Apolipoprotein A-II is atheroprotective

Apolipoprotein A-II, a component of high-density lipoprotein (HDL), was shown to be anti-atherogenic in one of the largest studies to date, based on the EPIC-Norfolk cohort. HDL Forum Editor Professor Kerry-Anne Rye discusses these data and their implications.

Birjmohun RS, Dallinga-Thie GM, Kuivenhoven JA et al. Apolipoprotein A-II is inversely associated with risk of future coronary artery disease. Circulation 2007;116:2029-35.

ApoA-II is the second most abundant apolipoprotein in HDL after apoA-I. While it is well established that plasma apoA-I levels are inversely related to coronary heart disease risk, the results from numerous animal studies have been conflicting, with some studies reporting that apoA-II protects against while others have found that it is associated with increased atherosclerosis.

The EPIC-Norfolk (European Prospective Investigation into Cancer and Nutrition-Norfolk) cohort study is part of a 9-country collaborative study aimed at investigating dietary and other determinants of cancer. In this report, the researchers performed a nested case-control study to evaluate whether apolipoprotein A-II (apoA-II) and apoA-I predict coronary artery disease (CAD). The cohort included middle-aged to elderly men and women (912 with CAD) who were matched for age, sex and enrolment date (1635 controls) and followed-up for an average of 6 years.

ApoA-II levels were significantly lower in subjects with CAD than in control subjects (34.5 ± 6.3 vs. 35.2 ± 5.8 mg/dL, p<0.0001). After stratifying apoA-II levels by quartiles, apoA-II levels were shown to be strongly predictive of risk of future CAD (p<0.0001 for linearity). Subjects in the highest apoA-II quartile (>38.1 mg/dL) had about half the adjusted odds of an event, compared with those in the lowest quartile (<31.1 mg/dL). This relationship was still evident even after adjusting for apoA-I levels (Table 1).

Table 1. Odds ratio (OR) with 95% CI for future CAD events


  
ApoA-II quartile (mg/dL)
 <31.131.1-34.334.3-38.1>38.1
Unadjusted OR1.000.72 (0.57-0.91)0.72 (0.57-0.91)0.59 (0.46-0.76)
Adjusted OR*1.000.72 (0.54-0.95)0.67 (0.49-0.90)0.49 (0.34-0.68)

However, it is also evident from data presented in this paper that people with diabetes remain at higher residual risk for vascular events, than those without diabetes, despite statin therapy. Subgroup analysis showed that event rates for major vascular events were higher in people with diabetes and low HDL cholesterol or elevated triglycerides than in those with values at current targets. Statistical tests for trends were however not statistically significant (table 2).

Even after adjusting for HDL particles and size, apoA-II levels were associated with decreased risk of CAD (odds ratio of 0.62, 95% CI 0.43-0.90, p=0.02 for linearity).

However, inclusion of apoA-II did not improve overall coronary artery risk prediction, using the Framingham risk score.

The findings from this study clearly demonstrate that apoA-II was associated with cardiovascular protection, even after adjustment for apoA-I levels. Even though apoA-II accounts for about 20% of HDL protein, the protective capacity of apoA-II was comparable to that of apoA-I., suggesting a potent anti-atherogenic effect.

While the EPIC-Norfolk study was primarily designed to investigate the relationship between diet and cancer, this cohort has provided extremely valuable information about a number of other diseases that have a significant inflammatory component, such as coronary heart disease, rheumatoid arthritis, and diabetes. In the most recent of these studies Birjmohun et al. present convincing evidence indicating that apoA-II is cardioprotective. The main strengths of this study are that the cohort that was investigated was quite large and that the inverse relationship between apoA-II levels and coronary heart disease risk persisted even when the data was corrected for apoA-I levels.

These observations raise a number of interesting questions, the most important of which relates to the underlying mechanism of the observation. In other words, how do apoA-II-containing HDL impart this cardioprotective effect? HDL are known to protect against coronary heart disease by a number of mechanisms, including their ability to remove cholesterol from macrophages in the artery wall in the first step of reverse cholesterol transport. HDL are also anti-oxidant, have potent anti-inflammatory properties and enhance endothelial repair. It remains to be seen if apoA-II-containing HDL exert their cardioprotective effects by one or more of these mechanisms. Irrespective of which mechanism(s) are involved, there is no doubt that this study will lead to renewed interest in this poorly understood apolipoprotein.

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