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Meta-Analysis
. 2018 Apr;154(5):1320-1333.e10.
doi: 10.1053/j.gastro.2018.01.002. Epub 2018 Jan 6.

Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases

Collaborators, Affiliations
Meta-Analysis

Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases

Mirna Šimurina et al. Gastroenterology. 2018 Apr.

Abstract

Background and aims: Causes of inflammatory bowel diseases are not well understood and the most prominent forms, Crohn's disease (CD) and ulcerative colitis (UC), are sometimes hard to distinguish. Glycosylation of IgG has been associated with CD and UC. IgG Fc-glycosylation affects IgG effector functions. We evaluated changes in IgG Fc-glycosylation associated with UC and CD, as well as with disease characteristics in different patient groups.

Methods: We analyzed 3441 plasma samples obtained from 2 independent cohorts of patients with CD (874 patients from Italy and 391 from the United States) or UC (1056 from Italy and 253 from the US and healthy individuals [controls]; 427 in Italy and 440 from the United States). IgG Fc-glycosylation (tryptic glycopeptides) was analyzed by liquid chromatography coupled to mass spectrometry. We analyzed associations between disease status (UC vs controls, CD vs controls, and UC vs CD) and glycopeptide traits, and associations between clinical characteristics and glycopeptide traits, using a logistic regression model with age and sex included as covariates.

Results: Patients with CD or UC had lower levels of IgG galactosylation than controls. For example, the odds ratio (OR) for IgG1 galactosylation in patients with CD was 0.59 (95% confidence interval [CI], 0.51-0.69) and for patients with UC was 0.81 (95% CI, 0.71-0.92). Fucosylation of IgG was increased in patients with CD vs controls (for IgG1: OR, 1.27; 95% CI, 1.12-1.44), but decreased in patients with UC vs controls (for IgG23: OR, 0.72; 95% CI, 0.63-0.82). Decreased galactosylation associated with more severe CD or UC, including the need for surgery in patients with UC vs controls (for IgG1: OR, 0.69; 95% CI, 0.54-0.89) and in patients with CD vs controls (for IgG23: OR, 0.78; 95% CI, 0.66-0.91).

Conclusions: In a retrospective analysis of plasma samples from patients with CD or UC, we associated levels of IgG Fc-glycosylation with disease (compared to controls) and its clinical features. These findings could increase our understanding of mechanisms of CD and UC pathogenesis and be used to develop diagnostics or guide treatment.

Keywords: Biomarker; Glycans; Glycopeptides; IBD.

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Conflict of interest statement

Conflict of Interest:

GL is founder and owner of Genos LTD, company that specializes in high-throughput glycomics and has several patents in this field. FV, JS, ITA and GR are employees of Genos. GL is also founder and shareholder of GlycanAge LTD, company that markets GlycanAge test as a biomarker of healthy ageing. DPBM has consulted for Janssen, Cidara, Q Biologics, and Pfizer. Other authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1. The most complex IgG Fc-glycan found in our samples: FA2BG2S2
A diantennary (A2) digalactosylated (G2) and disialylated (S2) glycan with a bisecting β(1,4) GlcNAc (B) and an α(1,6)fucose (F) attached to core N-acetylglucosamine (GlcNAc). Linkages and anomeric configurations are shown,. Blue square: N-acetylglucosamine, red triangle: fucose, green circle: mannose, yellow circle: galactose, pink diamond: N-acetylneuraminic acid.
Figure 2
Figure 2. Differences in derived IgG Fc-glycan traits between HC, UC and CD for all IgG subclasses in both cohorts
Differences in derived glycan traits for all IgG subclasses between HC, UC and CD are shown separately for the US (red) and ITA (blue) cohort. Data are shown as box and whiskers plots. Each box represents the 25th to 75th percentiles (IQR). Lines inside the boxes represent the median. The whiskers represent the lowest and highest values within the boxes ± 1.5x the IQR. Derived glycan traits are listed in Supp. Table 3.-4. and their glycoforms in Supp. Table 2. Analysis of the differences in glycan traits between UC and HC, CD and HC and UC and CD, were performed using a logistic regression model with age and sex included as additional covariates (Table 2., Supp. Table 6., 8., and 10.).
Figure 3
Figure 3. ROC curves illustrating the discriminative power of individual glycoforms per IgG subclass
Prediction of disease status was performed using a logistic (elastic net) regression model for the ITA cohort between UC and HC (A), CD and HC (B), UC and CD (C) and for the US cohort between UC and HC (D), CD and HC (E), and UC and CD (F). While models based only on age and sex did not show predictive power (dotted line), addition of individual glycoforms increased the predictive power of the models (solid line).
Figure 4
Figure 4. Associations between derived IgG Fc-glycan traits and clinical characteristics in UC (duration, location and surgery)
Odds ratios for the associations between derived glycan traits and clinical traits in UC (duration of disease: <5 years = 0, >5 years = 1, disease location: E1 (proctitis) + E2 (left-sided UC) = 0, E3 (extensive UC) = 1, and surgery: no = 0, yes = 1) for all IgG subclasses are shown for the ITA cohort (green) and the US cohort (red). Bars indicate positive/negative odds ratios. Derived glycan traits are explained in Supp. Table 3.-4. and their glycoforms in Supp. Table 2. Analysis of the association between derived glycan traits and clinical characteristics in UC were performed using a logistic regression model with age and sex included as additional covariates, statistically significant findings are indicated with an asterisk (*) (Supp. Table 12.).
Figure 5
Figure 5. Associations between derived IgG Fc-glycan traits and clinical characteristics in CD (duration, location, behavior and surgery)
Odds ratios for the associations between derived glycan traits and clinical characteristics in CD (duration of disease: <5 years = 0, >5 years = 1, disease location: L1 (ileal CD)= 0, L3 (ileocolonic CD) = 1, behavior: B1 (inflammatory CD) = 0, B2 (structuring CD) + B3 (penetrating CD) = 1, and surgery: no = 0, yes = 1) for all IgG subclasses are shown for the ITA cohort (green) and the US cohort (red). Bars indicate positive/negative odds ratios. Derived glycan traits are explained in Supp. Table 3.-4. and their glycoforms in Supp. Table 2. Analysis of the association between derived glycan traits and clinical characteristics in CD were performed using a logistic regression model with age and sex included as additional covariates, statistically significant findings are indicated with an asterisk (*) (Supp. Table 14.).

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