Physicians' Academy for Cardiovascular Education

ApoA-I not superior to HDL-c to predict coronary heart disease

Association of High-Density Lipoprotein-Cholesterol Versus Apolipoprotein A-I With Risk of Coronary Heart Disease: The European Prospective Investigation Into Cancer-Norfolk Prospective Population Study, the Atherosclerosis Risk in Communities Study, and the Women’s Health Study

Literature - Van Capelleveen JC, Bochem AE, Boekholdt M, et al. - JAHA 2017, Epub ahead of print


As mendelian studies cannot show a causal association between HDL-c levels and coronary heart disease (CHD) [1] and pharmacological HDL-c stimulation lacks prove of effect in humans [2-4], the hypothesis had been raised that HDL-c may not have a causal protective effect against atherosclerosis development itself and other parameters that reflect the physical structure and role of HDL may serve as a more relevant predictor of CHD risk.

For example, apolipoprotein A-I (apoA-I), which is the major constituent of HDL particles. However, prospective studies in which the association of apoA-I and HDL-c with CHD risk has been investigated, show conflicting data [5,6]. This may be due to the complex relationship between the two parameters, that is hard to dissect in conventional regression models.

Therefore, a new approach had been used in this study, in which HDL-c and apoA-I levels were categorized into quartiles in a 4x4 fashion. Subsequently, the association of apoA-I levels with CHD risk as well as with CHD risk factors, was assessed within the four HDL-c quartiles, and vice versa. This was done using a subset of the large European Prospective investigation into Cancer (EPIC) Norfolk cohort (United Kingdom, n=17,661) and a validation was executed with a subset of the Atherosclerosis Risk in Communities (ARIC) cohort (n=15,494) and Women’s Health Study (WHS, n=27,552). Risk factors: age, male sex, BMI, HbA1c, non-HDL-c, triglycerides, ApoB, systolic blood pressure (SBP), c-reactive protein (CRP), metabolic syndrome and alcohol intake.

Main results


In the EPIC-Norfolk cohort, HDL-c and apoA-I were strongly and inversely associated with CHD risk. However, these associations were not interchangeable as apoA-I levels did not show a similar trend within HDL-c quartiles, while vice versa, this was. Therefore, apoA-I levels do not offer predictive information over and above HDL-c. In contrast, an unexpected trend was even observed towards increased risk in some apoA-I quartiles. This was supported by a positive association of apoA-I levels with CHD risk factors within all HDL-c quartiles. All observations were confirmed in two independent cohorts, suggesting biological relevant associations.


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