Plasma protein profile associated with a family history of early-onset coronary heart disease

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 4,521 subjects, free of known CHD, from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Records of myocardial infarction and coronary revascularization therapies in any parent 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 GWAS summary data from UKB-PPP, CARDIoGRAMplusC4D and FinnGen. Results Of 4,251 subjects, family history of early-onset CHD was present in 9.5%. 38 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 for follistatin and cathepsin D, neither of which were attenuated by adjusting for cardiovascular risk factors.18 proteins were statistical interactors with family history in the association between each protein and the coronary atherosclerotic burden, most notably the LDL-receptor, transferrin receptor protein 1 and platelet endothelial cell adhesion molecule 1 (PECAM1). In two-sample mendelian randomization, a novel association was found for follistatin and myocardial infarction, and previous associations for PCSK9 and PECAM1 were repeated. Conclusions These findings highlight new potential mechanisms for heritable and general atherosclerosis. Clinical perspectives What’s new? Proteins involved in inflammation and tissue remodeling, such as follistatin and cathepsin D, are strongly and independently associated with family history of early-onset CHD, indicating novel pathophysiological mechanisms of these proteins in familial disease. In subjects with a family history of early-onset CHD, the LDL-receptor, transferrin receptor protein 1 and PECAM1 were more strongly associated with coronary atherosclerotic burden, as compared to in subjects without family history. A novel, potentially causal association between follistatin and myocardial infarction was reported from Mendelian randomization using summary data from several GWAS projects. What are the clinical implications? This work brings evidence of the plasma protein profile in familial coronary heart disease, guiding further research of pathophysiological mechanisms in familial and general atherosclerotic disease. New target treatments for familial and general atherosclerotic disease may evolve from identified plasma proteins of importance in familial disease.