Abstract Body (Do not enter title and authors here): Background: Coronary heart disease (CHD) is marked by dysfunctional high-density lipoproteins (HDL; impaired cholesterol efflux (CE), elevated oxidative stress, and inflammation). HDLs have a diverse proteome (>250 proteins), but simple protein abundances fail to fully capture its complexity and disease links. A proteoform is a specific molecular form of a protein that includes information of post-translational modifications (type, location, and combinations), which directly affect function. While HDL-associated apolipoproteins (apo), specially apoA-I, mediate HDL functions, it remains unknown whether apoA-I proteoforms are linked to CHD. Our prior work linking 15 apoA-I proteoforms to cardiometabolic traits supports uncovering proteoform-CHD relationships for mechanistic insight into CHD. This study aims to explore the spectrum of apoA-I proteoforms linked with incident CHD.
Method: From Dallas Heart Study cohort (>2,000 participants without prevalent CVD at baseline), 33 incident myocardial infarction (MI) cases during follow-up and 32 matched controls (age, sex, and race/ethnicity) were selected. We analyzed plasma using top-down proteomics to quantify apoA-I proteoforms. Unadjusted associations of apoA-I proteoforms with cardiometabolic traits were stratified by CHD status and analyzed using correlation analysis.
Results: Mean age was 56 years (45% women, 66% Black and 9% Hispanic). We identified 15 apoA-I proteoforms. Proteoform abundances were similar in cases vs. controls, the direction and magnitude of associations with cardiometabolic traits varied substantially. E.g., canonical (unmodified) apoA-I was positively correlated with oxidized LDL (Ox- LDL) in incident MI cases, but not in controls. Acylated apoA-I proteoforms showed different correlation directions with CE, TG and Ox-LDL in controls vs incident MI (Fig.1, p<0.05).
Conclusion: We observed different patterns of association between apoA1 proteoforms and cardiometabolic traits in individuals who experienced CHD events compared to those who did not. These findings suggest that proteoform biology may vary and be involved in CHD pathogenesis. Further investigation in larger cohorts may unveil therapeutic targets for CHD, improving patient outcomes.