This clinical study found that the LL-37-ApoB-100 complex serves as a biomarker of coronary artery disease. Since LL-37 binds to ApoB-containing lipoproteins in atherosclerotic contexts, the circulating complex may provide a novel diagnostic marker linking innate immunity to cardiovascular disease.
Abstract
BACKGROUND: ApoB (apolipoprotein B)-containing lipoproteins are causal risk factors for atherosclerotic coronary artery disease (CAD). Since human cathelicidin LL-37 binds to ApoB-100 in this pathological context, we investigated whether the circulating LL-37-ApoB-100 complex could serve as a biomarker for CAD.
METHODS: We performed surface plasmon resonance and protein-protein docking to demonstrate the direct LL-37-ApoB-100 interaction. We developed a specific polyclonal antibody against the complex and measured its levels in human atherosclerotic plaques and plasma, as well as inmice. An observational case-control study of 1103 patients undergoing coronary angiography from 2 independent centers assessed the association between LL-37-ApoB-100 and obstructive CAD.
RESULTS: We identified that LL-37 directly interacted with multiple distinct binding sites on ApoB-100. Plasma levels of LL-37-ApoB-100 complex were significantly elevated in human patients with atherosclerosis. Consistently, levels of this complex were positively correlated with atherosclerotic plaque area inmice. In the observational cohort from center 1, plasma LL-37-ApoB-100 levels were also significantly elevated in patients with obstructive CAD and strongly correlated with disease severity (Gensini score;=0.60,<0.001). Receiver operating characteristic curve analysis further demonstrated that LL-37-ApoB-100 was a valuable biomarker for the diagnosis of obstructive CAD, with an area under the curve of 0.82 (95% CIs, 0.81-0.85,<0.001). After adjustment for lipid and clinical measures, elevated LL-37-ApoB-100 levels remained an independent predictor of obstructive CAD, with an adjusted odds ratio of 6.51 (95% CI, 4.34-9.77,<0.001) for the upper quartiles. Observational analyses in center 2 showed consistent results.
CONCLUSIONS: Circulating LL-37-ApoB-100 levels are strongly associated with angiographically documented CAD, highlighting LL-37-ApoB-100 as an independent predictor for CAD.