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Arterioscler Thromb Vasc Biol. 2014 May;34(5):1069-77. doi: 10.1161/ATVBAHA.114.303284. Epub 2014 Feb 20.

Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: the Atherosclerosis Risk In Communities (ARIC) study.

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From the Department of Medicine, Baylor College of Medicine and Methodist DeBakey Heart and Vascular Center, Houston, TX (R.C.H., J.W.G., W.S., J.J., S.S.V., C.M.B.); Human Genetics Center, University of Texas Health Science Center School of Public Health, Houston (R.C.D., J.R.C., E.B.); Department of Biostatistics, University of North Carolina at Chapel Hill (D.C.); Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (S.S.V.); Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.); and Department of Medicine, Harvard Medical School, Boston, MA (S.K.).



To investigate the relationship between plasma levels of small dense low-density lipoprotein-cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among Atherosclerosis Risk in Communities (ARIC) study participants.


Plasma sdLDL-C was measured in 11 419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship among sdLDL-C, vascular risk factors, and risk for CHD events (n=1158) for a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in patients with diabetes mellitus than non-diabetes mellitus (49.6 versus 42.3 mg/dL; P<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio of 1.51 (95% confidence interval, 1.21-1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04-2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors.


sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.


coronary disease; genome-wide association study; triglycerides

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