High‐Density Lipoprotein Subspecies Defined by Apolipoprotein C‐III and Subclinical Atherosclerosis Measures: MESA (The Multi‐Ethnic Study of Atherosclerosis)

Abstract

BackgroundApolipoprotein C‐III (apoC‐III), a small proinflammatory protein present on 6% to 7% of high‐density lipoprotein (HDL) particles, defines a subspecies of HDL adversely associated with coronary heart disease in primarily white cohorts. In a multi‐ethnic population free of clinical cardiovascular disease, we evaluated the relationship between apoC‐III–defined HDL subspecies and subclinical markers of atherosclerotic pathology.Methods and ResultsWe investigated cross‐sectional associations between apolipoprotein A‐I concentrations of apoC‐III–defined HDL subspecies, measured via ELISA and imaging measures of subclinical atherosclerosis, among 4659 participants in the MESA (The Multi‐Ethnic Study of Atherosclerosis) at baseline (2000–2002). HDL particles containing and lacking apoC‐III were divergently associated with coronary artery calcification in women (P‐heterogeneity=0.002) but not in men (P‐heterogeneity=0.31) and with carotid plaque score (P‐heterogeneity=0.02) and intima‐media thickness (P‐heterogeneity=0.06) in the overall study population. HDL lacking apoC‐III was inversely associated with all outcome measures (coronary artery calcification, women: odds ratio per SD=0.81 [95% confidence interval [CI], 0.73–0.90]; carotid plaque, overall: odds ratio per SD=0.92 [95% CI, 0.84–1.00]; intima‐media thickness, overall: mean difference per SD=−14.0 µm [95% CI, −21.1 to −6.7 μm]), whereas HDL containing apoC‐III was positively associated (coronary artery calcification, women: odds ratio=1.10 [95% CI, 0.99–1.22]; plaque, overall: odds ratio=1.10 [95% CI, 1.01–1.19]) or unassociated. Neither total HDL nor HDL subspecies was associated with changes in subclinical atherosclerosis measures up to 10 years later.ConclusionsThe presence of apoC‐III defined a subspecies of HDL not inversely associated with baseline measures of subclinical atherosclerosis, supporting a role of apoC‐III in the pathophysiology of cardiovascular disease.

Apolipoprotein C-III and its defined lipoprotein subspecies in relation to incident diabetes: the Multi-Ethnic Study of Atherosclerosis

“…The current results and our prior findings [15,18,38] indicate that, beyond its inherent atherogenic and diabetogenic properties, apoC-III may be involved in cardiometabolic disease processes as a modulator of HDL function. We previously reported that only HDL lacking apoC-III was inversely associated with risk of coronary heart disease in four cohorts [38] and with cross-sectional measures of subclinical atherosclerosis in MESA [18], and thus HDL containing apoC-III may constitute a dysfunctional subspecies of HDL lacking cardioprotective potential. Little is currently known about the functional involvement of these apoC-III-defined HDL subspecies in the development of diabetes.…”

“…In addition to its direct role in cardiometabolic disease pathophysiology, apoC-III may modify the functions of the lipoproteins on which it resides. We previously demonstrated in several cohorts that the presence of apoC-III diminishes the established inverse association of HDL with CHD [17] and subclinical atherosclerosis [18] and strengthens the positive association of LDL with risk of CHD [19], suggesting that apoC-III may disrupt the cardioprotective functions of HDL and enhance the atherogenicity of LDL. Our findings for cardiovascular outcomes led us to hypothesise that apoC-III may similarly counter the emerging anti-diabetogenic properties of HDL, which include the regulation of glucose and insulin secretion and the suppression of inflammation in metabolic tissues [2].…”

Apolipoprotein CIII Is an Important Piece in the Type-1 Diabetes Jigsaw Puzzle

“…When carotid intima-media thickness was measured cross-sectionally and prospectively in subjects with T1D, it pointed to an adverse association to apoCIII [ 104 ]. Data from humans reveal that HDL containing apoCIII no longer acts as the “good protective cholesterol”, but instead is related to an increased risk of atherogenesis and diabetes, which further confirms the complexity of this apolipoprotein [ 105 , 106 ].…”

Serum apolipoproteins and apolipoprotein-defined lipoprotein subclasses: a hypothesis-generating prospective study of cardiovascular events in T1D

“…In our study, we observed the risk to increase by approximately 10% for every mg/dl increase in total APOC3 for "any CVD" event and for MACEs. In a recent report of 4,659 participants with CVD risk factors in the Multi-Ethnic Study of Atherosclerosis, HDL particles containing APOC3 were positively associated with coronary artery calcification in women (41). Our findings are consistent with these previous observations, as we observed nominally significant positive associations of the HDL-containing subfraction of APOC3 (APOC3-HS) with "any CVD" event and with MACEs: this persisted in our most rigorously adjusted model, which adjusted for SBP and pulse, both prespecified variables in our analytic plan.…”