Apolipoproteins (apo) C-I, C-II and C-III in circulation are in several post-translational forms with distinct effects on lipoprotein metabolism. ApoC-I and apoC-II exist as dominant native and minor truncated (C-I’; C-II’) forms; apoC-III appears as unglycosylated (C-III0a) , or glycosylated with zero (C-III0b) , one (C-III1, most abundant) or two (C-III2) sialic acids. The association of these proteoforms with peripheral artery disease (PAD) in a general population is unstudied. Total apoC-I, C-II and C-III concentrations and relative amounts of their proteoforms were measured in baseline plasma of 5,681 MESA participants. The ankle-brachial index (ABI) was assessed at baseline, 3 and years. Prevalent PAD was defined as baseline ABI ≤ 0.9. Incident PAD was follow-up ABI ≤ 0.9 or a hospital-based diagnosis of PAD to include revascularization. After adjustment for baseline characteristics, lipid lowering therapy and plasma lipids, low baseline ABI was associated with low C-III0b to C-III1 ratio (C-III0b/III1, p=0.01) and high C-III2 to C-III1 ratio (C-III2/III1, p<0.01) . Prevalent PAD (n=226) was only associated with C-III2/III1 (OR 1.16, 95% CI: 1.01-1.33, p=0.03) . Lower ABI at follow-up was associated with lower C-III0b/III1 and higher C-III2/III1 at baseline (p<0.both) . Incident PAD (n=244) was associated with C-III2/III1 (HR 1.22, 1.06-1.41, p=0.01) . Total apoC-I, C-II and C-III concentrations, or apoC-I and C-II truncations were not associated with ABI at baseline and follow-up, or with cross-sectional and prospective PAD determinations. ApoC-I and apoC-II and their truncations do not appear linked with PAD. In contrast, we find different associations of apoC-III0b and apoC-III2 with prevalent and incident PAD that are independent of other risk factors, including plasma lipids. Our data provide further support that proteoforms may have unique properties not captured by “total” apolipoprotein measures.
P.Reaven: Research Support; AstraZeneca, Dexcom, Inc. J.Koska: None. S.Hansen: None. Y.Hu: None. J.Furtado: Research Support; Eli Lilly and Company, Pfizer Inc. S.Sinari: None. D.Billheimer: None. D.Nedelkov: None. M.Budoff: Research Support; Amarin Corporation, Novo Nordisk, Speaker's Bureau; Boehringer Ingelheim International GmbH, Lilly. R.Mcclelland: None.
National Institutes of Health (R01-HL138969)