Relationship of apolipoprotein C-III proteoform composition with ankle-brachial index and peripheral artery disease in the Multi-Ethnic Study of Atherosclerosis (MESA)

Background and aims: Apolipoprotein C-III (apoC-III) proteoform composition shows distinct relationships with plasma lipids and cardiovascular risk. The present study tested whether apoC-III proteoforms are associated with risk of peripheral artery disease (PAD). Methods: ApoC-III proteoforms, i.e., native (C-III_0a), and glycosylated with zero (C-III_0b), one (C-III₁) or two (C-III₂) sialic acids, were measured by mass spectrometry immunoassay on 5,734 Multi-Ethnic Study of Atherosclerosis participants who were subsequently followed for clinical PAD over 17 years. Ankle-brachial index (ABI) was also assessed at baseline and then 3 and 10 years later in 4,830 participants. Results: Higher baseline C-III_0b/C-III₁ and lower baseline C-III₂/C-III₁ were associated with slower decline in ABI (follow-up adjusted for baseline) over time, independently of cardiometabolic risk factors, and plasma triglycerides and HDL cholesterol levels (estimated difference per 1 SD was 0.31 % for both, p < 0.01). The associations between C-III₂/C-III₁ and changes in ABI were stronger in men (−1.21 % vs. −0.27 % in women), and in Black and Chinese participants (−0.83 % and −0.86 % vs. 0.12 % in White). Higher C-III_0b/C-III₁ was associated with a trend for lower risk of PAD (HR = 0.84 [95%CI: 0.67–1.04]) that became stronger after excluding participants on lipid-lowering medications (0.73 [95%CI: 0.57–0.94]). Neither change in ABI nor clinical PAD was related to total apoC-III levels. Conclusions: We found associations of apoC-III proteoform composition with changes in ABI that were independent of other risk factors, including plasma lipids. Our data further support unique properties of apoC-III proteoforms in modulating vascular health that go beyond total apoC-III levels.