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Published on: January 28, 2020
Plasma proteomics and incident coronary heart disease
Matthew P Huber1, Jennifer A Brody1, Colleen M Sitlani1
1Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Insights
Plasma protein profiling identified novel coronary heart disease (CHD) risk factors. Macrophage metalloelastase (MMP12) showed a protective effect against CHD, but therapeutic inhibition may have adverse cardiovascular effects.
Area of Science:
- Cardiovascular disease research
- Proteomics
- Genetics
Background:
- Systematic plasma protein profiling in population studies aids in discovering novel risk factors for coronary heart disease (CHD).
- Understanding the circulating proteome offers insights into the underlying causes of cardiovascular disease.
Purpose of the Study:
- To investigate the associations between the plasma proteome and incident coronary heart disease (CHD).
- To identify specific proteins linked to CHD risk and validate findings in independent cohorts.
Main Methods:
- Evaluated 4780 plasma proteins for associations with incident CHD in the Cardiovascular Health Study (CHS).
- Replicated significant associations in the Atherosclerosis Risk in Communities Study (ARIC).
- Employed Mendelian randomization (MR) to assess causal relationships between proteins and CHD, and vice versa.
Main Results:
- Eleven proteins significantly associated with incident CHD after adjusting for risk factors; eight replicated in ARIC.
- Several proteins correlated with carotid intimal medial thickness, with attenuated CHD associations in individuals lacking subclinical atherosclerosis.
- Macrophage metalloelastase (MMP12) exhibited the strongest association with incident CHD (HR 1.31).
- Mendelian randomization indicated a causal relationship between higher MMP12 levels and reduced risk of CHD and ischemic stroke.
- Reverse MR suggested that genetic predisposition to CHD elevates MMP12 levels.
Conclusions:
- Proteomic analyses identified significant associations between plasma proteins and incident CHD.
- Genomic evidence indicates that therapeutic inhibition of MMP12 might lead to adverse cardiovascular effects, warranting caution.
Background:
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.
Methods:
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).
Results:
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.
Conclusions:
Proteomic analyses reveal associations with incident CHD and genomic evidence suggests that therapeutic MMP12 inhibition may confer adverse cardiovascular effects.
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