The genetics and epidemiology of N- and O-immunoglobulin A glycomics.
Glycosylation
IgA/IgG shared genetics
Immunoglobulin A
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
09 Aug 2024
09 Aug 2024
Historique:
received:
13
01
2024
accepted:
26
07
2024
medline:
10
8
2024
pubmed:
10
8
2024
entrez:
9
8
2024
Statut:
epublish
Résumé
Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation. We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species. We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries. Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.
Sections du résumé
BACKGROUND
BACKGROUND
Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation.
METHODS
METHODS
We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species.
RESULTS
RESULTS
We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries.
CONCLUSIONS
CONCLUSIONS
Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.
Identifiants
pubmed: 39123268
doi: 10.1186/s13073-024-01369-6
pii: 10.1186/s13073-024-01369-6
doi:
Substances chimiques
Immunoglobulin A
0
Polysaccharides
0
Immunoglobulin G
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
96Subventions
Organisme : Medical Research Council
ID : MR/K01353X/1-2
Pays : United Kingdom
Informations de copyright
© 2024. The Author(s).
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