OBJECTIVE N-glycosylation is a functional posttranslational modification of immunoglobulins (Igs). We hypothesized that specific IgG N-glycans are associated with incident type 2 diabetes and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS We performed case-cohort studies within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)–Potsdam cohort (2,127 in the type 2 diabetes subcohort [741 incident cases]; 2,175 in the CVD subcohort [417 myocardial infarction and stroke cases]). Relative abundances of 24 IgG N-glycan peaks (IgG-GPs) were measured by ultraperformance liquid chromatography, and eight glycosylation traits were derived based on structural similarity. End point–associated IgG-GPs were preselected with fractional polynomials, and prospective associations were estimated in confounder-adjusted Cox models. Diabetes risk associations were validated in three independent studies. RESULTS After adjustment for confounders and multiple testing correction, IgG-GP7, IgG-GP8, IgG-GP9, IgG-GP11, and IgG-GP19 were associated with type 2 diabetes risk. A score based on these IgG-GPs was associated with a higher diabetes risk in EPIC-Potsdam and independent validation studies (843 total cases, 3,149 total non-cases, pooled estimate per SD increase 1.50 [95% CI 1.37–1.64]). Associations of IgG-GPs with CVD risk differed between men and women. In women, IgG-GP9 was inversely associated with CVD risk (hazard ratio [HR] per SD 0.80 [95% CI 0.65–0.98]). In men, a weighted score based on IgG-GP19 and IgG-GP23 was associated with higher CVD risk (HR per SD 1.47 [95% CI 1.20–1.80]). In addition, several derived traits were associated with cardiometabolic disease incidence. CONCLUSIONS Selected IgG N-glycans are associated with cardiometabolic risk beyond classic risk factors, including clinical biomarkers.

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Atrial fibrillation is a disease with a complex pathophysiology, whose occurrence and persistence are caused not only by aberrant electrical signaling in the heart, but by the development of a susceptible heart substrate. These changes, such as the accumulation of adipose tissue and interstitial fibrosis, are characterized by the presence of inflammation. N-glycans have shown great promise as biomarkers in different diseases, specifically those involving inflammatory changes. To assess the changes in the N-glycosylation of the plasma proteins and IgG in atrial fibrillation, we analyzed the N-glycosylation of 172 patients with atrial fibrillation, before and six months after a pulmonary vein isolation procedure, with 54 cardiovascularly healthy controls. An analysis was performed using ultra-high-performance liquid chromatography. We found one oligomannose N-glycan structure from the plasma N-glycome and six IgG N-glycans, mainly revolving around the presence of bisecting N-acetylglucosamine, that were significantly different between the case and control groups. In addition, four plasma N-glycans, mostly oligomannose structures and a derived trait that was related to them, were found to be different in the patients who experienced an atrial fibrillation recurrence during the six-month follow-up. IgG N-glycosylation was extensively associated with the CHA2DS2-VASc score, confirming its previously reported associations with the conditions that make up the score. This is the first study looking at the N-glycosylation patterns in atrial fibrillation and warrants further investigation into the prospect of glycans as biomarkers for atrial fibrillation.

Introduction: Immunoglobulin G (IgG) are post-translationally modified proteins with the addition of complex carbohydrate molecules (glycans). These glycans can modulate IgG inflammatory capacity and determine the transition from healthy to diseased tissue. Hypothesis: A glycan score based on certain IgG glycosylation patterns is associated with CVD risk and can improve model prediction. Methods: IgG glycosylation profiles were measured on baseline plasma samples from nested CVD case-control participants from 2 studies: JUPITER (NCT00239681; Npairs=162; discovery) and the TNT (NCT00327691; Npairs=367, validation). Lasso regression was used to select IgG glycan peaks (GPs). The linear combination of selected IgG-GPs that significantly associated with CVD in a mutually adjusted conditional regression comprised the glycan score (IgG GS ). CVD prediction using IgG GS was investigated controlling for clinical risk factors. Using a parametric approach, we calculated the area under the curve (AUC) with and without IgG GS . Results: From 24 IgG-GPs, Lasso selected 4 IgG-GPs that were also associated with incident CVD (P<.05) in a mutually adjusted conditional logistic regression. These 4 IgG-GPs (9, 12, 19, 20) composed the IgG glycan score (IgG GS ; Fig1A), which was significantly associated with incident CVD in JUPITER after adjusting for clinical risk factors (model 2 hazard ratio [HR]: 2.1, 95% CI 1.55 - 2.84), with significant validation in TNT (HR = 1.2, 95% CI 1.03 - 1.4; Fig. 1B). The AUC was higher for the model with IgG GS (0.74, 95%CI = 0.69 - 0.81) than without (0.69, 95%CI = 0.67 - 0.71) in JUPITER; replicating in TNT: 0.72 [0.71 - 0.83] vs 0.64, [0.62 - 0.65]. The P-value for the likelihood ratio test comparing models with and without IgG GS was 5.9x10 -8 in JUPITER and .02 in TNT. Conclusions: An IgG glycan score with 4 IgG N-glycans was positively associated with incident CVD in the JUPITER primary prevention population, which replicated in TNT, a secondary prevention cohort, and improved model prediction performance.

<p>  </p> <p><strong>Objective:</strong> N-glycosylation is a functional posttranslational modification of immunoglobulins (Ig). We hypothesized that specific IgG N-glycans are associated with incident type 2 diabetes and cardiovascular disease (CVD).</p> <p><strong>Research Design and Methods: </strong>We performed case-cohort studies within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (type 2 diabetes: subcohort [N=2,127], incident cases [N=741]; CVD: subcohort [N=2,175], cases [myocardial infarction and stroke, N=417]). Relative abundances of 24 IgG N-glycan peaks (IgG-GPs) were measured by ultraperformance liquid chromatography, and 8 glycosylation traits were derived based on structural similarity. Endpoint-associated IgG-GPs were preselected with fractional polynomials, and prospective associations estimated in confounder-adjusted Cox models. Diabetes risk associations were validated in 3 independent studies.</p> <p><strong>Results:</strong> After adjustment for confounders and multiple testing correction, IgG-GP7, IgG-GP8, IgG-GP9, IgG-GP11, and IgG-GP19 were associated with type 2 diabetes risk. A score based on these IgG-GPs was associated with a higher diabetes risk in EPIC-Potsdam and independent validation studies (N cases=843, N total=3,149; pooled estimate per standard deviation [SD] increase: 1.50, 95% confidence interval [95%CI] 1.37-1.64). Associations of IgG-GPs with CVD risk differed between men and women. In women, IgG-GP9 was inversely associated with CVD risk (hazard ratio [HR] per SD 0.80, 95%CI 0.65-0.98). In men, a weighted score based on IgG-GP19 and IgG-GP23 was associated with higher CVD risk (HR per SD 1.47, 95%CI 1.20-1.80). In addition, several derived traits were associated with cardiometabolic disease incidence. </p> <p><strong>Conclusions:</strong> Selected IgG glycans are associated with cardiometabolic risk beyond classic risk factors, including clinical biomarkers.</p>