Circulating N-Linked Glycoprotein Acetyls and Longitudinal Mortality Risk

Abstract

Rationale Circulating glycoprotein N-acetyl glucosamine residues have recently been associated with incident cardiovascular disease (CVD) and diabetes mellitus. Objective Using a plasma glycan biosignature (GlycA) to identify circulating N-acetyl glycan groups, we examined the longitudinal association between GlycA and mortality among initially-healthy individuals. Methods and Results We quantified GlycA by 400 MHz 1H nuclear magnetic resonance (NMR) spectroscopy in 27,524 participants in the Women's Health Study (WHS; NCT00000479). The primary outcome was all-cause mortality. We replicated the findings in an independent cohort of 12,527 individuals in the JUPITER trial (NCT00239681). We also undertook secondary examination of CVD and cancer mortality in WHS. In WHS, during 524,515 person-years of follow-up (median 20.5 years) there were 3,523 deaths. Risk-factor adjusted multivariable Cox proportional hazard ratio (95% confidence interval) per standard deviation increment in GlycA for all-cause mortality was significantly increased at 5-years (1.21 [1.06, 1.40]) and during maximal follow-up (1.14 [1.09, 1.16]). Similar risk for all-cause mortality was observed in the replication cohort (1.33 [1.21, 1.45]). In WHS, risk of CVD mortality was increased at 5-years (1.43 [1.05, 1.95]) and during maximal follow-up (1.15 [1.04, 1.26]); and of cancer mortality at 5-years (1.23 [1.02, 1.47]) and during maximal follow-up (1.08 [1.01, 1.16]). Examination of correlations and mortality associations adjusted for hsCRP, fibrinogen, and ICAM-1, suggested that GlycA reflects summative risk related to multiple pathways of systemic inflammation. Conclusions Among initially-healthy individuals, elevated baseline circulating glycoprotein N-acetyl methyl groups were associated with longitudinal risk of all-cause, cardiovascular, and cancer mortality.

GlycA Is a Novel Biomarker of Inflammation and Subclinical Cardiovascular Disease in Psoriasis

“…GlycA, an NMR signal originating from a subset of glycan N-acetylglucosamine residues on enzymatically glycosylated acute-phase proteins, is a biomarker of systemic inflammation 9, 10 . Recent studies involving >25,000 subjects found GlycA to be predictive of 15-year CV events 11 , incident diabetes mellitus 13 , and all cause mortality 12, 28 . Fischer et al also found a 67% and 55% increase in mortality for every standard deviation increase in GlycA, in two independent populations totaling > 17,000 healthy adults 29 .…”

“…Fischer et al also found a 67% and 55% increase in mortality for every standard deviation increase in GlycA, in two independent populations totaling > 17,000 healthy adults 29 . Furthermore, these large population studies in subjects without pre-existing inflammatory diseases have revealed that GlycA either conferred additional value beyond traditional biomarkers of inflammation, such as hsCRP, IL-6, ICAM-1 and fibrinogen, or that it was equivalent to these traditional biomarkers in predicting long-term CV and all-cause mortality 11, 12, 28 . Strikingly, GlycA also showed associations with BMI and fitness among adolescents 30 , suggesting its role even in the early stages of cardiometabolic dysfunction.…”

Inflammatory glycoproteins in cardiometabolic disorders, autoimmune diseases and cancer

“…Haptoglobin, AGP, α1-antitrypsin and α1-antichymotrypsin are positive acute phase proteins that increase in concentration and glycan complexity in inflammatory states [7,[14][15][16][17], enabling GlycA to be a biomarker of systemic inflammation that is associated with inflammatory markers such as high-sensitivity CRP (hsCRP), fibrinogen, IL-6, serum amyloid A (SAA) and lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) [42,[46][47][48][49][50][51] as well as increased neutrophil activity [52]. It has also been reported that GlycA is related to increased mortality risk [1,52,53] [ Gruppen et al unpublished results]. Therefore, despite similarities in disease associations, GlycA, CRP, fibrinogen and other inflammatory markers likely capture different aspects of the inflammatory response [52].…”

“…Therefore, despite similarities in disease associations, GlycA, CRP, fibrinogen and other inflammatory markers likely capture different aspects of the inflammatory response [52]. Moreover, it has been reported that hsCRP, but not GlycA, levels were decreased after statin administration [53]. Therefore, it is clear that GlycA and other inflammatory biomarkers may at least be in part independent, and perhaps even additive, in the clinical information they impart.…”

“…Many tests are being developed to date that support the relevance of high throughput assays for biomarkers presumed to be associated with chronic cardiometabolic disorders like CVD, T2DM and NASH, as well as autoimmune disorders and cancer. Among other techniques, NMR spectroscopy holds promise to identify subjects at risk for a number of low grade inflammation-associated diseases, and may also have value to predict mortality [1,42,53,112,113]. As outlined in this review, it is increasingly appreciated that knowledge about alterations in the levels of glycoproteins in biological fluids as such, as well as with respect to the extent and specificity of the various glycan structures may improve risk stratification and identify novel pathogenic pathways.…”