Plasma N-Glycans as Emerging Biomarkers of Cardiometabolic Risk: A Prospective Investigation in the EPIC-Potsdam Cohort Study

Abstract

Plasma protein N-glycan profiling integrates information on enzymatic protein glycosylation, which is a highly controlled ubiquitous posttranslational modification. Here we investigate the ability of the plasma N-glycome to predict incidence of type 2 diabetes and cardiovascular diseases (CVDs; i.e., myocardial infarction and stroke). RESEARCH DESIGN AND METHODSBased on the prospective European Prospective Investigation of Cancer (EPIC)-Potsdam cohort (n 5 27,548), we constructed case-cohorts including a random subsample of 2,500 participants and all physician-verified incident cases of type 2 diabetes (n 5 820; median follow-up time 6.5 years) and CVD (n 5 508; median follow-up time 8.2 years). Information on the relative abundance of 39 N-glycan groups in baseline plasma samples was generated by chromatographic profiling. We selected predictive N-glycans for type 2 diabetes and CVD separately, based on cross-validated machine learning, nonlinear model building, and construction of weighted prediction scores. This workflow for CVD was applied separately in men and women. RESULTSThe N-glycan-based type 2 diabetes score was strongly predictive for diabetes risk in an internal validation cohort (weighted C-index 0.83, 95% CI 0.78-0.88), and this finding was externally validated in the Finland Cardiovascular Risk Study (FINRISK) cohort. N-glycans were moderately predictive for CVD incidence (weighted Cindices 0.66, 95% CI 0.60-0.72, for men; 0.64, 95% CI 0.55-0.73, for women). Information on the selected N-glycans improved the accuracy of established and clinically applied risk prediction scores for type 2 diabetes and CVD. CONCLUSIONSSelected N-glycans improve type 2 diabetes and CVD prediction beyond established risk markers. Plasma protein N-glycan profiling may thus be useful for risk stratification in the context of precisely targeted primary prevention of cardiometabolic diseases.

Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients with Type 2 Diabetes: A Multicenter Prospective Study with 5-year Follow up (U-CARE Study 2)

“…A lower relative abundance of simple biantennary N-glycans and a higher abundance of branched, galactosylated and sialylated complex N-glycans were increased both in type 1 [28] and type 2 [27] diabetes, and similar trends with increased levels of complex N-glycans (GP12, GP16 and GP22) were seen for higher UACR and greater annual loss of eGFR [26,28]. Recently, in the prospective European Prospective Investigation of Cancer (EPIC)-Potsdam cohort (n = 27,548), the increased levels of complex N-glycans, GP5 in women and GP16, GP23, and GP29 in men, improved the accuracy of risk production score for CVD [29].…”

“…The high throughput plasma or serum N-glycan pro ling studies using hydrophilic interaction liquid chromatography (HILIC) of peptide-N-glycosidase F digested and uorescently labelled N-glycans was reported and 46 N-glycan peaks (GP1-GP46) were demonstrated [25][26][27][28][29]. In the patients with normo-and hyperglycemia during acute in ammation, the comparison of N-glycan pro le demonstrated that increased branched, galactosylated, and sialylated tri-and tetraantennary N-glycans are associated with development of type 2 diabetes [25].…”

Elevated Serum Level of Cytokeratin 18 M65ED Is an Independent Indicator of Cardiometabolic Disorders

“…Recent studies demonstrated that some serum metabolites, ratios of several traditional metabolic parameters, and adipokines could have closed relationship with the cardiometabolic risk. Serum glycans could improve type 2 diabetes and CVD prediction beyond established risk markers [44]. TG : HDL-C ratio and triglyceride-glucose index are all reported to be associated with the cardiometabolic disorders [45,46].…”

Extensive weight loss can reduce immune age by altering IgG N-glycosylation

“…Besides age-related changes, specific IgG glycosylation patterns have been already associated with CVD risk score and subclinical atherosclerosis in two large independent UK cohorts [13]. Moreover, a prospective follow-up of the EPIC-Potsdam cohort confirmed that changes in plasma N-glycome composition are predictive of future CVD events, with comparable predictive power to the American Heart Association (AHA) score in men and even better predictive power in women [14]. The link between a proinflammatory IgG N-glycome and hypertension has also been extensively studied [15-17], and similar IgG glycosylation patterns were associated with increased body mass index (BMI) and measures of central adiposity [18,19].…”