Abstract 4370702: Proteomic Predictors of Incident Coronary Heart Disease in Individuals with CAC=0.

Introduction: Coronary artery calcium (CAC) is an increasingly important clinical marker of coronary heart disease (CHD) and disease progression. However, a significant proportion of individuals suffer from CHD without antecedent CAC. There have been no studies describing a biochemical signature of individuals with CAC=0 that subsequently develop CHD. Research Question: Are there a specific set of proteins that are associated with incident CHD in low-risk individuals, as defined by undetectable CAC? Methods: In a prospective, case-cohort analysis, we measured 2,941 proteins (Olink) in 6,033 participants in the Multi-Ethnic Study of Atherosclerosis (MESA, mean age 56), among which 3,016 had CAC= 0. Cox proportional hazards regression models were used for incident CHD analyses with 20 years of follow-up. Age-, sex-, and batch-adjusted regression analyses were performed for each protein. We further adjusted for the following covariates: BMI, eGFR, diabetes mellitus, hypertension, total cholesterol, and smoking status. Participants with prevalent CHD and those without CAC scores were excluded. We used an FDR adjusted q-value < 0.05 to account for multiple hypothesis testing. Replication was performed in a low risk subset in the UKBB (n= 21,021, mean age 56, free of obesity, kidney dysfunction, HTN, DM, hypercholesterolemia, and smoking) Results: There were a total of 90 cases of incident CHD (defined as myocardial infarction (MI), resuscitated cardiac arrest due to MI, CHD death). In MESA participants with CAC=0, 140 proteins associated with CHD in the fully adjusted model, of which 53 replicated in the UKBB. Novel proteins included pro-neuropeptide Y (HR 1.54, q-value 0.02) a potent vasoconstrictor; GPR 37 (HR 1.87, q-value 0.0003), a shed surface receptor enriched on neurons, and shisa 5 (HR 1.49, p-value 0.04) a DNA damage-related protein previously linked to MI in GWAS studies. Conclusion: We present novel findings of protein associations with incident CHD in in individuals with undetectable CAC, with replication of a subset of findings in a second low-risk cohort. These findings could ultimately better risk stratify low-risk individuals for CHD and illuminate pathways orthogonal to established atherosclerotic disease mechanisms.