Immunoglobulin G N-Glycosylation Signatures in Incident Type 2 Diabetes and Cardiovascular Disease
Anna Birukov, Branimir Plavša, Fabian Eichelmann, Olga Kuxhaus, Rosangela Hoshi, Najda Rudman, Tamara Štambuk, Irena Trbojević‐Akmačić, Catarina Schiborn, Jakub Morze, Matea Mihelčić, Ana Cindrić, Yanyan Liu, Olga Demler, Markus Perola, Samia Mora, Matthias B. Schulze, Gordan Lauc, Clemens Wittenbecher
Abstract
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.