Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Center for Biostatistics, Epidemiology and Public Health, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Genome Med. 2024 Aug 9;16(1):96. doi: 10.1186/s13073-024-01369-6.
Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation.
We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species.
We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries.
Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.
免疫球蛋白（Ig）的糖基化调节免疫反应，在衰老和疾病中起着关键作用。研究主要集中在 IgG 的糖基化上，而 IgA 糖基化的遗传学和流行病学知之甚少。
我们使用一种新的液相色谱-质谱法，在 2423 对双胞胎的血清中生成了第一个大规模的 IgA 糖组学数据集，其中包括 71 种 N-和 O-聚糖。
我们表明，尽管缺乏直接的遗传模板，糖基化具有高度的遗传性，糖肽结构具有性别特异性，并随着年龄的增长发生显著变化。我们观察到 IgA 和 IgG 糖组之间存在广泛的相关性，并利用双胞胎设计表明，它们主要受共同遗传因素的影响。全基因组关联研究确定了与 IgA 和 IgG 糖组都相关的八个位点（ST6GAL1、ELL2、B4GALT1、ABCF2、TMEM121、SLC38A10、SMARCB1 和 MGAT3）以及两个专门调节 IgA O-糖基化的新位点（C1GALT1 和 ST3GAL1）。在来自卡塔尔的 320 名个体的独立队列中验证我们的发现表明，遗传结构在不同的祖源中是保守的。
我们的研究描绘了 IgA 糖基化的遗传景观，并提供了与复杂免疫疾病发病机制的新的潜在功能联系，包括涉及 IgA 肾病风险的遗传因素。
