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Genome-wide association study on immunoglobulin G glycosylation patterns.

Front. Immunol. 9:277 (2018)
Publishers Version Research data DOI PMC
Open Access Gold
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Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with a wide range of diseases. Glycosylation of the Fc binding region of IgGs, responsible for the antibody's effector function, is essential for prompting a proper immune response. This study focuses on the general genetic impact on IgG glycosylation as well as corresponding subclass specificities. To identify genetic loci involved in IgG glycosylation, we performed a genome-wide association study (GWAS) on liquid chromatography electrospray mass spectrometry (LC-ESI-MS)-measured IgG glycopeptides of 1,823 individuals in the Cooperative Health Research in the Augsburg Region (KORA F4) study cohort. In addition, we performed GWAS on subclass-specific ratios of IgG glycans to gain power in identifying genetic factors underlying single enzymatic steps in the glycosylation pathways. We replicated our findings in 1,836 individuals from the Leiden Longevity Study (LLS). We were able to show subclass-specific genetic influences on single IgG glycan structures. The replicated results indicate that, in addition to genes encoding for glycosyltransferases (i.e.,, and), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboring, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of thefamily are cross-regulated, andis involved in both IgA class switching and B-cell maturation as well as T-cell differentiation and apoptosis. Besides the involvement of glycosyltransferases in IgG glycosylation, we suggest that, due to the impact of variants within, potentially mechanisms involved in B-cell activation and T-cell differentiation during the immune response as well as cell migration and invasion involve IgG glycosylation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Lc–esi-ms ; Runx3 ; Genome-wide Association Study ; Glycosylation ; Immunoglobulin G; Therapeutic Monoclonal-antibodies; Igg Subclasses; T-cells; Leiden Longevity; N-glycosylation; Cancer; Runx3; Metaanalysis; Expression; Immunity
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