Abstract
ObjectiveTo determine the extent to which genetic and epigenetic factors contribute to variations in glycosylation of immunoglobulin G (IgG) in humans.Methods76 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. Results51 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 (h2<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%).ConclusionsGlycome 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.
Highlights
Glycans constitute the most abundant and diverse form of the post-translational modifications
Among glycan traits with a low heritability we identified 2 CpG-sites at which DNA methylation levels were associated with levels of 4 immunoglobulin G (IgG) glycan traits with P
We tested if the glycan traits measured could have some clinical relevance and we found that 4 of the 76 glycan traits are significantly associated with circulating levels of triglycerides, a well known risk factor of cardiovascular risk [17] and 3 are associated with circulating levels of C-reactive protein (CRP), a well known marker of systemic inflammation [18] (Table S2)
Summary
Glycans constitute the most abundant and diverse form of the post-translational modifications. Glycans can influence disease development in many syndromes such as congenital disorders of Phenotype MZ DZ P N age, yrs 58.71(9.37) 57.83(9.61) BMI, kg/m2 26.65(4.85) 26.50(4.68). Glycans are key in the recognition of non-self events and an altered glycome can lead to autoimmune disorders [3]. The biological functions of glycans go from basic structural roles to development, protein folding and immune response. Glycosylation is known to be affected by factors such as sugar nucleotide concentration, type of glyco-enzymes and their expression levels [1]
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