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Comparative Study
. 2020 Nov;40(11):2714-2727.
doi: 10.1161/ATVBAHA.120.314609. Epub 2020 Sep 10.

Protein-Defined Subspecies of HDLs (High-Density Lipoproteins) and Differential Risk of Coronary Heart Disease in 4 Prospective Studies

Frank M Sacks #  1   2 , Liang Liang #  3 , Jeremy D Furtado #  1 , Tianxi Cai  3 , W Sean Davidson  4 , Zeling He  3 , Robyn L McClelland  5 , Eric B Rimm  1   2 , Majken K Jensen  1   6
Affiliations
Comparative Study

Protein-Defined Subspecies of HDLs (High-Density Lipoproteins) and Differential Risk of Coronary Heart Disease in 4 Prospective Studies

Frank M Sacks et al. Arterioscler Thromb Vasc Biol. 2020 Nov.

Abstract

Objective: HDL (high-density lipoprotein) contains functional proteins that define single subspecies, each comprising 1% to 12% of the total HDL. We studied the differential association with coronary heart disease (CHD) of 15 such subspecies. Approach and Results: We measured plasma apoA1 (apolipoprotein A1) concentrations of 15 protein-defined HDL subspecies in 4 US-based prospective studies. Among participants without CVD at baseline, 932 developed CHD during 10 to 25 years. They were matched 1:1 to controls who did not experience CHD. In each cohort, hazard ratios for each subspecies were computed by conditional logistic regression and combined by meta-analysis. Higher levels of HDL subspecies containing alpha-2 macroglobulin, CoC3 (complement C3), HP (haptoglobin), or PLMG (plasminogen) were associated with higher relative risk compared with the HDL counterpart lacking the defining protein (hazard ratio range, 0.96-1.11 per 1 SD increase versus 0.73-0.81, respectively; P for heterogeneity <0.05). In contrast, HDL containing apoC1 or apoE were associated with lower relative risk compared with the counterpart (hazard ratio, 0.74; P=0.002 and 0.77, P=0.001, respectively).

Conclusions: Several subspecies of HDL defined by single proteins that are involved in thrombosis, inflammation, immunity, and lipid metabolism are found in small fractions of total HDL and are associated with higher relative risk of CHD compared with HDL that lacks the defining protein. In contrast, HDL containing apoC1 or apoE are robustly associated with lower risk. The balance between beneficial and harmful subspecies in a person's HDL sample may determine the risk of CHD pertaining to HDL and paths to treatment.

Keywords: HDL; apoC1; apolipoproteins; coronary heart disease; haptoglobins; plasminogen; prospective studies.

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Figures

Figure 1.
Figure 1.. ApoA1 concentrations of minor HDL subspecies defined by the indicated protein in whites.
Upper panel: apoA1 concentrations (mean, SD); Lower panel: percentage of plasma total apoA1 (mean, SD). *p<0.05 comparing sexes. Data tables for the Black cohorts and the whites are in Supplemental Table II.
Figure 2.
Figure 2.. Relative Risk of CHD for the apoA1 concentrations of HDL subspecies and of plasma total apoA1: white women and white men combined.
Hazard Ratios with 95% confidence intervals for HDL subspecies that contain or lack the indicated defining proteins with FDR-adjusted p-values for heterogeneity (pHet). Each subspecies was studied in a separate model (not mutually adjusted). Each model includes covariates, plasma total concentration of the protein that defines the subspecies, apoA1 concentration of the minor subspecies that contains the defining protein, and the apoA1 concentration of HDL that lacks the defining protein. Plasma total apoA1 is studied in a separate model that does not contain the subspecies.
Figure 3.
Figure 3.. All minor HDL subspecies and total apoA1 included in one model.
The nested case-control designs were matched on age, smoking, and fasting status.
Figure 4.
Figure 4.. ApoE and Relative Risk for CHD.
ApoE concentration in total plasma; in HDL; apoA1 concentration of HDL that contains apoE; and HDL apoE density (HR with 95% CI). ApoE density was defined as the ratio of apoE concentration divided by apoA1 concentration in HDL that contains apoE. Plasma total apoE and apoA1 concentration of HDL that contains apoE were studied in the same model that included the covariates. ApoE concentration in HDL and HDL apoE density were studied in separate models that included the covariates. The covariates were hypertension, diabetes, body mass index, physical activity, and use of medications for hyperlipidemia. The nested case-control designs were matched on age, smoking, and fasting status.
Figure 5.
Figure 5.
Plasma triglycerides added to the standard model described in Figure 2. Relative risk of CHD for minor HDL subspecies. Hazard ratio with 95% confidence interval.
See this image and copyright information in PMC

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