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

Abstract

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.

Keywords: coronary disease; genome-wide association study; triglycerides.

Figure 1

Cumulative incidence curves for risk of CHD by sdLDL-C and lbLDL-C quartiles, adjusted for age, race, and gender.

Figure 2

Adjusted hazard ratios for incident CHD by sdLDL-C quartiles stratified by LDL-C risk categories, adjusted for age, sex, and race, smoking, BMI, hypertension, diabetes, diabetes medications, and log hs-CRP.

Figure 3

Cumulative incidence of cardiovascular events in sub-groups with LDL-C <100 mg/dL (<25^th percentile) and/or sdLDL-C <27.8 mg/dL (<25^th percentile), from proportional hazards models adjusted for age, gender, and race.