Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers.
Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers.
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与人免疫球蛋白G的N-糖基化相关的基因座与自身免疫性疾病和血液学癌症显示出多效性。
DOI：
10.1371/journal.pgen.1003225
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Rudan I
中科院分区：
文献类型：
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作者：
Lauc G;Huffman JE;Pučić M;Zgaga L;Adamczyk B;Mužinić A;Novokmet M;Polašek O;Gornik O;Krištić J;Keser T;Vitart V;Scheijen B;Uh HW;Molokhia M;Patrick AL;McKeigue P;Kolčić I;Lukić IK;Swann O;van Leeuwen FN;Ruhaak LR;Houwing-Duistermaat JJ;Slagboom PE;Beekman M;de Craen AJ;Deelder AM;Zeng Q;Wang W;Hastie ND;Gyllensten U;Wilson JF;Wuhrer M;Wright AF;Rudd PM;Hayward C;Aulchenko Y;Campbell H;Rudan I
免疫球蛋白G（IgG）的糖基化通过调节与Fc受体的结合来影响IgG效应子功能。为了鉴定与IgG糖基化相关的遗传基因座，我们使用两种方法定量N-连接的IgG聚糖。从人血浆中分离出IgG后，我们使用超高效液相色谱法（UPLC）对来自四个欧洲发现人群的2，247名个体进行了77次N-糖基化定量测量。同时，我们使用MALDI-TOF质谱法（MS）在1，848名欧洲人的重复队列中测量IgG N-聚糖。全基因组关联研究（GWAS）结果的荟萃分析在发现分析中确定了9个全基因组显著位点（P<2.27×10−9），在复制队列中确定了两个相同的位点（B4 GALT 1和MGAT 3）。4个基因座含有编码糖基转移酶的基因（ST 6 GAL 1、B4 GALT 1、FUT 8和MGAT 3），而其余5个基因座含有先前未涉及蛋白质糖基化的基因（IKZF 1、IL 6ST-ANKRD 55、ABCF 2-SMARD 3、SUV 420 H1和SMARCB 1-DERL 3）。然而，它们中的大多数与自身免疫性和炎症性疾病密切相关（例如，全身性红斑狼疮、类风湿性关节炎、溃疡性结肠炎、克罗恩病、1型糖尿病、多发性硬化症、格雷夫斯病、乳糜泻、结节性硬化症）和/或血液学癌症（急性成淋巴细胞性白血病、霍奇金淋巴瘤和多发性骨髓瘤）。在单倍缺陷型Ikzf 1基因敲除小鼠中进行的后续功能实验显示了与荟萃分析中鉴定的IgG糖基化变化相同的一般模式。由于IKZF 1与多种IgG N-聚糖性状相关，我们在101例SLE患者和183例匹配对照中探索了受影响N-聚糖的生物标志物潜力，并在ROC曲线分析中证明了显著的区分能力（曲线下面积= 0.842）。 我们的研究表明，它是可能的，以确定新的基因座，控制糖基化的一个单一的血浆蛋白使用GWAS。这些结果也可能为报道的自身免疫性疾病和血液肿瘤相关基因座的多效性和拮抗作用提供解释。在分析了4，095个个体中与人免疫球蛋白G连接的聚糖后，我们对单个蛋白质的糖组进行了第一次全基因组关联研究（GWAS）。发现9个遗传位点与具有全基因组意义的聚糖相关。其中，4种酶直接参与IgG糖基化，因此观察到的相关性是生物学上建立的。其余5个基因座先前未涉及蛋白质糖基化，但已报道它们中的大多数与自身免疫性和炎性病症和/或血液学癌症相关。一个特别有趣的基因，IKZF 1被发现与多种IgG N-聚糖相关。该基因与许多疾病有关，包括系统性红斑狼疮（SLE）。我们分析了101例SLE患者和183例匹配对照的N-聚糖，并证明了它们的生物标志物潜力。我们的研究表明，它是可能的，以确定新的基因座，控制糖基化的一个单一的血浆蛋白使用GWAS。我们的研究结果也可能为某些基因在自身免疫性疾病和血液肿瘤中的相反作用提供解释。
Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27×10−9) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, diabetes type 1, multiple sclerosis, Graves' disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve = 0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer. After analysing glycans attached to human immunoglobulin G in 4,095 individuals, we performed the first genome-wide association study (GWAS) of the glycome of an individual protein. Nine genetic loci were found to associate with glycans with genome-wide significance. Of these, four were enzymes that directly participate in IgG glycosylation, thus the observed associations were biologically founded. The remaining five genetic loci were not previously implicated in protein glycosylation, but the most of them have been reported to be relevant for autoimmune and inflammatory conditions and/or haematological cancers. A particularly interesting gene, IKZF1 was found to be associated with multiple IgG N-glycans. This gene has been implicated in numerous diseases, including systemic lupus erythematosus (SLE). We analysed N-glycans in 101 cases with SLE and 183 matched controls and demonstrated their substantial biomarker potential. Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. Our results may also provide an explanation for opposite effects of some genes in autoimmune diseases and haematological cancer.
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影响因子：
20.3
作者：
Cozen, Wendy;Li, Dalin;Onel, Kenan
通讯作者：
Onel, Kenan
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
2.1
作者：
Aouizerat BE;Vittinghoff E;Musone SL;Pawlikowska L;Kwok PY;Olgin JE;Tseng ZH
通讯作者：
Tseng ZH
影响因子：
4.5
作者：
Cunninghame Graham DS;Morris DL;Bhangale TR;Criswell LA;Syvänen AC;Rönnblom L;Behrens TW;Graham RR;Vyse TJ
通讯作者：
Vyse TJ
影响因子：
30.8
作者：
通讯作者：
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