Glycosylation of Immunoglobulin G: Role of Genetic and Epigenetic Influences

<div><p>Objective</p><p>To determine the extent to which genetic and epigenetic factors contribute to variations in glycosylation of immunoglobulin G (IgG) in humans.</p> <p>Methods</p><p>76  <i>N</i>-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. </p> <p>Results</p><p>51 of the 76 glycan traits studied have an additive genetic component (heritability, <i>h</i><sup><i>2</i></sup>)≥  0.5. In contrast, 12 glycan traits had a low genetic contribution (h<sup>2</sup><0.35). We then tested for association between methylation levels and glycan levels (<i>P</i><2 x10<sup>-6</sup>). Among glycan traits with low heritability probe cg08392591 maps to a CpG island 5’ from the <i>ANKRD11</i> gene, a p53 activator on chromosome 16. Probe cg26991199 maps to the <i>SRSF10</i> 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 <i>NRN1L</i> gene) and cg16029957 mapping near the <i>QPCT</i> gene to be array-wide significant. The proportion of array-wide epigenetic associations was significantly larger (<i>P</i><0.005) among glycans with low heritability (42%) than in those with high heritability (6.2%).</p> <p>Conclusions</p><p>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.</p> </div>