Objective-Angiopoietin-like protein 2 (ANGPTL2), a proinflammatory mediator, has been reported to accelerate the development of insulin resistance, endothelial dysfunction, and atherosclerosis in mice. However, no cohort studies have examined the relationship between serum ANGPTL2 levels and the development of cardiovascular disease (CVD) in a general population. Approach and Results-A total of 3005 community-dwelling Japanese aged ≥40 years without a history of CVD were divided into 4 groups according to the quartiles of serum ANGPTL2 concentrations (Q1, lowest and Q4, highest) and followed up for 10 years. The hazards ratios and their 95% confidence intervals for the development of CVD (coronary heart disease or stroke) were estimated using a Cox proportional hazards model. During the follow-up, 219 first-ever CVD events were observed. The risk of CVD increased significantly with elevating ANGPTL2 levels after adjustment for age, sex, serum total cholesterol, use of lipid-lowering agents, ECG abnormalities, smoking habits, alcohol intake, and regular exercise (hazards ratios [
Materials and MethodsMaterials and Methods are available in the online-only Data Supplement.
ResultsThe baseline characteristics of the study population according to the quartiles of serum ANGPTL2 concentrations are shown in Table 1. The mean values of age, waist circumference, body mass index, systolic and diastolic blood pressures, fasting plasma glucose, and serum levels of low-density lipoprotein cholesterol, triglycerides, and hs-CRP increased significantly with elevating serum ANGPTL2 levels. The subjects with higher serum ANGPTL2 levels had significantly higher frequencies of antihypertensive medication, antidiabetic medication, lipid-lowering medication, ECG abnormalities, regular exercise, metabolic syndrome, and its components. In contrast, the mean values of serum high-density lipoprotein cholesterol and frequencies of current smoking and drinking decreased significantly with higher serum ANGPTL2 levels. Serum ANGPTL2 levels did not show a clear association with sex and total cholesterol levels. Figure I in the online-only Data Supplement shows the distributions of baseline serum ANGPTL2 concentrations in subjects with and without CVD events during the follow-up. The distribution of serum ANGPTL2 in subjects with CVD was significantly higher than in those without CVD (P<0.001). Figure demonstrates the age-and sex-adjusted incidence rates of CVD and its subtypes according to the serum ANGPTL2 levels. The incidence rates of total CVD and coronary heart disease increased significantly with elevating serum ANGPTL2 levels (P for trend=0.005 and 0.01, respectively). A similar but nonsignificant trend was observed for the incidence rate of stroke (P for trend=0.07). Table 2 and Figure II in the online-only Data Supplement show the hazard ratios (HRs) for the development of CVD and its subtypes according to the serum ANGPTL2 levels. In model 1 with adjustment for age and sex, higher serum ANGPTL2 levels were significantly associated...