Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 34; no. 5; pp. 1069 - 1077
• Main Authors: Hoogeveen, Ron C, Gaubatz, John W, Sun, Wensheng, Dodge, Rhiannon C, Crosby, Jacy R, Jiang, Jennifer, Couper, David, Virani, Salim S, Kathiresan, Sekar, Boerwinkle, Eric, Ballantyne, Christie M
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.05.2014
• Subjects: Aged; Atherosclerosis - blood; Atherosclerosis - diagnosis; Atherosclerosis - epidemiology; Atherosclerosis - genetics; Biomarkers - blood; Cholesterol, LDL - blood; Coronary Disease - blood; Coronary Disease - diagnosis; Coronary Disease - epidemiology; Coronary Disease - genetics; Female; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Incidence; Linear Models; Logistic Models; Male; Middle Aged; Particle Size; Phenotype; Predictive Value of Tests; Prevalence; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Subtilisins - genetics; Time Factors; United States - epidemiology; United States; coronary disease; genome-wide association study; triglycerides
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.114.303284

OBJECTIVE—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. APPROACH AND RESULTS—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. CONCLUSIONS—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.