IgG glycan patterns are associated with type 2 diabetes in independent European populations

Lemmers, Roosmarijn; Vilaj, Marija; Urda, Daniel; Agakov, Felix; Šimurina, Mirna; Klarić, Lucija; Rudan, Igor; Campbell, Harry; Hayward, Caroline; Wilson, Jim; Lieverse, Aloysius G.; Gornik, Olga; Sijbrands, Eric J.G.; Lauc, Gordan; Hoek, Mandy van

doi:10.1016/j.bbagen.2017.06.020

Cited by 100 publications

(114 citation statements)

References 42 publications

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“…various large cohort studies using higher-resolution techniques a reduced fucosylation of diantennary structures in T2D and metabolic syndrome was found, notably, in Caucasians as well as Chinese and Ghanaian populations, even after adjustment for possible confounders including age, sex, and BMI [13,27,45]. Consistent results were reported for IgG fucosylation in the same, large T2D case-control cohort as presented here [46]. Increased branching/antennarity as well as sialylation of both di-and triantennary glycans were consistently reported by our and other groups (Fig.…”

Section: Association Of N-glycome With Type 2 Diabetessupporting

confidence: 88%

N‐glycome signatures in human plasma: associations with physiology and major diseases

Dotz

Wuhrer

2019

FEBS Letters

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N‐glycome analysis in total plasma or serum yields information about the levels and glycosylation patterns of major plasma glycoproteins, including immunoglobulins, acute‐phase proteins, and apolipoproteins. Until recently, glycomic studies in disease settings largely suffered from small cohort sizes, poor analytical resolution, and poor comparability of results owing to the diversity of analytical techniques. Here, we report on recent advances in high‐throughput mass spectrometry glycomics technology that enabled elucidation of N‐glycome signatures in the plasma of patients with type 2 diabetes, inflammatory bowel disease, or colorectal cancer. Use of this technology revealed both commonalities and differences among disease fingerprints. Moreover, we summarize findings on glycomic signatures associated with age, sex, and body mass index. High‐throughput, high‐resolution glycomics technologies, together with robust data analysis workflows, will advance clinical translation.

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Section: Association Of N-glycome With Type 2 Diabetessupporting

confidence: 88%

N‐glycome signatures in human plasma: associations with physiology and major diseases

Dotz

Wuhrer

2019

FEBS Letters

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“…Our study of IgG N-glycosylation in type 2 diabetes has shown that a proinflammatory and biologically aged state is reflected on IgG N-glycan profiles [41]. In this study, decrease in galactosylation and sialylation of IgG was observed, as well as increase in IgG fucosylated structures with bisecting GlcNac and decrease in IgG fucosylated structures without bisecting GlcNac.…”

Section: Total Plasma Protein and Igg N-glycan Profiling In Type 2 DIsupporting

confidence: 56%

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

2019

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N‐glycosylation is a ubiquitous protein modification, and N‐glycosylation profiles are emerging as both biomarkers and functional effectors in various types of diabetes. Genome‐wide association studies identified glycosyltransferase genes as candidate causal genes for type 1 and type 2 diabetes. Studies focused on N‐glycosylation changes in type 2 diabetes demonstrated that patients can be distinguished from healthy controls based on N‐glycome composition. In addition, individuals at an increased risk of future disease development could be identified based on N‐glycome profiles. Moreover, accumulating evidence indicates that N‐glycans have a major role in preventing the impairment of glucose‐stimulated insulin secretion by maintaining the glucose transporter in proper orientation, indicating that interindividual variation in protein N‐glycosylation might be a novel risk factor contributing to diabetes development. Defective N‐glycosylation of T cells has been implicated in type 1 diabetes pathogenesis. Furthermore, studies of N‐glycan alterations have successfully been used to identify individuals with rare types of diabetes (such as the HNF1A‐MODY), and also to evaluate functional significance of novel diabetes‐associated mutations. In conclusion, both N‐glycans and glycosyltransferases emerge as potential therapeutic targets in diabetes.

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“…T ype 2 diabetes mellitus (T2DM) prevalence and its public health burden are rising worldwide in the 21st century. Genomic and other host factors, and their interactions with environment shape the risk for T2DM (Lemmers et al, 2017). The overall global prevalence of diabetes in adults between the ages of 20-79 years is reportedly 8.8% or 425 million adults who suffer from diabetes (International Diabetes Federation, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Glycosylation itself is regulated by complex systems including genetic and epigenetic factors (Kizuka and Taniguchi, 2016;Menni et al, 2013). For example, immunoglobulin G (IgG), a key effector of the humoral immune system with diverse roles in balancing inflammation at a system scale (Schwab and Nimmerjahn, 2013), displays changes in glycosylation in several diseases (Lauc et al, 2016), including T2DM (Adua et al, 2019;Keser et al, 2017b;Lemmers et al, 2017), and may possibly be involved in a mechanistic manner with diabetes in some situations (Tanigaki et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have reported changes in N-glycosylation in T2DM (Adua et al, 2019;Keser et al, 2017b;Lemmers et al, 2017). While these reports have only analyzed the total released IgG and/or total plasma protein glycans, for example, in European and African populations, they did not take into account variability due to individual IgG subclasses or the glycan location (Lemmers et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Glycomics for Type 2 Diabetes Biomarker Discovery: Promise of Immunoglobulin G Subclass-Specific Fragment Crystallizable N-glycosylation in the Uyghur Population

Liu

Mamatyusupu

Štambuk

et al. 2019

OMICS: A Journal of Integrative Biology

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Aberrant immunoglobulin G (IgG) N-glycosylation offers new prospects to detect changes in cell metabolism and by extension, for biomarker discovery in type 2 diabetes mellitus (T2DM). However, past studies did not analyze the individual IgG subclasses in relation to T2DM pathophysiology. We report here original findings through a comparison of the IgG subclass-specific fragment crystallizable (Fc) glycan biosignatures in 115 T2DM patients with 122 healthy controls within the Uyghur population in China. IgG Fc glycosylation profiles were analyzed using nano-liquid chromatography-mass spectrometry to exclude changes attributed to fragment antigen binding N-glycosylation. After correction for clinical covariates, 27 directly measured and 4 derived glycan traits of the IgG subclass-specific N-glycopeptides were significantly associated with T2DM. Furthermore, we observed in T2DM a decrease in bisecting N-acetylglucosamine of IgG2 and agalactosylation of IgG4, and an increase in sialylation of IgG4 and digalactosylation of IgG2. Classification model based on IgG subclass-specific N-glycan traits was able to distinguish patients with T2DM from controls with an area under the receiver operating characteristic curve of 0.927 (95% confidence interval 0.894-0.960, p < 0.001). In conclusion, a robust association between the IgG subclass-specific Fc N-glycomes and T2DM was observed in the Uyghur population sample in China, suggesting a potential for the IgG Fc glycosylation as a biomarker candidate for type 2 diabetes. The integration of glycomics with other system science biomarkers might offer further hope for innovation in diagnosis and treatment of T2DM in the future. Finally, it is noteworthy that ''Population Glycomics'' is an emerging approach to biomarker discovery for common complex diseases.

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IgG glycan patterns are associated with type 2 diabetes in independent European populations

Abstract: This work shows that IgG glycomic changes have biomarker potential and may yield important insights into pathophysiology of complex public health diseases, illustrated here for the first time in type 2 diabetes.

Cited by 100 publications

References 42 publications

N‐glycome signatures in human plasma: associations with physiology and major diseases

N‐glycome signatures in human plasma: associations with physiology and major diseases

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

Glycomics for Type 2 Diabetes Biomarker Discovery: Promise of Immunoglobulin G Subclass-Specific Fragment Crystallizable N-glycosylation in the Uyghur Population

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