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CLINICAL RESEARCH: ATHEROSCLEROSIS

Value of Low-Density Lipoprotein Particle Number and Size as Predictors of Coronary Artery Disease in Apparently Healthy Men and Women

The EPIC-Norfolk Prospective Population Study

Karim El Harchaoui, MD^_*, Wim A. van der Steeg, MD^_*, Erik S.G. Stroes, MD, PhD^_*, Jan Albert Kuivenhoven, PhD^_*, James D. Otvos, PhD^||,1, Nicholas J. Wareham, MBBS, PhD, Barbara A. Hutten, PhD, John J.P. Kastelein, MD, PhD^_*,_*, Kay-Tee Khaw, MBBChir and S. Matthijs Boekholdt, MD, PhD^_*

^_* Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
Medical Research Council Epidemiology Unit, Cambridge, United Kingdom
Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
^|| LipoScience Inc., Raleigh, North Carolina

Manuscript received August 4, 2006; revised manuscript received September 22, 2006, accepted September 28, 2006.

^_* Reprint requests and correspondence: Dr. John J. P. Kastelein, F4.159-2, Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. (Email: j.j.kastelein{at}amc.uva.nl).

OBJECTIVES: We assessed relations of low-density lipoprotein (LDL) particle number (LDL-P) and LDL particle size as measured by nuclear magnetic resonance spectroscopy with LDL cholesterol (LDL-C) and the risk of future coronary artery disease (CAD).

BACKGROUND: Whereas LDL-C is an established risk factor for CAD, its discriminative power is limited. Measuring LDL-P and size may have stronger associations with CAD than LDL-C.

METHODS: A nested case-control study was performed in the prospective EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study, which comprises 25,663 subjects. Cases (n = 1,003) were individuals who developed CAD during 6 year follow-up. Control subjects (n = 1,885) were matched for age, gender, and enrollment time. Odds ratios (ORs) for future CAD were calculated, and we also evaluated whether LDL-P could improve the Framingham risk score (FRS) to predict CAD.

RESULTS: In univariate analyses, LDL-P (OR 2.00, 95% confidence interval [CI] 1.58 to 2.59) and non-high-density lipoprotein cholesterol (non–HDL-C) (OR 2.14, 95% CI 1.69 to 2.69) were more closely associated with CAD than LDL-C (OR 1.73, 95% CI 1.37 to 2.18). The additional value of LDL-P was lost after adjustment for HDL-C and triglyceride levels. Whereas LDL size was inversely related to CAD (OR 0.60, 95% CI 0.47 to 0.76), this relation was abolished upon adjustment for LDL-P. In a model adjusted for the FRS, LDL-P retained its association with CAD (p for trend 0.02).

CONCLUSIONS: In this large study of individuals with moderately elevated LDL-C, LDL-P was related to CAD on top of FRS as well as after adjusting for LDL-C. The additional value of LDL-P was comparable to non–HDL-C, and it was abolished after adjusting for triglycerides and HDL-C.

Abbreviations and Acronyms   apoB = apolipoprotein B   BMI = body mass index   CAD = coronary artery disease   CI = confidence interval   FRS = Framingham risk score   HDL-C = high-density lipoprotein cholesterol   LDL = low-density lipoprotein   LDL-C = low-density lipoprotein cholesterol   LDL-P = low-density lipoprotein-particle number   NMR = nuclear magnetic resonance   OR = odds ratio

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