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  1. Article ; Online: Defining type 2 diabetes polygenic risk scores through colocalization and network-based clustering of metabolic trait genetic associations

    Samuel Ghatan / Jeroen van Rooij / Mandy van Hoek / Cindy G. Boer / Janine F. Felix / Maryam Kavousi / Vincent W. Jaddoe / Eric J. G. Sijbrands / Carolina Medina-Gomez / Fernando Rivadeneira / Ling Oei

    Genome Medicine, Vol 16, Iss 1, Pp 1-

    2024  Volume 15

    Abstract: Abstract Background Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and ... ...

    Abstract Abstract Background Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations. Methods We applied colocalization between T2D and 20 related metabolic traits, across 243 loci, to obtain inferences of shared casual variants. Network-based unsupervised hierarchical clustering was performed on variant-trait associations. Partitioned polygenic risk scores (PRSs) were generated for each cluster using T2D summary statistics and validated in 21,742 individuals with T2D from 3 cohorts. Inferences of directionality and causality were obtained by applying Mendelian randomization Steiger’s Z-test and further validated in a pediatric cohort without diabetes (aged 9–12 years old, n = 3866). Results We identified 146 T2D loci that colocalized with at least one metabolic trait locus. T2D variants within these loci were grouped into 5 clusters. The clusters corresponded to the following pathways: obesity, lipodystrophic insulin resistance, liver and lipid metabolism, hepatic glucose metabolism, and beta-cell dysfunction. We observed heterogeneity in associations between PRSs and metabolic measures across clusters. For instance, the lipodystrophic insulin resistance (Beta − 0.08 SD, 95% CI [− 0.10–0.07], p = 6.50 × 10−32) and beta-cell dysfunction (Beta − 0.10 SD, 95% CI [− 0.12, − 0.08], p = 1.46 × 10−47) PRSs were associated to lower BMI. Mendelian randomization Steiger analysis indicated that increased T2D risk in these pathways was causally associated to lower BMI. However, the obesity PRS was conversely associated with increased BMI (Beta 0.08 SD, 95% CI 0.06–0.10, p = 8.0 × 10−33). Analyses within a pediatric cohort supported this finding. Additionally, the lipodystrophic ...
    Keywords Polygenic risk score ; Type 2 diabetes ; Colocalization ; Clustering ; Personalized medicine ; Medicine ; R ; Genetics ; QH426-470
    Subject code 571
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The (cost) effectiveness of a very low-energy diet intervention with the use of eHealth in patients with type 2 diabetes and obesity

    Karlijn A. M. Geurts / Behiye Ozcan / Mandy van Hoek / Roel van de Laar / Jolande van Teeffelen / Joost van Rosmalen / Elisabeth F. C. van Rossum / Kirsten A. Berk

    Trials, Vol 24, Iss 1, Pp 1-

    study protocol for a randomised controlled non-inferiority trial (E-diet trial)

    2023  Volume 12

    Abstract: Abstract Background Despite preventive measures, the number of people with type 2 diabetes and obesity is increasing. Obesity increases morbidity and mortality in people with type 2 diabetes, making weight loss a cornerstone of treatment. We previously ... ...

    Abstract Abstract Background Despite preventive measures, the number of people with type 2 diabetes and obesity is increasing. Obesity increases morbidity and mortality in people with type 2 diabetes, making weight loss a cornerstone of treatment. We previously developed a very low energy diet (VLED) intervention that effectively reduced weight in people with type 2 diabetes in the long term. However, this intervention requires considerable time and manpower, which reduces the number of people who can benefit from it. eHealth offers more efficient solutions but has proven to be less effective than face-to-face interventions. Therefore, we want to investigate whether a blended version of our VLED intervention (in which face-to-face contact is partly replaced by an eHealth (mobile) application (E-VLED)) would be more cost-effective than the current face-to-face intervention. Methods We will conduct a randomised, controlled trial with non-inferiority design in patients with type 2 diabetes and obesity (BMI > 30 kg/m2), aged 18–75 years. The control group will receive the usual care VLED intervention, while the intervention group will receive the E-VLED intervention for 1 year, where face-to-face contact will be partly replaced by an eHealth (mobile) application. The main study endpoint is the difference in weight (% change) between the control and intervention group after 1 year, plus the difference between the total costs (euro) of the treatment in the control and intervention groups. The secondary aims are to investigate the effectiveness of the E-VLED diet intervention regarding cardiovascular risk factors, quality of life, patient satisfaction, compliance, and to study whether there is a difference in effectiveness in pre-specified subgroups. General linear models for repeated measurements will be applied for the statistical analysis of the data. Discussion We hypothesise that the E-VLED intervention will be equally effective compared to the usual care VLED but lower in costs due to less time invested by the ...
    Keywords Type 2 diabetes ; Overweight ; Obesity ; Diet ; Very low energy diet ; eHealth ; Medicine (General) ; R5-920
    Subject code 796
    Language English
    Publishing date 2023-10-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Apolipoprotein-CIII O -Glycosylation, a Link between GALNT2 and Plasma Lipids

    Annemieke Naber / Daniel Demus / Roderick Slieker / Simone Nicolardi / Joline W. J. Beulens / Petra J. M. Elders / Aloysius G. Lieverse / Eric J. G. Sijbrands / Leen M. ’t Hart / Manfred Wuhrer / Mandy van Hoek

    International Journal of Molecular Sciences, Vol 24, Iss 14844, p

    2023  Volume 14844

    Abstract: Apolipoprotein-CIII (apo-CIII) is involved in triglyceride-rich lipoprotein metabolism and linked to beta-cell damage, insulin resistance, and cardiovascular disease. Apo-CIII exists in four main proteoforms: non-glycosylated (apo-CIII 0a ), and ... ...

    Abstract Apolipoprotein-CIII (apo-CIII) is involved in triglyceride-rich lipoprotein metabolism and linked to beta-cell damage, insulin resistance, and cardiovascular disease. Apo-CIII exists in four main proteoforms: non-glycosylated (apo-CIII 0a ), and glycosylated apo-CIII with zero, one, or two sialic acids (apo-CIII 0c , apo-CIII 1 and apo-CIII 2 ). Our objective is to determine how apo-CIII glycosylation affects lipid traits and type 2 diabetes prevalence, and to investigate the genetic basis of these relations with a genome-wide association study (GWAS) on apo-CIII glycosylation. We conducted GWAS on the four apo-CIII proteoforms in the DiaGene study in people with and without type 2 diabetes ( n = 2318). We investigated the relations of the identified genetic loci and apo-CIII glycosylation with lipids and type 2 diabetes. The associations of the genetic variants with lipids were replicated in the Diabetes Care System ( n = 5409). Rs4846913-A, in the GALNT2 -gene, was associated with decreased apo-CIII 0a . This variant was associated with increased high-density lipoprotein cholesterol and decreased triglycerides, while high apo-CIII 0a was associated with raised high-density lipoprotein-cholesterol and triglycerides. Rs67086575-G, located in the IFT172 -gene, was associated with decreased apo-CIII 2 and with hypertriglyceridemia. In line, apo-CIII 2 was associated with low triglycerides. On a genome-wide scale, we confirmed that the GALNT2 -gene plays a major role i O -glycosylation of apolipoprotein-CIII, with subsequent associations with lipid parameters. We newly identified the IFT172 / NRBP1 region, in the literature previously associated with hypertriglyceridemia, as involved in apolipoprotein-CIII sialylation and hypertriglyceridemia. These results link genomics, glycosylation, and lipid metabolism, and represent a key step towards unravelling the importance of O -glycosylation in health and disease.
    Keywords apolipoprotein C-III ; glycomics ; genome-wide association study ; hypertriglyceridemia ; diabetes mellitus type 2 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 571
    Language English
    Publishing date 2023-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Large-Scale Analysis of Apolipoprotein CIII Glycosylation by Ultrahigh Resolution Mass Spectrometry

    Daniel Demus / Annemieke Naber / Viktoria Dotz / Bas C. Jansen / Marco R. Bladergroen / Jan Nouta / Eric J. G. Sijbrands / Mandy Van Hoek / Simone Nicolardi / Manfred Wuhrer

    Frontiers in Chemistry, Vol

    2021  Volume 9

    Abstract: Apolipoprotein-CIII (apo-CIII) is a glycoprotein involved in lipid metabolism and its levels are associated with cardiovascular disease risk. Apo-CIII sialylation is associated with improved plasma triglyceride levels and its glycosylation may have an ... ...

    Abstract Apolipoprotein-CIII (apo-CIII) is a glycoprotein involved in lipid metabolism and its levels are associated with cardiovascular disease risk. Apo-CIII sialylation is associated with improved plasma triglyceride levels and its glycosylation may have an effect on the clearance of triglyceride-rich lipoproteins by directing these particles to different metabolic pathways. Large-scale sample cohort studies are required to fully elucidate the role of apo-CIII glycosylation in lipid metabolism and associated cardiovascular disease. In this study, we revisited a high-throughput workflow for the analysis of intact apo-CIII by ultrahigh-resolution MALDI FT-ICR MS. The workflow includes a chemical oxidation step to reduce methionine oxidation heterogeneity and spectrum complexity. Sinapinic acid matrix was used to minimize the loss of sialic acids upon MALDI. MassyTools software was used to standardize and automate MS data processing and quality control. This method was applied on 771 plasma samples from individuals without diabetes allowing for an evaluation of the expression levels of apo-CIII glycoforms against a panel of lipid biomarkers demonstrating the validity of the method. Our study supports the hypothesis that triglyceride clearance may be regulated, or at least strongly influenced by apo-CIII sialylation. Interestingly, the association of apo-CIII glycoforms with triglyceride levels was found to be largely independent of body mass index. Due to its precision and throughput, the new workflow will allow studying the role of apo-CIII in the regulation of lipid metabolism in various disease settings.
    Keywords high-throughput ; mass spectrometry ; apolipoprotein-CIII ; glycosylation ; oxidation ; Chemistry ; QD1-999
    Subject code 500
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Effects of Diabetes Mellitus on Fibrin Clot Structure and Mechanics in a Model of Acute Neutrophil Extracellular Traps (NETs) Formation

    Judith J. de Vries / Tamara Hoppenbrouwers / Cristina Martinez-Torres / Rezin Majied / Behiye Özcan / Mandy van Hoek / Frank W.G. Leebeek / Dingeman C. Rijken / Gijsje H. Koenderink / Moniek P.M. de Maat

    International Journal of Molecular Sciences, Vol 21, Iss 7107, p

    2020  Volume 7107

    Abstract: Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased formation of neutrophil extracellular traps (NETs) in ... ...

    Abstract Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased formation of neutrophil extracellular traps (NETs) in DM. NETs are mainly formed during the acute phase of disease and form a network within the fibrin matrix, thereby influencing clot properties. Previous research has shown separate effects of NETs and DM on clot properties, therefore our aim was to study how DM affects clot properties in a model resembling an acute phase of disease with NETs formation. Clots were prepared from citrated plasma from subjects with and without DM with the addition of NETs, induced in neutrophils by S. aureus bacteria or phorbol myristate acetate (PMA). Structural parameters were measured using scanning electron microscopy, mechanical properties using rheology, and sensitivity to lysis using a fluorescence-based fibrinolysis assay. Plasma clots from subjects with DM had significantly thicker fibers and fewer pores and branch points than clots from subjects without DM. In addition, fibrinolysis was significantly slower, while mechanical properties were similar between both groups. In conclusion, in a model of acute NETs formation, DM plasma shows prothrombotic effects on fibrin clots.
    Keywords diabetes mellitus ; fibrin ; fibrinolysis ; neutrophil extracellular traps ; arterial thrombosis ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 571
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article: Plasma protein N-glycan signatures of type 2 diabetes

    Dotz, Viktoria / Agnes L. Hipgrave Ederveen / Aloysius G. Lieverse / Eric J.G. Sijbrands / Karli R. Reiding / Mandy van Hoek / Manfred Wuhrer / Monique T. Mulder / Roosmarijn F.H. Lemmers

    Biochimica et biophysica acta. 2018 Dec., v. 1862, no. 12

    2018  

    Abstract: Little is known about enzymatic N-glycosylation in type 2 diabetes, a common posttranslational modification of proteins influencing their function and integrating genetic and environmental influences. We sought to gain insights into N-glycosylation to ... ...

    Abstract Little is known about enzymatic N-glycosylation in type 2 diabetes, a common posttranslational modification of proteins influencing their function and integrating genetic and environmental influences. We sought to gain insights into N-glycosylation to uncover yet unexplored pathophysiological mechanisms in type 2 diabetes.Using a high-throughput MALDI-TOF mass spectrometry method, we measured N-glycans in plasma samples of the DiaGene case-control study (1583 cases and 728 controls). Associations were investigated with logistic regression and adjusted for age, sex, body mass index, high-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol, and smoking. Findings were replicated in a nested replication cohort of 232 cases and 108 controls.Eighteen glycosylation features were significantly associated with type 2 diabetes. Fucosylation and bisection of diantennary glycans were decreased in diabetes (odds ratio (OR) = 0.81, p = 1.26E-03, and OR = 0.87, p = 2.84E-02, respectively), whereas total and, specifically, alpha2,6-linked sialylation were increased (OR = 1.38, p = 9.92E-07, and OR = 1.40, p = 5.48E-07). Alpha2,3-linked sialylation of triantennary glycans was decreased (OR = 0.60, p = 6.38E-11).While some glycosylation changes were reflective of inflammation, such as increased alpha2,6-linked sialylation, our finding of decreased alpha2,3-linked sialylation in type 2 diabetes patients is contradictory to reports on acute and chronic inflammation. Thus, it might have previously unreported immunological implications in type 2 diabetes.This study provides new insights into N-glycosylation patterns in type 2 diabetes, which can fuel studies on causal mechanisms and consequences of this complex disease.
    Keywords blood proteins ; body mass index ; case-control studies ; glycosylation ; inflammation ; matrix-assisted laser desorption-ionization mass spectrometry ; noninsulin-dependent diabetes mellitus ; odds ratio ; patients ; polysaccharides ; regression analysis
    Language English
    Dates of publication 2018-12
    Size p. 2613-2622.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 840755-1
    ISSN 0304-4165
    ISSN 0304-4165
    DOI 10.1016/j.bbagen.2018.08.005
    Database NAL-Catalogue (AGRICOLA)

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  7. Article: IgG glycan patterns are associated with type 2 diabetes in independent European populations

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

    Elsevier B.V. Biochimica et biophysica acta. 2017 Sept., v. 1861, no. 9

    2017  

    Abstract: Type 2 diabetes results from interplay between genetic and acquired factors. Glycans on proteins reflect genetic, metabolic and environmental factors. However, associations of IgG glycans with type 2 diabetes have not been described. We compared IgG N- ... ...

    Abstract Type 2 diabetes results from interplay between genetic and acquired factors. Glycans on proteins reflect genetic, metabolic and environmental factors. However, associations of IgG glycans with type 2 diabetes have not been described. We compared IgG N-glycan patterns in type 2 diabetes with healthy subjects.In the DiaGene study, a population-based case-control study, (1886 cases and 854 controls) 58 IgG glycan traits were analyzed. Findings were replicated in the population-based CROATIA-Korcula-CROATIA-Vis-ORCADES studies (162 cases and 3162 controls), and meta-analyzed. AUCs of ROC-curves were calculated using 10-fold cross-validation for clinical characteristics, IgG glycans and their combination.After correction for extensive clinical covariates, 5 IgG glycans and 13 derived traits significantly associated with type 2 diabetes in meta-analysis (after Bonferroni correction). Adding IgG glycans to age and sex increased the AUC from 0.542 to 0.734. Adding them to the extensive model did not substantially improve the AUC. The AUC for IgG glycans alone was 0.729.Several IgG glycans and traits firmly associate with type 2 diabetes, reflecting a pro-inflammatory and biologically-aged state. IgG glycans showed limited improvement of AUCs. However, IgG glycans showed good prediction alone, indicating they may capture information of combined covariates. The associations found may yield insights in type 2 diabetes pathophysiology.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.
    Keywords biomarkers ; case-control studies ; environmental factors ; glycomics ; immunoglobulin G ; meta-analysis ; models ; noninsulin-dependent diabetes mellitus ; pathophysiology ; polysaccharides ; prediction ; public health
    Language English
    Dates of publication 2017-09
    Size p. 2240-2249.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 840755-1
    ISSN 0304-4165
    ISSN 0304-4165
    DOI 10.1016/j.bbagen.2017.06.020
    Database NAL-Catalogue (AGRICOLA)

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  8. Article ; Online: A genome-wide association search for type 2 diabetes genes in African Americans.

    Nicholette D Palmer / Caitrin W McDonough / Pamela J Hicks / Bong H Roh / Maria R Wing / S Sandy An / Jessica M Hester / Jessica N Cooke / Meredith A Bostrom / Megan E Rudock / Matthew E Talbert / Joshua P Lewis / DIAGRAM Consortium / MAGIC Investigators / Assiamira Ferrara / Lingyi Lu / Julie T Ziegler / Michele M Sale / Jasmin Divers /
    Daniel Shriner / Adebowale Adeyemo / Charles N Rotimi / Maggie C Y Ng / Carl D Langefeld / Barry I Freedman / Donald W Bowden / Benjamin F Voight / Laura J Scott / Valgerdur Steinthorsdottir / Andrew P Morris / Christian Dina / Ryan P Welch / Eleftheria Zeggini / Cornelia Huth / Yurii S Aulchenko / Gudmar Thorleifsson / Laura J McCulloch / Teresa Ferreira / Harald Grallert / Najaf Amin / Guanming Wu / Cristen J Willer / Soumya Raychaudhuri / Steve A McCarroll / Claudia Langenberg / Oliver M Hofmann / Josée Dupuis / Lu Qi / Ayellet V Segrè / Mandy van Hoek

    PLoS ONE, Vol 7, Iss 1, p e

    2012  Volume 29202

    Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African ... ...

    Abstract African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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