TY - JOUR

T1 - Mapping of the gene network that regulates glycan clock of ageing

AU - Frkatović-Hodžić, Azra

AU - Mijakovac, Anika

AU - Miškec, Karlo

AU - Nostaeva, Arina

AU - Sharapov, Sodbo Z

AU - Landini, Arianna

AU - Haller, Toomas

AU - Akker, Erik van den

AU - Sharma, Sapna

AU - Cuadrat, Rafael R C

AU - Mangino, Massimo

AU - Li, Yong

AU - Keser, Toma

AU - Rudman, Najda

AU - Štambuk, Tamara

AU - Pučić-Baković, Maja

AU - Trbojević-Akmačić, Irena

AU - Gudelj, Ivan

AU - Štambuk, Jerko

AU - Pribić, Tea

AU - Radovani, Barbara

AU - Tominac, Petra

AU - Fischer, Krista

AU - Beekman, Marian

AU - Wuhrer, Manfred

AU - Gieger, Christian

AU - Schulze, Matthias B

AU - Wittenbecher, Clemens

AU - Polasek, Ozren

AU - Hayward, Caroline

AU - Wilson, James F

AU - Spector, Tim D

AU - Köttgen, Anna

AU - Vučković, Frano

AU - Aulchenko, Yurii S

AU - Vojta, Aleksandar

AU - Krištić, Jasminka

AU - Klarić, Lucija

AU - Zoldoš, Vlatka

AU - Lauc, Gordan

N1 - This work was supported by European Structural and Investment Funds grant for the Croatian National Centre of Competence in Molecular Diagnostics grant KK.01.2.2.03.0006, Croatian National Centre of Research Excellence in Personalized Healthcare grant KK.01.1.1.01.0010, IRI “CardioMetabolic” grant KK.01.2.1.02.0321. The work was co-funded by the European Union (ERC, GlycanSwitch, 101071386). AFH was supported by H2020-MSCA-ITN IMforFUTURE grant 721815. The work of AN was supported by the Ministry of Education and Science of the Russian Federation via the state assignment of the Novosibirsk State University (project “Graduates 2020”). The work of SZS and YSA was partially supported by the Research Program at the MSU Institute for Artificial Intelligence. The work of LK was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). The work of YL was supported by the German Research Foundation (grant KO_3598/4-2 to AK). The work of AK was supported by the German Research Foundation (grant KO_3598/5-1). RRCC, CW and MBS were supported by German Ministry of Education and Research (BMBF) and the State of Brandenburg DZD grants 82DZD00302 and 82DZD03D03. CW was also supported by SciLifeLab and Wallenberg Data Driven Life Science Program grant KAW 2020.0239. TwinsUK study was funded by Wellcome Trust grant 212904/Z/18/Z, Medical Research Council AIMHY grant MR/M016560/1, European Union H2020 grant 733100. TwinsUK and MM were also supported National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.

PY - 2023/12/26

Y1 - 2023/12/26

N2 - 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.

AB - 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.

KW - Genome-Wide Association Study

KW - Galactose

KW - Gene Regulatory Networks

KW - Immunoglobulin G/genetics

KW - Polysaccharides/metabolism

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85181763900&origin=inward&txGid=f15c9ab6748de71bd7b2dc3882b9d887

UR - https://www.mendeley.com/catalogue/45d9ee72-88b7-319e-8e14-583ac135795d/

U2 - 10.18632/aging.205106

DO - 10.18632/aging.205106

M3 - Article

C2 - 38149987

VL - 15

SP - 14509

EP - 14552

JO - Aging

JF - Aging

SN - 1945-4589

IS - 24

ER -