Genetic Regulation of Immunoglobulin G Glycosylation.
Genetic Regulation of Immunoglobulin G Glycosylation.
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DOI：
10.1007/978-3-030-76912-3_8
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发表时间：
2021-01-01
影响因子：
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通讯作者：
Klaric, Lucija
中科院分区：
文献类型：
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作者：
Frkatovic, Azra;Zaytseva, Olga O;Klaric, Lucija
确定控制人类免疫球蛋白G(Ig G)糖基化的遗传成分是一项持续的努力，迄今已通过遗传性、连锁和全基因组关联研究(Gwas)来解决。与蛋白质的合成不同，N-糖基化生物合成不是一个模板驱动的过程，而是一个受遗传和环境因素共同调控的复杂过程。目前的遗传力研究表明，虽然高达75%的某些Ig G葡聚糖性状水平的变化可以用遗传来解释，但有些葡聚糖性状完全由环境影响决定。高通量基因分型和葡聚糖定量方法的进步使全基因组关联研究成为可能，这些研究越来越多地被用于估计数百万个单核苷酸多态和糖基化特性的关联。利用这种方法，到目前为止，已有18个基因组区域与Ig G糖基化相关，发现与编码糖基转移酶的基因有关，但也与转录因子、辅因子、膜转运蛋白等基因有关，而在Ig G糖基化中没有明显的作用。进一步的计算分析表明，免疫球蛋白的糖基化可能是通过糖基转移酶的表达来调节的，但也首次暗示了哪些转录因子参与了这一过程。此外，研究还表明，免疫球蛋白糖基化和炎症性疾病具有共同的致病基因变异，这表明研究免疫球蛋白糖基化的遗传调控不仅有助于更好地理解这一复杂的过程，而且有助于理解疾病中多糖发生变化的原因。然而，还需要进一步的研究来揭示是免疫球蛋白糖基化的变化导致了这些疾病，还是糖基的变化是由疾病引起的。
Defining the genetic components that control glycosylation of the human immunoglobulin G (IgG) is an ongoing effort, which has so far been addressed by means of heritability, linkage and genome-wide association studies (GWAS). Unlike the synthesis of proteins, N-glycosylation biosynthesis is not a template-driven process, but rather a complex process regulated by both genetic and environmental factors. Current heritability studies have shown that while up to 75% of the variation in levels of some IgG glycan traits can be explained by genetics, some glycan traits are completely defined by environmental influences. Advances in both high-throughput genotyping and glycan quantification methods have enabled genome-wide association studies that are increasingly used to estimate associations of millions of single-nucleotide polymorphisms and glycosylation traits. Using this method, 18 genomic regions have so far been robustly associated with IgG N-glycosylation, discovering associations with genes encoding glycosyltransferases, but also transcription factors, co-factors, membrane transporters and other genes with no apparent role in IgG glycosylation. Further computational analyses have shown that IgG glycosylation is likely to be regulated through the expression of glycosyltransferases, but have also for the first time suggested which transcription factors are involved in the process. Moreover, it was also shown that IgG glycosylation and inflammatory diseases share common underlying causal genetic variants, suggesting that studying genetic regulation of IgG glycosylation helps not only to better understand this complex process but can also contribute to understanding why glycans are changed in disease. However, further studies are needed to unravel whether changes in IgG glycosylation are causing these diseases or the changes in the glycome are caused by the disease.