Dataset Information

Glycosylation of immunoglobulin g: role of genetic and epigenetic influences.

ABSTRACT:

Objective

To determine the extent to which genetic and epigenetic factors contribute to variations in glycosylation of immunoglobulin G (IgG) in humans.

Methods

76 N-glycan traits in circulating IgG were analyzed by UPLC in 220 monozygotic and 310 dizygotic twin pairs from TwinsUK. A classical twin study design was used to derive the additive genetic, common and unique environmental components defining the variance in these traits. Epigenome-wide association analysis was performed using the Illumina 27k chip.

Results

51 of the 76 glycan traits studied have an additive genetic component (heritability, h (2) ) ? 0.5. In contrast, 12 glycan traits had a low genetic contribution (h(2)<0.35). We then tested for association between methylation levels and glycan levels (P<2 x10(-6)). Among glycan traits with low heritability probe cg08392591 maps to a CpG island 5' from the ANKRD11 gene, a p53 activator on chromosome 16. Probe cg26991199 maps to the SRSF10 gene involved in regulation of RNA splicing and particularly in regulation of splicing of mRNA precursors upon heat shock. Among those with high heritability we found cg13782134 (mapping to the NRN1L gene) and cg16029957 mapping near the QPCT gene to be array-wide significant. The proportion of array-wide epigenetic associations was significantly larger (P<0.005) among glycans with low heritability (42%) than in those with high heritability (6.2%).

Conclusions

Glycome analyses might provide a useful integration of genetic and non-genetic factors to further our understanding of the role of glycosylation in both normal physiology and disease.

SUBMITTER: Menni C

PROVIDER: S-EPMC3855797 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Glycosylation of immunoglobulin g: role of genetic and epigenetic influences.

Menni Cristina C Keser Toma T Mangino Massimo M Bell Jordana T JT Erte Idil I Akmačić Irena I Vučković Frano F Pučić Baković Maja M Gornik Olga O McCarthy Mark I MI Zoldoš Vlatka V Spector Tim D TD Lauc Gordan G Valdes Ana M AM

PloS one 20131206 12

<h4>Objective</h4>To determine the extent to which genetic and epigenetic factors contribute to variations in glycosylation of immunoglobulin G (IgG) in humans.<h4>Methods</h4>76 N-glycan traits in circulating IgG were analyzed by UPLC in 220 monozygotic and 310 dizygotic twin pairs from TwinsUK. A classical twin study design was used to derive the additive genetic, common and unique environmental components defining the variance in these traits. Epigenome-wide association analysis was performed ...[more]

PMID: 24324808

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Project description: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., ST6GAL1, B4GALT1, FUT8, and MGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboring RUNX3, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of the RUNX family are cross-regulated, and RUNX3 is 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 RUNX3, 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.

Dataset Information

Glycosylation of immunoglobulin g: role of genetic and epigenetic influences.

Objective

Methods

Results

Conclusions

Publications

Glycosylation of immunoglobulin g: role of genetic and epigenetic influences.

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