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Influence of genetic and environmental factors on N-glycosylation of immunoglobulin G and total plasma proteins determined by twin study

Glycans constitute the most abundant and diverse form of the post-translational modifications. While genes unequivocally determine the structure of each polypeptide, there is no genetic template for the glycan part. Instead, hundreds of genes and their products interact in the very complex pathway of glycan biosynthesis which is further complicated by environmental influences. Therefore, the aim of this thesis was to determine the extent to which individual differences in immunoglobulin G and total plasma proteins glycosylation patterns reflect genetic versus environmental influences. A twin study design was used and study subjects were twins enrolled in the TwinsUK registry, a national register of adult twins. More than 4500 samples were analyzed by HILIC-UPLC (Hydrophilic Interaction Ultra Performance Liquid Chromatography). A high contribution of the genetic component to N-glycome composition was found. Variation in levels of 51 of the 76 IgG glycan traits studied was at least 50% heritable and only a small proportion of N- glycan traits had a low genetic contribution. Heritability of plasma N-glycome was also high, with half of the plasma glycan traits being at least 50% heritable. Further, epigenome-wide association (EWA) analysis showed that methylation levels at some genes are also implicated in glycome composition, both in those with high heritability and those with a lower genetic contribution. The study to investigate the potential role of glycosylation in kidney function was also conducted. Fourteen IgG glycan traits were associated with renal function in discovery population and remained significant after validation in an independent subset of monozygotic twins discordant for renal disease, reflecting difference in galactosylation, sialylation, and level of bisecting N-acetylglucosamine. Using the weighted correlation network analysis (WGCNA) for IgG glycan traits, a correlation between low back pain (LBP) and glycan modules was established. There was a weak positive correlation between pain phenotypes and "pro- antibody-dependent cell-mediated cytotoxicity (ADCC)" WGCNA glycan modules (high bisecting N- acetylglucosamine and low core fucose) and a weak negative correlation between pain phenotypes and "anti-ADCC" module (high core fucose, no bisecting N-acetylglucosamine). This suggests that glycans are promising candidates for biomarkers in many different diseases.

IgG glycome; total plasma glycome; N-glycosylation; glycan analysis; HILIC; twin study; heritability; chronic kidney disease; low back pain

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