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Published on: January 28, 2020
Plasma Protein Profile Associated With a Family History of Early-Onset Coronary Heart Disease
Agnes Wahrenberg1, Lars Lind2,3, Natan Åberg1
1Department of Clinical Science and Education, Södersjukhuset (A.W., N.Å., P.S.), Karolinska Institutet, Stockholm, Sweden.
Insights
This study identifies 38 proteins associated with a family history of early-onset coronary heart disease (CHD), revealing new insights into atherosclerosis mechanisms. Key proteins like cathepsin D and follistatin highlight potential pathways for heritable heart disease.
Area of Science:
- Cardiovascular Science
- Proteomics
- Genetics
Background:
- Heritable coronary heart disease (CHD) may involve novel pathophysiological mechanisms in atherosclerosis.
- Understanding the protein profile associated with family history of early-onset CHD is crucial.
Purpose of the Study:
- To investigate the protein profile associated with family history of early-onset CHD.
- To determine if protein-atherosclerosis relationships differ by family history status.
- To explore causal associations using Mendelian randomization.
Main Methods:
- Utilized computed tomography angiography and Olink proteomics on 4521 subjects from the SCAPIS study.
- Retrieved family history data from national registers.
- Performed Mendelian randomization using genome-wide association study data from UKB-PPP, CARDIoGRAMplusC4D, and FinnGen.
Main Results:
- Identified 38 proteins associated with family history of early-onset CHD, including cathepsin D, paraoxonase 3, renin, and follistatin.
- Eighteen proteins interacted with family history in relation to coronary atherosclerotic burden, notably LDL receptor and PECAM1.
- Mendelian randomization revealed a novel association for follistatin with myocardial infarction and confirmed associations for PCSK9 and PECAM1.
Conclusions:
- Findings suggest new potential mechanisms underlying heritable and general atherosclerosis.
- The identified proteins offer novel targets for understanding and potentially treating atherosclerosis.
Background:
Proteins linked to heritable coronary heart disease (CHD) could uncover new pathophysiological mechanisms of atherosclerosis. We report on the protein profile associated with a family history of early-onset CHD and whether the relation between proteins and coronary atherosclerotic burden differs according to family history status, as well as inferences from Mendelian randomization.
Methods:
Data on coronary atherosclerotic burden from computed tomography angiography and Olink proteomics were retrieved for 4521 subjects, free of known CHD, from SCAPIS (the Swedish Cardiopulmonary Bioimage Study). Records of myocardial infarction and coronary revascularization therapies in any parent or sibling of subjects were retrieved from national registers. Linear associations between family history and proteins were adjusted for age, sex, and study site. Statistical interactions between proteins and family history for the association between proteins and the coronary atherosclerotic burden were also studied. Mendelian randomization for causal associations between proteins and CHD was performed with genome-wide association study summary data from UKB-PPP (UK Biobank Pharma Proteomics Project), CARDIoGRAMplusC4D, and FinnGen.
Results:
Of 4251 subjects, family history of early-onset CHD was present in 9.5%. Thirty-eight proteins, with biological features of inflammation, lipid metabolism, and vascular function, were associated with family history using a false discovery rate of 0.05. The strongest associations were observed with cathepsin D, paraoxonase 3, renin andfollistatin, neither of which was attenuated by adjusting for cardiovascular risk factors. Eighteen proteins were statistical interactors with family history in the association between each protein and the coronary atherosclerotic burden, most notably the LDL (low-density lipoprotein) receptor, transferrin receptor protein 1, and PECAM1 (platelet endothelial cell adhesion molecule 1). In 2-sample Mendelian randomization, a novel association was found for follistatin and myocardial infarction, and previous associations for PCSK9 (proprotein convertase subtilisin/kexin type 9) and PECAM1 were repeated.
Conclusions:
These findings highlight new potential mechanisms for heritable and general atherosclerosis.
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