Laboratory of Glycogenomics, Institute of Cytology and Genetics, Novosibirsk 630090, Russia.
Genos Glycoscience Research Laboratory, Zagreb 10000, Croatia.
Hum Mol Genet. 2021 Jun 17;30(13):1259-1270. doi: 10.1093/hmg/ddab072.
The N-glycosylation of immunoglobulin G (IgG) affects its structure and function. It has been demonstrated that IgG N-glycosylation patterns are inherited as complex quantitative traits. Genome-wide association studies identified loci harboring genes encoding enzymes directly involved in protein glycosylation as well as loci likely to be involved in regulation of glycosylation biochemical pathways. Many of these loci could be linked to immune functions and risk of inflammatory and autoimmune diseases. The aim of the present study was to discover and replicate new loci associated with IgG N-glycosylation and to investigate possible pleiotropic effects of these loci onto immune function and the risk of inflammatory and autoimmune diseases. We conducted a multivariate genome-wide association analysis of 23 IgG N-glycosylation traits measured in 8090 individuals of European ancestry. The discovery stage was followed up by replication in 3147 people and in silico functional analysis. Our study increased the total number of replicated loci from 22 to 29. For the discovered loci, we suggest a number of genes potentially involved in the control of IgG N-glycosylation. Among the new loci, two (near RNF168 and TNFRSF13B) were previously implicated in rare immune deficiencies and were associated with levels of circulating immunoglobulins. For one new locus (near AP5B1/OVOL1), we demonstrated a potential pleiotropic effect on the risk of asthma. Our findings underline an important link between IgG N-glycosylation and immune function and provide new clues to understanding their interplay.
免疫球蛋白 G（IgG）的 N-糖基化影响其结构和功能。已经证明，IgG N-糖基化模式是作为复杂的数量性状遗传的。全基因组关联研究鉴定了编码直接参与蛋白质糖基化的酶的基因以及可能参与糖基化生化途径调节的基因座。这些基因座中的许多都可能与免疫功能以及炎症性和自身免疫性疾病的风险有关。本研究的目的是发现与 IgG N-糖基化相关的新基因座并进行复制，并研究这些基因座对免疫功能和炎症性及自身免疫性疾病风险的可能多效性影响。我们对 8090 名欧洲血统个体的 23 种 IgG N-糖基化特征进行了多变量全基因组关联分析。在发现阶段之后，我们在 3147 人和计算机功能分析中进行了复制。我们的研究将已复制的基因座总数从 22 个增加到 29 个。对于发现的基因座，我们建议了一些可能参与控制 IgG N-糖基化的基因。在新发现的基因座中，有两个（靠近 RNF168 和 TNFRSF13B）先前与罕见的免疫缺陷有关，并且与循环免疫球蛋白的水平有关。对于一个新的基因座（靠近 AP5B1/OVOL1），我们证明了其对哮喘风险的潜在多效性影响。我们的研究结果强调了 IgG N-糖基化与免疫功能之间的重要联系，并为了解它们的相互作用提供了新的线索。
