Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers

被引：292

作者：

Lauc, Gordan ^{[1
,2
]}

Huffman, Jennifer E. ^{[3
]}

Pucic, Maja ^{[1
]}

Zgaga, Lina ^{[4
,5
]}

Adamczyk, Barbara ^{[6
]}

Muzinic, Ana ^{[1
]}

Novokmet, Mislav ^{[1
]}

Polasek, Ozren ^{[7
]}

Gornik, Olga ^{[2
]}

Kristic, Jasminka ^{[1
]}

Keser, Toma ^{[2
]}

Vitart, Veronique ^{[3
]}

Scheijen, Blanca ^{[8
]}

Uh, Hae-Won ^{[9
,10
]}

Molokhia, Mariam ^{[11
]}

Patrick, Alan Leslie ^{[12
]}

McKeigue, Paul ^{[4
]}

Kolcic, Ivana ^{[7
]}

Lukic, Ivan Kresimir ^{[7
]}

Swann, Olivia ^{[4
]}

van Leeuwen, Frank N. ^{[8
]}

Ruhaak, L. Renee ^{[13
]}

Houwing-Duistermaat, Jeanine J. ^{[9
]}

Slagboom, P. Eline ^{[10
,14
]}

Beekman, Marian ^{[10
,14
]}

de Craen, Anton J. M. ^{[15
]}

Deelder, Andre M. ^{[16
]}

Zeng, Qiang ^{[17
]}

Wang, Wei ^{[18
,19
,20
]}

Hastie, Nicholas D. ^{[3
]}

Gyllensten, Ulf ^{[21
]}

Wilson, James F. ^{[4
]}

Wuhrer, Manfred ^{[16
]}

Wright, Alan F. ^{[3
]}

Rudd, Pauline M. ^{[6
]}

Hayward, Caroline ^{[3
]}

Aulchenko, Yurii ^{[4
,22
]}

Campbell, Harry ^{[4
]}

Rudan, Igor ^{[4
]}

机构：

[1] Genos, Glycobiol Lab, Zagreb, Croatia

[2] Univ Zagreb, Fac Pharm & Biochem, Zagreb 41000, Croatia

[3] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[4] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[5] Univ Zagreb, Fac Med, Zagreb 41000, Croatia

[6] Natl Inst Bioproc Res & Training, Dublin Oxford Glycobiol Lab, Dublin, Ireland

[7] Univ Split, Fac Med, Split, Croatia

[8] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[9] Leiden Univ, Dept Med Stat & Bioinformat, Med Ctr, Leiden, Netherlands

[10] Netherlands Consortium Healthy Aging, Leiden, Netherlands

[11] Kings Coll London, Dept Primary Care & Publ Hlth Sci, London WC2R 2LS, England

[12] Kavanagh St Med Ctr, Port Of Spain, Trinidad Tobago

[13] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA

[14] Leiden Univ, Dept Mol Epidemiol, Med Ctr, Leiden, Netherlands

[15] Leiden Univ, Dept Gerontol & Geriatr, Med Ctr, Leiden, Netherlands

[16] Leiden Univ, Dept Parasitol, Biomol Mass Spectrometry Unit, Med Ctr, Leiden, Netherlands

[17] Chinese Peoples Liberat Army Gen Hosp, Beijing, Peoples R China

[18] Capital Med Univ, Sch Publ Hlth, Beijing, Peoples R China

[19] Chinese Acad Sci, Grad Univ, Beijing, Peoples R China

[20] Edith Cowan Univ, Sch Med Sci, Perth, WA, Australia

[21] Uppsala Univ, Dept Immunol Genet & Pathol, SciLifeLab Uppsala, Rudbeck Lab, Uppsala, Sweden

[22] Inst Cytol & Genet SD RAS, Novosibirsk, Russia

来源：

PLOS GENETICS | 2013年 / 9卷 / 01期

基金：

英国医学研究理事会; 芬兰科学院;

关键词：

GENOME-WIDE ASSOCIATION; DEPENDENT CELLULAR CYTOTOXICITY; SITE-SPECIFIC GLYCOSYLATION; COLITIS-RISK LOCI; SUSCEPTIBILITY LOCI; ULCERATIVE-COLITIS; RHEUMATOID-ARTHRITIS; STEM-CELLS; FC; METAANALYSIS;

D O I：

10.1371/journal.pgen.1003225

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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<2.27x10(-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.

引用

页数：17

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