Search

Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B , changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system.

Aims/hypothesis: We previously demonstrated that N-glycosylation of plasma proteins and IgGs is different in children with recent-onset type 1 diabetes compared with their healthy siblings. To search for genetic variants contributing to these changes, we undertook a genetic association study of the plasma protein and IgG N-glycome in type 1 diabetes., Methods: A total of 1105 recent-onset type 1 diabetes patients from the Danish Registry of Childhood and Adolescent Diabetes were genotyped at 183,546 genetic markers, testing these for genetic association with variable levels of 24 IgG and 39 plasma protein N-glycan traits. In the follow-up study, significant associations were validated in 455 samples., Results: This study confirmed previously known plasma protein and/or IgG N-glycosylation loci (candidate genes MGAT3, MGAT5 and ST6GAL1, encoding beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 gene, respectively) and identified novel associations that were not previously reported for the general European population. First, novel genetic associations of IgG-bound glycans were found with SNPs on chromosome 22 residing in two genomic intervals close to candidate gene MGAT3; these include core fucosylated digalactosylated disialylated IgG N-glycan with bisecting N-acetylglucosamine (GlcNAc) (p discovery =7.65 × 10 -12 , p replication =8.33 × 10 -6 for the top associated SNP rs5757680) and core fucosylated digalactosylated glycan with bisecting GlcNAc (p discovery =2.88 × 10 -10 , p replication =3.03 × 10 -3 for the top associated SNP rs137702). The most significant genetic associations of IgG-bound glycans were those with MGAT3. Second, two SNPs in high linkage disequilibrium (missense rs1047286 and synonymous rs2230203) located on chromosome 19 within the protein coding region of the complement C3 gene (C3) showed association with the oligomannose plasma protein N-glycan (p discovery =2.43 × 10 -11 , p replication =8.66 × 10 -4 for the top associated SNP rs1047286)., Conclusions/interpretation: This study identified novel genetic associations driving the distinct N-glycosylation of plasma proteins and IgGs identified previously at type 1 diabetes onset. Our results highlight the importance of further exploring the potential role of N-glycosylation and its influence on complement activation and type 1 diabetes susceptibility., (© 2023. The Author(s).)

Objective: Previously we have shown that plasma protein N-glycosylation is changed in children at the onset of type 1 diabetes. In this study, we aim to identify N-glycan changes in adults with T1DM, compare them to those in children, and investigate their associations with disease duration, complications, glycaemic status, and smoking., Methods: Serum protein N-glycans from 200 adults with type 1 diabetes and 298 healthy controls were analysed using ultra-high performance liquid chromatography and divided into 39 directly measured glycan groups from which 16 derived traits were calculated., Results: Compared to healthy controls, subjects with type 1 diabetes showed differences in 19 glycan groups and a decrease in monogalactosylated, an increase in digalactosylated, monosialylated, and antennary fucosylated derived traits, from which changes in monogalactosylation and seven directly measured traits overlapped with previously reported in children. Changes in four directly measured and two derived traits previously seen in children were not detected in adults. HbA1c was positively associated with sialylated and highly branched structures, whereas N-glycome was not influenced by disease duration or diabetic complications., Conclusions: Our results suggest potential N-glycome involvement in different stages of type 1 diabetes, including processes underlying its development, the disease itself, as well as those occurring after disease establishment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2022 by the American Diabetes Association.)

Aims/hypothesis: Individual variation in plasma N-glycosylation has mainly been studied in the context of diabetes complications, and its role in type 1 diabetes onset is largely unknown. Our aims were to undertake a detailed characterisation of the plasma and IgG N-glycomes in patients with recent onset type 1 diabetes, and to evaluate their discriminative potential in risk assessment., Methods: In the first part of the study, plasma and IgG N-glycans were chromatographically analysed in a study population from the DanDiabKids registry, comprising 1917 children and adolescents (0.6-19.1 years) who were newly diagnosed with type 1 diabetes. A follow-up study compared the results for 188 of these participants with those for their 244 unaffected siblings. Correlation of N-glycan abundance with the levels and number of various autoantibodies (against IA-2, GAD, ZnT8R, ZnT8W), as well as with sex and age at diagnosis, were estimated by using general linear modelling. A disease predictive model was built using logistic mixed-model elastic net regression, and evaluated using a 10-fold cross-validation., Results: Our study showed that onset of type 1 diabetes was associated with an increase in the proportion of plasma and IgG high-mannose and bisecting GlcNAc structures, a decrease in monogalactosylation, and an increase in IgG disialylation. ZnT8R autoantibody levels were associated with higher IgG digalactosylated glycan with bisecting GlcNAc. Finally, an increase in the number of autoantibodies (which is a better predictor of progression to overt diabetes than the level of any individual antibody) was accompanied by a decrease in the proportions of some of the highly branched plasma N-glycans. Models including age, sex and N-glycans yielded notable discriminative power between children with type 1 diabetes and their healthy siblings, with AUCs of 0.915 and 0.869 for addition of plasma and IgG N-glycans, respectively., Conclusions/interpretation: We defined N-glycan changes accompanying onset of type 1 diabetes, and developed a predictive model based on N-glycan profiles that could have valuable potential in risk assessment. Increasing the power of tests to identify individuals at risk of disease development would be a considerable asset for type 1 diabetes prevention trials., (© 2022. The Author(s).)

Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the 16 loci reported previously, 15 were replicated in our study. For the remaining locus (near the KREMEN1 gene), the replication power was low, and hence, replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The 15 replicated loci present a good target for further functional studies. Among these, eight loci contain genes encoding glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4 and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Changes of the ST segment are commonly used as predictors of the culprit vessel during an acute myocardial infarction. In case of combined ST elevation in both inferior and anterior leads, these changes can be due to a distal occlusion of a "wrapped" left anterior descending artery (LAD) or a two-vessel disease. Our case of anterior wall myocardial infarction with inferior ST elevation and anterior ST depression shows that electrocardiographic changes during acute myocardial infarction cannot always be explained by logical sequelae of the injury current, vessel anatomy, and their irrigation territory., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Marko Perčić et al.)

Objective: Plasma protein N -glycan profiling integrates information on enzymatic protein glycosylation, which is a highly controlled ubiquitous posttranslational modification. Here we investigate the ability of the plasma N -glycome to predict incidence of type 2 diabetes and cardiovascular diseases (CVDs; i.e., myocardial infarction and stroke)., Research Design and Methods: Based on the prospective European Prospective Investigation of Cancer (EPIC)-Potsdam cohort ( n = 27,548), we constructed case-cohorts including a random subsample of 2,500 participants and all physician-verified incident cases of type 2 diabetes ( n = 820; median follow-up time 6.5 years) and CVD ( n = 508; median follow-up time 8.2 years). Information on the relative abundance of 39 N -glycan groups in baseline plasma samples was generated by chromatographic profiling. We selected predictive N -glycans for type 2 diabetes and CVD separately, based on cross-validated machine learning, nonlinear model building, and construction of weighted prediction scores. This workflow for CVD was applied separately in men and women., Results: The N -glycan-based type 2 diabetes score was strongly predictive for diabetes risk in an internal validation cohort (weighted C-index 0.83, 95% CI 0.78-0.88), and this finding was externally validated in the Finland Cardiovascular Risk Study (FINRISK) cohort. N -glycans were moderately predictive for CVD incidence (weighted C-indices 0.66, 95% CI 0.60-0.72, for men; 0.64, 95% CI 0.55-0.73, for women). Information on the selected N -glycans improved the accuracy of established and clinically applied risk prediction scores for type 2 diabetes and CVD., Conclusions: Selected N -glycans improve type 2 diabetes and CVD prediction beyond established risk markers. Plasma protein N -glycan profiling may thus be useful for risk stratification in the context of precisely targeted primary prevention of cardiometabolic diseases., (© 2020 by the American Diabetes Association.)

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., (© 2019 Federation of European Biochemical Societies.)

Objectives: Performance on neuropsychological tests can be influenced by non-cognitive factors, including deliberate underperformance, stress, the need to fulfil a sick role, depression, un-cooperativeness, fatigue and unhappiness with the evaluative situation. Tests to detect suboptimal effort are becoming widely used in clinical practice and are based on their reported insensitivity to cognitive dysfunction. A diagnosis of dementia has life-changing implications for an individual of working age. It is therefore crucial that clinicians can be confident they have obtained a valid estimate of current cognitive functioning. This study aimed to establish whether mood or cognitive functioning adversely influenced performance on symptom validity tests (SVTs) in individuals with working age dementia, who were judged to be using full effort., Method: Forty-two participants with dementia diagnosed before the age of 65 completed measures of emotional and cognitive functioning and six SVTs., Results: There were no significant correlations between emotional functioning and measures of effort. However, cognitive functioning, in particular new learning, was significantly related to SVT performance. Participants with mild dementia performed significantly better on all six SVTs than those with moderate/severe dementia. The results also suggest that the SVTs are not equally sensitive to cognitive dysfunction. Rey's Dot Counting Test (DCT) (times criterion) achieved 100% specificity, and was the only test passed by every participant., Conclusion: Rey's DCT is the only SVT that can be recommended for use in those under 65 years with possible dementia at this time until further validation studies are undertaken.

This article reviews the clinical and diagnostic evaluation of patients with injuries to the hip and thigh. The history and physical examination, appropriate imaging strategies, complications and associated injuries, analgesia, treatment, and appropriate patient disposition are emphasized.

Current suction equipment is often inadequate at clearing the oropharynx. This study tested the hypothesis that evacuation times of simulated vomitus could be significantly improved by increasing suction tube and connection port diameters. Two standard suction systems and a new large-diameter suction system were tested. Mean evacuation times for 90 mL (an average mouthful) of three different vomitus-simulating substances--water, activated charcoal, and Progresso vegetable soup--were compared. All parameters other than suction tubing and attachment port diameters remained constant. The data were analyzed with analysis of variance and Fisher's protected least significant difference post hoc test. Use of large-diameter suction tubing significantly (P < .0001) improved evacuation time for each of the three substances. This improvement was most evident in the trials with activated charcoal and the vegetable soup, where there was a tenfold decrease in mean evacuation time. These results show that large-diameter 3/4-inch suction tubing connected to the 1-inch port is superior to the standard 1/4-inch tubing and connection ports currently used. The tenfold reduction in evacuation time of viscous and particulate materials may have important clinical implications in preventing or minimizing complications from aspiration.