Plasma proteomics and incident coronary heart disease

Systematic profiling of plasma proteins in population studies offers a complementary approach to discovery of novel risk factors and may provide new insights into the causes of coronary heart disease. To explore relationships between the circulating proteome and coronary heart disease (CHD), we evaluated associations of 4780 plasma proteins with incident CHD in the Cardiovascular Health Study (CHS, N=2856, 575 CHD events) and replicated significant associations in the Atherosclerosis Risk in Communities Study (ARIC, N = 10456; 1375 events). We find that 11 proteins significantly associate with incident CHD after adjusting for risk factors; and eight significantly replicated in ARIC. Several proteins correlate with carotid intimal medial thickness and CHD associations are attenuated in participants without subclinical atherosclerosis. Macrophage metalloelastase (MMP12) is the strongest observed association (Hazard Ratio, 1.31; 95% Confidence Interval, 1.19-1.44). Mendelian randomization (MR) identifies a causal relationship between higher MMP12 and lower CHD (Odds Ratio, OR 0.94) and ischemic stroke (OR 0.90) risk, while reverse MR found that genetic propensity to CHD increased MMP12. Taken together, multivariable MR confirms a direct protective effect of higher plasma MMP12 on CHD risk and a genetic effect of atherosclerosis and CHD on elevating MMP12. Proteomic analyses reveal associations with incident CHD and genomic evidence suggests that therapeutic MMP12 inhibition may confer adverse cardiovascular effects. Measuring many protein levels in the blood may provide new insights into the causes of heart disease (CHD). We evaluated thousands of plasma proteins in a study of older adults to determine whether any predicted risk of heart attacks or heart-related deaths and confirmed the findings in a second study. Eleven proteins showed evidence of association with CHD; often with stronger effects among those with pre-existing atherosclerosis. The strongest finding was for macrophage metalloelastase (MMP12), an endopeptidase expressed in vascular tissue and atherosclerotic plaque with roles in tissue repair, vascular remodeling, and reduction of inflammation. Our findings point to a complex role for this protein in response to underlying heart disease risk factors. Huber et al. measure 4,780 plasma proteins in the Cardiovascular Health Study to examine the association with incident coronary heart disease. They identify 11 proteins using genomic analyses and show the complexity of MMP12 in response to atherosclerosis and development of heart disease.