Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Klarić, Lucija; Tsepilov, Yakov A.; Stanton, Chloe; Mangino, Massimo; Sikka, Timo Tõnis; Esko, Tõnu; Pakhomov, Eugene; Salo, Perttu; Deelen, Joris; McGurnaghan, Stuart J.; Keser, Toma; Vučković, Frano; Ugrina, Ivo; Krištić, Jasminka; Gudelj, Ivan; Štambuk, Tamara; Plomp, Rosina; Pučić‐Baković, Maja; Pavić, Tamara; Vilaj, Marija; Trbojević‐Akmačić, Irena; Drake, Camilla; Dobrinić, Paula; Mlinarec, Jelena; Jelušić, Barbara; Richmond, Anne; Timofeeva, Maria; Grishchenko, Alexander K.; Dmitrieva, Julia; Bermingham, Mairead Lesley; Sharapov, Sodbo; Farrington, Susan M.; Τheodoratou, Evropi; Uh, Hae‐Won; Beekman, Marian; Slagboom, Eline; Louis, Édouard; Georges, Michel; Wuhrer, Manfred; Colhoun, Helen M.; Dunlop, Malcolm G.; Perola, Markus; Fischer, Krista; Polašek, Ozren; Campbell, Harry; Rudan, Igor; Wilson, James F.; Zoldoš, Vlatka; Vitart, Véronique; Spector, Tim D.; Aulchenko, Yurii S.; Lauc, Gordan; Hayward, Caroline

doi:10.1126/sciadv.aax0301

Cited by 101 publications

(127 citation statements)

References 85 publications

(70 reference statements)

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“…In the gure on the left, the more papers published in the journal, the longer the vertical axis of the ellipse; the more the number of authors, the longer the horizontal axis of the ellipse. 60, England (53), Australia (28), Japan (27), Ireland (24), and Scotland (22). Centrality describes the importance of nodes.…”

Section: Resultsmentioning

confidence: 99%

“…A total of 2,408 authors were involved in the writing of Igg glycosylation studies, with the most proli c contributors being Wuhrer, Manfred, (74 articles) , or Nmax 74, m27.7 can be calculated from Price's law, which indicates that the authors of more than 28 papers are the core authors in the eld of IGG glycosylation, That's Wuhrer, Manfred, and LAUC, Gordan. According to the latest research from Wuhrer, Manfred of Leiden University in the Netherlands, variation in key transcription factors coupled with regulatory variation in glycogenes modi es IgG glycosylation and has in uence on in ammatory diseases [24] . Croatia, LAUC, Gordan's group at the University of Zagreb, Selected N-glycans improve type 2 diabetes and CVD prediction established beyond risk marker.…”

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confidence: 99%

See 1 more Smart Citation

Knowledge Domain and Emerging Trends of IgG Glycosylation: A Bibliometric Study Based on CiteSpace

Lv¹,

Chen²,

Li³

et al. 2020

Preprint

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Background: The purpose of this paper is to evaluate the international scientific output of Igg glycosylation research by a stoichiometric analysis of the related papers published in the field of IGG glycosylation from 2009 to 2020, to explore the hot spot of IGG glycosylation and the evolution path of IGG glycosylation.Methods: Using the Web of Science core database (WoSCC) to collect the articles related to IgG glycosylation from 2009 to 2020 as the research object, using CiteSpace visualization software to analyze the co-occurrence of countries and institutions, core authors, and keywords. Cited authors and literature, Co-citation analysis of journals, obtaining cooperation maps of research countries / institutions and core authors, literature citation and clustering maps, co-occurrence maps of high-frequency subject headings, displaying related clusters, mutual influences between clusters and Keyword timeline view spectrum of the historical span of important keywords in clustering.Results: We searched 482 articles related to IgG glycosylation published in 227 journals, and observed that in the past 10 years, the number of articles published has generally increased year by year; it has been cited 13262 times, with an average of 27.5 citations per article, showing an upward trend year by year. The core team in the field of IGG glycosylation is mainly from University and research institutes in USA, Australia, Netherlands, Croatia, England, Germany, Ireland, Scotland, China and Japan. A total of 2408 authors participated in the writing of literature on Igg glycosylation, Among them, Wuhrer, Manfred、Lauc, Gordan、Irena Trbojevic Akmacic, Wei Wang and other scholars are the representatives of this research field and have important influence. There are 281 keywords under the theme of IgG glycosylation, of which there are 4 keywords with word frequency ≥100, and hot keywords that serve as bridges are pregnancy、complex、glycan、biosimilar、N-linked glycosylation、hilic-uplc、glycation and form 8 clusters. IgG glycosylation, as the "biomarker" of disease diagnosis and its mechanism has been a research hotspot in recent years.Conclusion: The use of CiteSpace software for quantitative analysis of IgG glycosylation related literature can intuitively demonstrate its development history and current research hotspots and trends, and can provide researchers with reference to the topic selection and research direction. Value and meaning.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Knowledge Domain and Emerging Trends of IgG Glycosylation: A Bibliometric Study Based on CiteSpace

Lv¹,

Chen²,

Li³

et al. 2020

Preprint

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“…To define genetic variants (i.e., single nucleotide polymorphisms (SNP), short insertions and deletions (indels)) associated with glycosylation profiles regardless of specific phenotypes in the TwinsUK cohort, we ran analyses with the GenABEL software package [44] designed for genome-wide association study (GWAS) analysis of family-based data by incorporating pairwise kinship matrix calculated using genotyping data in the polygenic model to correct relatedness and hidden population stratification. Data were recently published with other datasets [26,45]. We selected genetic variants for each IgG N-glycan traits with a p-value under the GWAS threshold (p-value < 5 × 10 −8 ) and added the list of previously-defined genetic variants [29,45] (Appendix A).…”

Section: Genome-wide Association Analysis On Igg N-glycan Traitsmentioning

confidence: 99%

“…In peripheral blood, we identified both depleted core fucosylation of IgG antibodies and decreased antennary α1,2 fucosylation of PBMC to be associated with autoantibodies to thyroid peroxidase (TPOAb) and AITD status [4]. We also identified a network of genes, including FUT8 and IKZF1 that regulate fucosylation, to be implicated in the development of AITD [4,26]. Based on these findings, we speculated that IgG core fucose deficiencies together with elevated levels of autoantibodies may participate in autoimmune responses in AITD by enhancing effector cell activation and heightened immune and inflammatory signals.…”

Section: Introductionmentioning

confidence: 96%

Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases

Martin

Ilieva

Visconti

et al. 2020

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The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335- CD314+ CD158b+ NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1α positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD.

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“…This direction of inquiry can be extended to other ''omic'' data types to gain further insights into the mechanistic pathway between genetic variant and causally associated trait [22,23]. A recent study showed that variants involved in the regulation of glycoenzymes play an important role in IgG N-glycosylation [24], thus we hypothesized that identifying IgG N-glycosylation quantitative trait loci (IgG N-glycan-QTLs) variants and linking them to diseaseassociated genetic variants from GWAS might pinpoint molecular mechanisms underlying genetic susceptibility to human diseases that are due, at least in part, to altered IgG N-glycosylation.…”

mentioning

confidence: 99%

Leveraging IgG N-glycosylation quantitative-trait loci to characterize the relationship between Type 2 Diabetes and hypertension: A network with bidirectional mendelian randomization study

Liu¹,

Zhang²,

Zhang³

et al. 2020

Preprint

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Abstract Background: The relationship between IgG N-glycosylation, type 2 diabetes (T2D) and hypertension is not well understood.Methods: A genome-wide association study (GWAS) of IgG N-glycosylation traits from 536 individuals was performed and 1203 IgG N-glycan quantitative trait loci (IgG N-glycan-QTL) variants targeting 24 IgG N-glycosylation were mapped traits after multi-testing correction. Network with bidirectional mendelian randomization (MR) analysis was performed to examine the causal association between IgG N-glycosylation, T2D and hypertension.Results: By linking IgG N-glycan-QTL variants with GWAS results for T2D and hypertension, 19 putatively causal IgG N-glycans for T2D and 21 putatively causal IgG N-glycans for hypertension were identified. IgG N-glycan-QTL determined IgG N-glycosylation to higher T2D was associated with higher hypertension risk (β [95% CI] =1.234 [0.939-1.529], P <0.001). In addition, IgG N-glycan-QTL determined IgG N-glycosylation to higher hypertension was associated with higher T2D risk (β [95% CI] =0.753 [0.140-1.3669], P =0.016). No evidence of pleiotropic bias was detected in MR-Egger analysis.Conclusions: Overall, our study showed that IgG N-Glycosylation-QTLs determined T2D is associated with higher hypertension risk, and vice versa, performing bidirectional regulation through IgG N-Glycosylation.

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Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Cited by 101 publications

References 85 publications

Knowledge Domain and Emerging Trends of IgG Glycosylation: A Bibliometric Study Based on CiteSpace

Knowledge Domain and Emerging Trends of IgG Glycosylation: A Bibliometric Study Based on CiteSpace

Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases

Leveraging IgG N-glycosylation quantitative-trait loci to characterize the relationship between Type 2 Diabetes and hypertension: A network with bidirectional mendelian randomization study

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