LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA)

Background: Previous studies showing that smaller low-density lipoprotein (LDL) size is associated with greater atherosclerotic risk did not adequately control for small and large LDL particle correlation. Methods and results: We studied the association of lipoproteins measured by proton nuclear magnetic resonance spectroscopy with carotid intima-media thickness (IMT) in apparently healthy individuals (N = 5538, 38% White, 28% African American, 22% Hispanic, 12% Chinese). Small and large LDL particle concentrations (LDL-p) were inversely correlated (r = -0.63, P < 0.0001). Controlling for risk factors but not for LDL subclass correlation, LDL size and small LDL-p separately were associated with IMT (-20.9 and 31.7 μm change in IMT per 1-S.D., respectively, both P < 0.001), but large LDL-p was not (4.9 μm, P = 0.27). When LDL subclasses were included in the same model, large and small LDL-p were both associated with IMT (36.6 and 52.2 μm higher IMT per 1-S.D., respectively, both P < 0.001; 17.7 and 11.6 μm per 100 nmol/L, respectively). LDL size was not significant after accounting for LDL subclasses and risk factors (P = 0.10). Conclusion: Both LDL subclasses were significantly associated with subclinical atherosclerosis, with small LDL confounding the association of large LDL with atherosclerosis. Future studies of LDL size should account for the strong inverse correlation of LDL subclasses.