Trbojević Akmačić Irena, Ventham Nicholas T, Theodoratou Evropi, Vučković Frano, Kennedy Nicholas A, Krištić Jasminka, Nimmo Elaine R, Kalla Rahul, Drummond Hazel, Štambuk Jerko, Dunlop Malcolm G, Novokmet Mislav, Aulchenko Yurii, Gornik Olga, Campbell Harry, Pučić Baković Maja, Satsangi Jack, Lauc Gordan
*Genos Glycoscience Research Laboratory, Zagreb, Croatia; †Gastrointestinal Unit, Centre for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; ‡Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom; §Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and Medical Research Council Human Genetics Unit, Edinburgh, United Kingdom; ‖Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia; ¶Novosibirsk State University, Novosibirsk, Russia; and **Department of Biochemistry and Molecular Biology, University of Zagreb, Faculty of Pharmacy and Biochemistry, Zagreb, Croatia.
Inflamm Bowel Dis. 2015 Jun;21(6):1237-47. doi: 10.1097/MIB.0000000000000372.
Glycobiology is an underexplored research area in inflammatory bowel disease (IBD), and glycans are relevant to many etiological mechanisms described in IBD. Alterations in N-glycans attached to the immunoglobulin G (IgG) Fc fragment can affect molecular structure and immunological function. Recent genome-wide association studies reveal pleiotropy between IBD and IgG glycosylation. This study aims to explore IgG glycan changes in ulcerative colitis (UC) and Crohn's disease (CD).
IgG glycome composition in patients with UC (n = 507), CD (n = 287), and controls (n = 320) was analyzed by ultra performance liquid chromatography.
Statistically significant differences in IgG glycome composition between patients with UC or CD, compared with controls, were observed. Both UC and CD were associated with significantly decreased IgG galactosylation (digalactosylation, UC: odds ratio [OR] = 0.71; 95% confidence interval [CI], 0.5-0.9; P = 0.01; CD: OR = 0.41; CI, 0.3-0.6; P = 1.4 × 10) and significant decrease in the proportion of sialylated structures in CD (OR = 0.46, CI, 0.3-0.6, P = 8.4 × 10). Logistic regression models incorporating measured IgG glycan traits were able to distinguish UC and CD from controls (UC: P = 2.13 × 10 and CD: P = 2.20 × 10), with receiver-operator characteristic curves demonstrating better performance of the CD model (area under curve [AUC] = 0.77) over the UC model (AUC = 0.72) (P = 0.026). The ratio of the presence to absence of bisecting GlcNAc in monogalactosylated structures was increased in patients with UC undergoing colectomy compared with no colectomy (FDR-adjusted, P = 0.05).
The observed differences indicate significantly increased inflammatory potential of IgG in IBD. Changes in IgG glycosylation may contribute to IBD pathogenesis and could alter monoclonal antibody therapeutic efficacy. IgG glycan profiles have translational potential as IBD biomarkers.
糖生物学在炎症性肠病（IBD）中是一个未被充分探索的研究领域，聚糖与IBD中描述的许多病因机制相关。附着于免疫球蛋白G（IgG）Fc片段的N -聚糖的改变可影响分子结构和免疫功能。最近的全基因组关联研究揭示了IBD与IgG糖基化之间的多效性。本研究旨在探讨溃疡性结肠炎（UC）和克罗恩病（CD）中IgG聚糖的变化。
通过超高效液相色谱分析UC患者（n = 507）、CD患者（n = 287）和对照组（n = 320）的IgG糖组组成。
观察到UC或CD患者与对照组相比，IgG糖组组成存在统计学显著差异。UC和CD均与IgG半乳糖基化显著降低相关（双半乳糖基化，UC：比值比[OR]=0.71；95%置信区间[CI]，0.5 - 0.9；P = 0.01；CD：OR = 0.41；CI，0.3 - 0.6；P = 1.4×10），且CD中唾液酸化结构比例显著降低（OR = 0.46；CI，0.3 - 0.6；P = 8.4×10）。纳入测量的IgG聚糖特征的逻辑回归模型能够将UC和CD与对照组区分开来（UC：P = 2.13×10；CD：P = 2.20×10），受试者工作特征曲线显示CD模型（曲线下面积[AUC]=0.77）比UC模型（AUC = 0.72）表现更好（P = 0.026）。与未行结肠切除术的UC患者相比，行结肠切除术的UC患者单半乳糖基化结构中存在平分型N -乙酰葡糖胺与不存在平分型N -乙酰葡糖胺的比例增加（经FDR校正，P = 0.05）。
观察到的差异表明IBD中IgG的炎症潜能显著增加。IgG糖基化的变化可能有助于IBD发病机制，并可能改变单克隆抗体治疗效果。IgG聚糖谱作为IBD生物标志物具有转化潜力。
