N 型和 O 型免疫球蛋白 A 糖症的遗传学和流行病学。

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Alessia Visconti, Niccolò Rossi, Albert Bondt, Agnes Hipgrave Ederveen, Gaurav Thareja, Carolien A M Koeleman, Nisha Stephan, Anna Halama, Hannah J Lomax-Browne, Matthew C Pickering, Xu-Jie Zhou, Manfred Wuhrer, Karsten Suhre, Mario Falchi
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引用次数: 0

摘要

背景:免疫球蛋白(Ig)糖基化调节免疫反应,在衰老和疾病中起着关键作用。研究主要集中于 IgG 糖基化,而对 IgA 糖基化的遗传学和流行病学知之甚少:方法:我们使用一种新型液相色谱-质谱联用方法,在 2423 对双胞胎的血清中生成了首个大规模 IgA 糖基化数据集,其中包括 71 种 N-和 O-聚糖:结果:我们发现,尽管缺乏直接的遗传模板,但糖基化具有高度遗传性,糖肽结构具有性别特异性,并随着年龄的增长而发生巨大变化。我们观察到 IgA 和 IgG 糖基化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。一项全基因组关联研究发现了八个与 IgA 和 IgG 糖化相关的基因位点(ST6GAL1、ELL2、B4GALT1、ABCF2、TMEM121、SLC38A10、SMARCB1 和 MGAT3)以及两个专门调节 IgA O 型糖基化的新基因位点(C1GALT1 和 ST3GAL1)。我们的研究结果在一个由 320 名卡塔尔人组成的独立队列中得到了验证,结果表明不同祖先的基本遗传结构是一致的:我们的研究描述了 IgA 糖基化的遗传结构,并提供了与复杂免疫疾病病因学的潜在功能联系,包括与 IgA 肾病风险有关的遗传因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The genetics and epidemiology of N- and O-immunoglobulin A glycomics.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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