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

Abstract Introduction Although family history of coronary heart disease (CHD) is an established risk factor for subsequent CHD, its relation to the circulating proteome is unknown. Proteins linked to coronary atherosclerosis in subjects with a family history could uncover new pathophysiological mechanisms of heritable CHD. Purpose Firstly, we aimed to study the protein profile associated with a family history of early-onset CHD. Secondly, we aimed to identify proteins among which family history was an effect modifier for the association between each protein and coronary atherosclerosis. Methods Plasma levels of proteins were assessed with Olink panels CVD-II and -III in the population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort. The coronary segment involvement score (SIS) was assessed from computed tomography angiography. Subjects without known CHD were cross-referenced with national registers to identify records of myocardial infarction or coronary revascularization in any parent before 55 or 65 years of age in males and females, respectively. The associations between a family history of CHD and each protein were studied with linear regression adjusted for age, sex and study site, using a False Discovery Rate (FDR) of 5%. Associations were subsequently adjusted for cardiovascular risk factors. Similarly, associations between each protein and SIS were modelled linearly with an FDR of 5%. For significant proteins, the statistical interactions between each protein and family history for the association between proteins and SIS were studied. Results Of 4,251 subjects, 9.5% had a family history CHD. 43 proteins were significantly associated with family history, and when adjusted for risk factors 29 protein associations remained significant (p<0,05) [Figure 1]. The strongest associations were observed for cathepsin D, paraoxonase 3, interleukin-1 receptor antagonist protein and renin. 79 proteins were associated with SIS at FDR<5%, and family history was a significant effect modifier 18 for proteins [Figure 2]. The strongest modifying effects were observed for transferrin receptor protein 1 (β 0.64, 95% CI 0.25–1.04 for those with family history vs β -0.04, 95% CI -0.14–0.06 in those without, p for interaction=0.001), LDL-receptor (β 0.68, 95% CI 0.36–1.00 vs β 0.18, 95% CI 0.08–0.26) and tissue-type plasminogen activator (β 0.45, 95% CI 0.19–0.70 vs β 0.13, 95% CI 0.05–0.21). Conclusion We found that 43 proteins, with biological features of inflammation and vascular function, were associated with a family history of early-onset CHD. Most were also linked to the coronary atherosclerosis burden. Notably, 18 biomarkers, among them transferrin receptor protein 1, LDL-receptor and tissue-type plasminogen activator, exhibited strong statistical interactions with family history in the association with SIS, indicating that they are of particular importance for the genetic susceptibility and the pathophysiology of heritable CHD.