A novel protein glycan biomarker and future cardiovascular disease events

Abstract

Background: Glycosylated proteins partake in multiple cellular processes including inflammation. We hypothesized that GlycA, a novel biomarker of protein glycan N-acetyl groups, is related to incident cardiovascular disease (CVD), and we compared it with high-sensitivity C-reactive protein (hsCRP).

Methods and results: In 27 491 initially healthy women, baseline GlycA was quantified by nuclear magnetic resonance spectroscopy and hsCRP by an immunoturbidimetric assay. During median follow-up of 17.2 years, 1648 incident CVD events occurred (myocardial infarction, ischemic stroke, coronary revascularization, and CVD death). GlycA and hsCRP were moderately correlated (Spearman r=0.61, P<0.0001). In Cox regression models that included age, ethnicity, smoking, blood pressure, medications, menopausal status, body mass index, and diabetes, hazard ratios for CVD across quartiles 1 to 4 of GlycA were 1.00, 1.10 (95% CI, 0.92 to 1.30), 1.34 (95% CI, 1.13 to 1.58), and 1.64 (95% CI, 1.39 to 1.93), similar to hsCRP, for which hazard ratios were 1.00, 1.18 (95% CI, 0.99 to 1.41), 1.35 (95% CI, 1.14 to 1.61), and 1.75 (95% CI, 1.47 to 2.09) (both Ptrend<0.0001). Associations were attenuated after additionally adjusting for lipids: the hazard ratio of quartile 4 versus 1 for GlycA was 1.23 (95% CI, 1.04 to 1.46; Ptrend=0.002) and for hsCRP was 1.44 (95% CI, 1.20 to 1.72; Ptrend<0.0001). Further adjustment for the other biomarker resulted in a hazard ratio of quartile 4 versus 1 for GlycA of 1.03 (95% CI, 0.85 to 1.24; Ptrend=0.41) and for hsCRP of 1.29 (95% CI, 1.06 to 1.56; Ptrend=0.001).

Conclusions: In this prospective study of initially healthy women, baseline GlycA was associated with incident CVD, consistent with a possible role for protein glycans in inflammation and CVD.

Clinical trial registration url: http//clinicaltrials.gov/. Unique identifier NCT00000479.

Keywords: cardiovascular; epidemiology; glycoproteins; inflammation.

Figure 1.

Kaplan–Meier curves of incident CVD according to quartiles of GlycA (A) and hsCRP (B). Quartile concentrations were ≤326, 327 to 369, 370 to 416, and ≥417 μmol/L for GlycA and ≤0.81, 0.82 to 2.03, 2.04 to 4.38, and ≥4.39 mg/L for hsCRP. CVD indicates cardiovascular disease; hsCRP, high‐sensitivity C‐reactive protein.

Figure 2.

Kaplan–Meier curve of incident CVD according to joint levels of GlycA and hsCRP. High levels of GlycA were defined as greater than top tertile (>399 μmol/L). High levels of hsCRP were defined as >3 mg/L, according to clinical guidelines, which corresponded approximately to the top‐tertile value in this study. CVD indicates cardiovascular disease; hsCRP, high‐sensitivity C‐reactive protein.

Figure 3.

Hazard ratios for incident CVD events are shown on the y‐axis (log scale) for categories of GlycA and high‐sensitivity CRP (hsCRP). The hazard ratios are adjusted for age, ethnicity, smoking, systolic blood pressure, hypertensive medications, cholesterol treatment, postmenopausal status, use of hormone replacement therapy, body mass index, history of diabetes, trial treatment assignments, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol and log triglycerides. Categories of GlycA are based on tertile cut points (<341, 341 to 399, and >399 μmol/L). Categories of hsCRP are based on clinical cut points (<1, 1 to 3, and >3 mg/L), as recommended by clinical guidelines. CRP indicates C‐reactive protein; CVD, cardiovascular disease.