Published Online
on October 8, 2007

A more recent version of this article appeared on October 30, 2007

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Submitted on April 4, 2007
Accepted on August 31, 2007

Apolipoprotein A-II Is Inversely Associated With Risk of Future Coronary Artery Disease

Rakesh S. Birjmohun MD, Geesje M. Dallinga-Thie PhD, Jan Albert Kuivenhoven PhD, Erik S.G. Stroes MD, PhD, James D. Otvos PhD, Nicholas J. Wareham MBBS, PhD, Robert Luben BSc, John J.P. Kastelein MD, PhD^*, Kay-Tee Khaw MBBChir, and S. Matthijs Boekholdt MD, PhD

From Departments of Vascular Medicine (R.S.B., G.M.D.-T., J.A.K., E.S.G.S., J.J.P.K.) and Cardiology (S.M.B.), Academic Medical Center, Amsterdam, The Netherlands; LipoScience Inc (J.D.O.), Raleigh, NC; Medical Research Council Epidemiology Unit (N.J.W.) Cambridge, United Kingdom; and Department of Public Health and Primary Care (R.L., K.-T.K.), Institute of Public Health, University of Cambridge, Cambridge, United Kingdom.

^* To whom correspondence should be addressed. E-mail: j.j.kastelein{at}amc.uva.nl.

Background—Although the vasculoprotective effects of apolipoprotein A-I (apoA-I), the major protein associated with high-density lipoprotein, have been universally accepted, apoA-II has been suggested to have poor antiatherogenic or even proatherogenic properties. To study this suggestion more closely, we evaluated how serum levels of apoA-II and apoA-I relate to the risk of future coronary artery disease (CAD) in a large, prospective study.

Methods and Results—We performed a nested case-control study in the prospective EPIC-Norfolk (European Prospective Investigation into Cancer and Nutrition–Norfolk) cohort. Case subjects (n=912) were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Control subjects (n=1635) were matched by age, gender, and enrollment time. Conditional logistic regression was used to quantify the relationship between serum apoA-II levels and risk of CAD. Serum apoA-II concentration was significantly lower in case subjects (34.5±6.3 mg/dL) than in control subjects (35.2±5.8 mg/dL) and was inversely associated with risk of CAD, such that patients in the upper quartile (>38.1 mg/dL) had an odds ratio of 0.59 (95% confidence interval 0.46 to 0.76) versus those in the lowest quartile (<31.1 mg/dL; P for linearity <0.0001). After adjustment for fasting time, alcohol use, and cardiovascular risk factors (systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index, smoking, diabetes mellitus, and C-reactive protein), the corresponding risk estimate was 0.48 (95% confidence interval 0.34 to 0.67, P for linearity <0.0001). Surprisingly, additional adjustment for serum apoA-I levels did not affect risk prediction of apoA-II for future CAD (odds ratio 0.49, 95% confidence interval 0.34 to 0.68, P for linearity <0.0001). Also, after adjustment for high-density lipoprotein particle number and size, apoA-II was still associated with the risk of future CAD (odds ratio 0.62, 95% confidence interval 0.43 to 0.90, P for linearity 0.02).

Conclusions—ApoA-II is associated with a decreased risk of future CAD in apparently healthy people. These findings imply that apoA-II itself exerts effects on specific antiatherogenic pathways. On the basis of these findings, discussion of the potential proatherogenic effects of apoA-II can cease.

Key words: apolipoproteins • coronary disease • risk factors • cholesterol • atherosclerosis

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