A Novel Protein Glycan–Derived Inflammation Biomarker Independently Predicts Cardiovascular Disease and Modifies the Association of HDL Subclasses with Mortality

Abstract

BACKGROUND Evidence suggests that systemic inflammation may adversely impact HDL function. In this study we sought to evaluate the independent and incremental predictive performance of glycoprotein acetylation (GlycA)—a novel serum inflammatory biomarker that is an aggregate measure of enzymatically glycosylated acute phase proteins—and HDL subclasses on adverse events in a retrospective observational study of a secondary prevention population and to understand a priori defined potential interactions between GlycA and HDL subclasses. METHODS GlycA and HDL subclasses were measured using proton nuclear magnetic resonance spectroscopy in 7617 individuals in the CATHGEN (CATHeterization GENetics) cardiac catheterization biorepository. RESULTS GlycA was associated with presence [odds ratio (OR) 1.07 (1.02–1.13), P = 0.01] and extent [OR 1.08 (1.03, 1.12) P < 0.0005] of coronary artery disease and with all-cause mortality [hazard ratio (HR) 1.34 (1.29–1.39), P < 0.0001], cardiovascular mortality [1.37 (1.30–1.45), P < 0.0001] and noncardiovascular mortality [1.46 (1.39–1.54) P <0.0001] in models adjusted for 10 cardiovascular risk factors. GlycA and smaller HDL subclasses had independent but opposite effects on mortality risk prediction, with smaller HDL subclasses being protective [HR 0.69 (0.66–0.72), P < 0.0001]. There was an interaction between GlycA and smaller HDL subclasses—increasing GlycA concentrations attenuated the inverse association of smaller HDL subclasses with mortality. Adding GlycA and smaller HDL subclasses into the GRACE (Global Registry of Acute Coronary Events) and Framingham Heart Study Risk Scores improved mortality risk prediction, discrimination and reclassification. CONCLUSIONS These findings highlight the interaction of systemic inflammation and HDL with clinical outcomes and may increase precision for clinical risk assessment in secondary prevention populations.

Association Between Smoking and Serum GlycA and High‐Sensitivity C‐Reactive Protein Levels: The Multi‐Ethnic Study of Atherosclerosis (MESA) and Brazilian Longitudinal Study of Adult Health (ELSA‐Brasil)

“…Previous studies have shown that there is a progressive increase in the CVD risk with the increase in both GlycA and hsCRP beyond traditional CVD risk factors and independent of each other . A recent study by McGarrah et al showed that GlycA could independently predict coronary artery disease, all‐cause death, CVD death, and non‐CVD death in models adjusted for 10 CVD risk factors . Another study showed that GlycA is associated with similar CVD and non‐CVD outcomes after adjusting for several inflammatory markers including hsCRP, IL‐6, and D‐dimer .…”

“…We found a moderate positive correlation between GlycA and hsCRP. Previous studies have shown that there is a progressive increase in the CVD risk with the increase in both GlycA and hsCRP beyond traditional CVD risk factors and independent of each other . A recent study by McGarrah et al showed that GlycA could independently predict coronary artery disease, all‐cause death, CVD death, and non‐CVD death in models adjusted for 10 CVD risk factors .…”

Elevated GlycA in severe obesity is normalized by bariatric surgery

“…GlycA is a novel, composite nuclear magnetic resonance (NMR)‐measured biomarker that integrates quantities of several abundant acute phase glycoproteins to provide a more global assessment of inflammation with much lower intra‐individual variability than hsCRP . GlycA has been shown to be a strong and independent predictor of CVD, even among patients with concurrent inflammatory diseases .…”

Association of the Composite Inflammatory Biomarker GlycA, with Exercise‐Induced Changes in Body Habitus in Men and Women with Prediabetes

“…As such, GlycA is a biomarker for cardiometabolic disease risk [25]. In support of this claim are data that show that GlycA is associated with CVD in a secondary prevention cardiovascular cohort (CATHGEN) [26] and with incident CVD events in the Women's Health Study (WHS) [27], the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study [28], the Multi-Ethnic Study of Atherosclerosis (MESA) [29], and the JUPITER trial [30], independent of traditional CVD risk factors. Notably, following adjustment for traditional risk factors (e.g., BMI, LDL, and age), these associations were often only slightly attenuated by CRP, implying that GlycA measures CVD risk independently of CRP and may be a marker of a different inflammatory process.…”