Serum levels of angiopoietin-like protein 2 and the risk of cause-specific mortality in a general population: the Hisayama Study

Background: Angiopoietin-like protein 2 (ANGPTL2) is an aging-associated protein that contributes to the maintenance of tissue homeostasis. Excessive activation of ANGPTL2 disrupts this homeostatic process, leading to several adverse conditions, such as chronic inflammation, abnormal tissue remodeling, insulin resistance, and carcinogenesis. Nevertheless, only a very few studies have investigated the relationship between circulating ANGPTL2 concentrations and cause-specific mortality risk in the general population. Methods: We conducted a prospective cohort study involving 2,912 community-dwelling Japanese adults aged ≥40 years with no prior history of cardiovascular diseases or cancer. Baseline serum ANGPTL2 concentrations (collected in 2002–2003) were quantified, and the participants were followed up for a median of 15.2 years. Hazards ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality were estimated using Cox proportional hazards models. Results: During the follow-up period, 601 participants died (139 from cardiovascular diseases, 200 from cancer, 142 from infectious diseases, and 120 from other causes). Higher serum ANGPTL2 levels were significantly associated with increased risks of all-cause and cause-specific mortality (HR [95% CI] per 1-SD increment in log-transformed serum ANGPTL2 concentration: 1.34 [1.23–1.47] for all-cause mortality; 1.28 [1.06–1.55] for cardiovascular death; 1.31 [1.12–1.53] for cancer death; and 1.27 [1.05–1.54] for death from infectious diseases) after adjustment for potential confounders. These associations were modestly attenuated after additional adjustment for mediators related to insulin resistance and chronic inflammation. Conclusions: These findings indicate that elevated serum ANGPTL2 concentrations are associated with a higher risk of mortality from multiple causes.