What is the clinical evidence from this study?

Study design: Cohort. Population: Coronary Heart Disease (n=2856). Primary outcome: Incident coronary heart disease (HR 1.24, 95% CI 1.12-1.38, p=2.3×10-5).

What question did this study set out to answer?

This research aims to examine the relationship between plasma proteins and the risk of developing coronary heart disease.

January 10, 2026Open Access

Plasma proteomics and incident coronary heart disease

Key Result

Increased concentrations of ADP-ribosylation factor-like protein 5B are associated with a higher risk of incident coronary heart disease.

Key Points

This research aims to examine the relationship between plasma proteins and the risk of developing coronary heart disease.
Evaluated associations of 4780 plasma proteins with incident coronary heart disease in two large population studies.
Conducted analysis in the Cardiovascular Health Study (N=2856, 575 CHD events) and replicated findings in the Atherosclerosis Risk in Communities Study (N=10456; 1375 events).
Used Mendelian randomization to explore causal relationships between MMP12 levels and coronary heart disease.
Identified 11 significant proteins associated with incident coronary heart disease after risk factor adjustment.
Eight of these associations were replicated in the Atherosclerosis Risk in Communities Study.
Macrophage metalloelastase (MMP12) showed the strongest correlation with an increased risk of coronary heart disease.
Mendelian randomization suggested that higher levels of MMP12 could lower risk for coronary heart disease and ischemic stroke.

Study Design

Type

Cohort (n=2,856)

Multicenter

Yes

Structured PICO

Do specific plasma protein concentrations associate with incident coronary heart disease in older adults?

Population

2,856 adults ages 65 years and older without prior myocardial infarction from the Cardiovascular Health Study (CHS), mean age 74 years, 62% female, 16% Black. Replicated in 10,456 participants from the Atherosclerosis Risk in Communities (ARIC) study.

Intervention

Measurement of 4,780 plasma proteins using the SomaScan V4 assay

Outcome

Incident coronary heart disease (physician-adjudicated incident myocardial infarction or death from CHD)hard clinical

Proteomic profiling identified 11 proteins associated with incident CHD, with MMP12 showing a strong observational association with increased risk but a causal protective effect in Mendelian randomization, highlighting the complex role of proteins in atherosclerosis.

Main Result

Effect estimate: HR 1.24 (95% CI 1.12-1.38)

p-value: p=2.3×10-5

Limitations

Observational study design may limit causal inference.
Possible confounding factors not accounted for despite adjustments.

Abstract

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.

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Cite This Study

Huber et al. (Sat,) conducted a cohort in Coronary Heart Disease (n=2,856). Increased concentrations of ADP-ribosylation factor-like protein 5B are associated with a higher risk of incident coronary heart disease.

synapsesocial.com/papers/696321b391e05aa366cb7ebe https://doi.org/https://doi.org/10.1038/s43856-025-01363-y

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