Polymorphisms in B3GAT1, SLC9A9 and MGAT5 are associated with variation within the human plasma N-glycome of 3533 European adults

被引：75

作者：

Huffman, Jennifer E. ^{[1
]}

Knezevic, Ana ^{[2
]}

Vitart, Veronique ^{[1
]}

Kattla, Jayesh ^{[3
]}

Adamczyk, Barbara ^{[3
]}

Novokmet, Mislav ^{[2
]}

Igl, Wilmar ^{[4
]}

Pucic, Maja ^{[2
]}

Zgaga, Lina ^{[5
]}

Johannson, Asa ^{[4
]}

Redzic, Irma ^{[6
]}

Gornik, Olga ^{[6
]}

Zemunik, Tatijana ^{[7
]}

Polasek, Ozren ^{[7
]}

Kolcic, Ivana ^{[7
]}

Pehlic, Marina ^{[7
]}

Koeleman, Carolien A. M. ^{[8
]}

Campbell, Susan ^{[1
]}

Wild, Sarah H. ^{[5
]}

Hastie, Nicholas D. ^{[1
]}

Campbell, Harry ^{[5
]}

Gyllensten, Ulf ^{[4
]}

Wuhrer, Manfred ^{[8
]}

Wilson, James F. ^{[5
]}

Hayward, Caroline ^{[1
]}

Rudan, Igor ^{[5
,7
]}

Rudd, Pauline M. ^{[3
]}

Wright, Alan F. ^{[1
]}

Lauc, Gordan ^{[2
,6
]}

机构：

[1] Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[2] Genos Ltd, Glycobiol Div, Zagreb 10000, Croatia

[3] Univ Coll Dublin, Dublin Oxford Glycobiol Lab, Natl Inst Bioproc Res & Training, Conway Inst, Dublin 4, Ireland

[4] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, S-75185 Uppsala, Sweden

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

[6] Univ Zagreb, Fac Pharm & Biochem, Zagreb 10000, Croatia

[7] Univ Split, Fac Med, Split 21000, Croatia

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

来源：

HUMAN MOLECULAR GENETICS | 2011年 / 20卷 / 24期

基金：

英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; C-REACTIVE PROTEIN; ALPHA(1)-ACID GLYCOPROTEIN; GLYCOSYLATION; LOCI; GLYCANS; HNF1A; SCAN; GLUCURONOSYLTRANSFERASE; BIOSYNTHESIS;

D O I：

10.1093/hmg/ddr414

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The majority of human proteins are post-translationally modified by covalent addition of one or more complex oligosaccharides (glycans). Alterations in glycosylation processing are associated with numerous diseases and glycans are attracting increasing attention both as disease biomarkers and as targets for novel therapeutic approaches. Using a recently developed high-throughput high-performance liquid chromatography (HPLC) analysis method, we have reported, in a pilot genome-wide association study of 13 glycan features in 2705 individuals from three European populations, that polymorphisms at three loci (FUT8, FUT6/FUT3 and HNF1A) affect plasma levels of N-glycans. Here, we extended the analysis to 33 directly measured and 13 derived glycosylation traits in 3533 individuals and identified three novel gene association (MGAT5, B3GAT1 and SLC9A9) as well as replicated the previous findings using an additional European cohort. MGAT5 (meta-analysis association P-value = 1.80 x 10(-10) for rs1257220) encodes a glycosyltransferase which is known to synthesize the associated glycans. In contrast, neither B3GAT1 (rs7928758, P = 1.66 x 10(-08)) nor SLC9A9 (rs4839604, P = 3.50 x 10(-13)) had previously been associated functionally with glycosylation of plasma proteins. Given the glucuronyl transferase activity of B3GAT1, we were able to show that glucuronic acid is present on antennae of plasma glycoproteins underlying the corresponding HPLC peak. SLC9A9 encodes a proton pump which affects pH in the endosomal compartment and it was recently reported that changes in Golgi pH can impair protein sialylation, giving a possible mechanism for the observed association.

引用

页码：5000 / 5011

页数：12

共 62 条

[1] GenABEL: an R library for genome-wide association analysis [J].

Aulchenko, Yurii S. ;

Ripke, Stephan ;

Isaacs, Aaron ;

Van Duijn, Cornelia M. .

BIOINFORMATICS, 2007, 23 (10) :1294-1296

[2] Inflammation-induced expression of sialyl Lewisx is not restricted to α1-acid glycoprotein but also occurs to a lesser extent on α1-antichymotrypsin and haptoglobin [J].

Brinkman-van der Linden, ECM ;

de Haan, PF ;

Havenaar, EC ;

van Dijk, W .

GLYCOCONJUGATE JOURNAL, 1998, 15 (02) :177-182

[3] A missense mutation in the FUT6 gene results in total absence of alpha 3-fucosylation of human alpha(1)-acid glycoprotein [J].

BrinkmanVanderLinden, ECM ;

Mollicone, R ;

Oriol, R ;

Larson, G ;

VandenEijnden, DH ;

VanDijk, W .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (24) :14492-14495

[4] The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder:: association signals in DRD4, DAT1 and 16 other genes [J].

Brookes, K. ;

Xu, X. ;

Chen, W. ;

Zhou, K. ;

Neale, B. ;

Lowe, N. ;

Aneey, R. ;

Franke, B. ;

Gill, M. ;

Ebstein, R. ;

Buitelaar, J. ;

Sham, P. ;

Campbell, D. ;

Knight, J. ;

Andreou, P. ;

Altink, M. ;

Arnold, R. ;

Boer, F. ;

Buschgens, C. ;

Butler, L. ;

Christiansen, H. ;

Feldman, L. ;

Fleischman, K. ;

Fliers, E. ;

Howe-Forbes, R. ;

Goldfarb, A. ;

Heise, A. ;

Gabriels, I. ;

Korn-Lubetzki, I. ;

Marco, R. ;

Medad, S. ;

Minderaa, R. ;

Mulas, F. ;

Mueller, U. ;

Mulligan, A. ;

Rabin, K. ;

Rommelse, N. ;

Sethna, V. ;

Sorohan, J. ;

Uebel, H. ;

Psychogiou, L. ;

Weeks, A. ;

Barrett, R. ;

Craig, I. ;

Banaschewski, T. ;

Sonuga-Barke, E. J. S. ;

Eisenberg, J. ;

Kuntsi, J. ;

Manor, I. ;

McGuffin, P. .

MOLECULAR PSYCHIATRY, 2006, 11 (10) :934-953

[5] MGAT5 alters the severity of multiple sclerosis [J].

Brynedal, B. ;

Wojcik, J. ;

Esposito, F. ;

Debailleul, V. ;

Yaouanq, J. ;

Martinelli-Boneschi, F. ;

Edan, G. ;

Comi, G. ;

Hillert, J. ;

Abderrahim, H. .

JOURNAL OF NEUROIMMUNOLOGY, 2010, 220 (1-2) :120-124

[6] GlycoBase and autoGU: tools for HPLC-based glycan analysis [J].

Campbell, Matthew P. ;

Royle, Louise ;

Radcliffe, Catherine M. ;

Dwek, Raymond A. ;

Rudd, Pauline M. .

BIOINFORMATICS, 2008, 24 (09) :1214-1216

[7] GlycoWorkbench: A tool for the computer-assisted annotation of mass spectra of Glycans [J].

Ceroni, Alessio ;

Maass, Kai ;

Geyer, Hildegard ;

Geyer, Rudolf ;

Dell, Anne ;

Haslam, Stuart M. .

JOURNAL OF PROTEOME RESEARCH, 2008, 7 (04) :1650-1659

[8] Family-based association tests for genomewide association scans [J].

Chen, Wei-Min ;

Abecasis, Goncalo R. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (05) :913-926

[9] Siglecs and their roles in the immune system [J].

Crocker, Paul R. ;

Paulson, James C. ;

Varki, Ajit .

NATURE REVIEWS IMMUNOLOGY, 2007, 7 (04) :255-266

[10] The repertoire of glycan determinants in the human glycome [J].

Cummings, Richard D. .

MOLECULAR BIOSYSTEMS, 2009, 5 (10) :1087-1104

← 1 2 3 4 5 6 7 →