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Immunoglobulin G N-glycosylation signatures in incident type 2 diabetes and cardiovascular disease

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posted on 2022-09-29, 19:48 authored by Anna Birukov, Branimir Plavša, Fabian Eichelmann, Olga Kuxhaus, Rosangela Akemi 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

  

Objective: 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).

Research Design and Methods: 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.

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 (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. 

Conclusions: Selected IgG glycans are associated with cardiometabolic risk beyond classic risk factors, including clinical biomarkers.

Funding

The recruitment phase of the EPIC-Potsdam Study was supported by the Federal Ministry of Science, Germany (01 EA 9401) and the European Union (SOC 95201408 05F02). The follow-up of the EPIC-Potsdam Study was supported by German Cancer Aid (70-2488-Ha I) and the European Community (SOC 98200769 05F02). This work was furthermore supported by a grant from the German Ministry of Education and Research (BMBF) and the State of Brandenburg (DZD grants 82DZD00302 and 82DZD03D03). CW was supported by the German Research Foundation (DFG) individual fellowship (#WI5132/1-1) and the SciLifeLab & Wallenberg Data Driven Life Science Program (grant: KAW 2020.0239). AB was supported bythe German Research Foundation (DFG) individual fellowship (BI 2427/1-1). SM was supported by research grant support from the National Heart Lung and Blood Institute (NHLBI) grants R01 HL134811, HL 117861, and K24 HL136852 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK112940. RAH was funded by the Lemann Foundation. OD was supported by K01HL135342. IgG N-glycome analysis was performed in the Genos Glycoscience Research Laboratory and partly supported by the European Union’s Horizon 2020 Framework Programme grants IM for FUTURE (grant agreement no. 721815) and GlySign (grant agreement no. 722095) as well as by the European Structural and Investment Funds: Research and Development (IRI) grant (no. KK.01.2.1.01.0003), Centre of Competence (CEKOM) grant (no. KK.01.2.2.03.0006), and Croatian National Centre of Research Excellence in Personalized Healthcare grant (no. KK.01.1.1.01.0010).

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