207-OR: ADA Presidents' Select Abstract: Apolipoprotein C-III Proteoforms and Their Relationships with Plasma Lipids and Cardiovascular Events in Multiethnic Study of Atherosclerosis (MESA)

Apolipoprotein C-III (apoC-III) exists in four major proteoforms - unglycosylated form (C-III_0a) , and glycosylated forms with zero (C-III_0b) , one (C-III₁, most abundant) or two (C-III₂) sialic acids - which modify lipoprotein metabolism. The relation of these proteoforms with plasma lipids and cardiovascular disease (CVD) risk in a general population is unknown. Total apoC-III concentrations and apoC-III proteoforms were measured in baseline plasma of 5,787 MESA participants. Plasma lipids and CVD risk were assessed over 15 years. Proteoform percentages correlated modestly with total apoC-III (r²<0.10) . ApoC-III_0b decreased and C-III₂ increased with age (by 11% per 5 yrs) . Compared to non-Hispanic whites, African Americans had lower (35%) total apoC-III and C-III_0b and higher C-III₂ (88%) , and Chinese Americans and Hispanics had higher C-III_0a (88%; 40%) . Females had higher total apoC-III, C-III₁ and C-III_0b (23%; 31%; 30%) , and lower C-III_0a and C-III₂ (17%; 28%) . Total apoC-III, C-III_0b, C-III₁ and C-III₂ were higher in diabetes. Prospectively, in models that included baseline characteristics, lipid-lowering medications and total apoC-III, higher C-III₂ to C-III₁ ratio (C-III₂/III₁) was associated with lower triglycerides (22%) and higher HDL (19%) . After adjustment for baseline characteristics (including lipids) and total apoC-III, higher C-III_0b to C-III₁ ratio was associated with reduced risk of CVD (n=629 events, HR= 0.89) and coronary heart disease (n=426, HR=0.86) . In contrast, despite links with better lipids, higher C-III₂/III₁ was associated with increased risk of CVD (HR=1.09) . No CVD events were related to total apoC-III. Our data indicate differences in clinical and demographic determinants of total apoC-III concentrations and apoC-III proteoforms and highlight the importance of apoC-III proteoform distribution in predicting future lipid concentrations and CVD risk.