Immunoglobulin G N-Glycosylation Signatures in Incident Type 2 Diabetes and Cardiovascular Disease

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.

Leveraging IgG N-glycosylation to infer the causality between T2D and hypertension

“…In addition, a study of Chinese Muslim ethnicity and the Han population reported associations of IgG-glycans with hypertension and type 2 diabetes mellitus comorbidity [ 45 ]. A study of European samples developed a score based on significant IgG-GPs, which was associated with higher diabetes risk and was robust against confounder and clinical biomarkers [ 46 ]. Similarly, using the 2617 participants of the TwinsUK cohort, the glycan score of hypertension was built and indicated that the IgG glycome changes prior to the development of hypertension [ 47 ].…”

The N-Glycosylation of Total Plasma Proteins and IgG in Atrial Fibrillation

“…The most unique change was the decrease in the bisecting structures, stemming mainly from the decrease in the FA2B and FA2[6]BG1. An increased bisecting is noticed throughout the literature, in studies looking at the IgG N -glycosylation in inflammation, diabetes, CVD, and hypertension, which are all states that are associated with AF [ 24 , 27 , 28 ]. Furthermore, higher levels of bisecting N-acetlyglucosamine have been associated with proinflammatory IgG changes due to an increased binding to FcγRIII, and consequently, an increased antibody-dependent cellular cytotoxicity (ADCC) [ 44 ].…”

“…Furthermore, higher levels of bisecting N-acetlyglucosamine have been associated with proinflammatory IgG changes due to an increased binding to FcγRIII, and consequently, an increased antibody-dependent cellular cytotoxicity (ADCC) [ 44 ]. The changes in FA2[3]G1 are also of the opposite direction compared to those that are noticed in diabetes and CVD [ 24 , 28 , 29 ]. Overall, an inflammatory IgG profile, present in these conditions and consisting of decreased galactosylation and sialylation, is not reveled in AF.…”

“…It was found that GlycA, a glycan-based plasma biomarker, correlates with the incidence of cardiovascular events [ 23 ], and that the same association has been observed for the total plasma protein and IgG N -glycome [ 24 , 25 ]. Besides cardiovascular events, IgG N -glycosylation has also been found to associate with the atherosclerotic risk score, as well as with the development of femoral and carotid plaques [ 24 , 26 ]. IgG glycosylation changes were also reported in hypertension [ 27 ].…”

“…IgG glycosylation changes were also reported in hypertension [ 27 ]. In addition to different CVDs, N -glycans have been studied in diabetes, with both plasma and IgG N -glycans showing extensive alterations connected to the disease onset, as well as the progression of both type 1 and type 2 diabetes [ 24 , 28 , 29 , 30 ].…”