = 8.05 ), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03-1.07; p = 1.41 ). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects.
Conclusions: Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.
期刊介绍:
RCM is an international, peer-reviewed, open access journal. RCM publishes research articles, review papers and short communications on cardiovascular medicine as well as research on cardiovascular disease. We aim to provide a forum for publishing papers which explore the pathogenesis and promote the progression of cardiac and vascular diseases. We also seek to establish an interdisciplinary platform, focusing on translational issues, to facilitate the advancement of research, clinical treatment and diagnostic procedures. Heart surgery, cardiovascular imaging, risk factors and various clinical cardiac & vascular research will be considered.