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

English version České info

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.

Vyšlo v časopise: Loci Associated with -Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003225
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003225

Souhrn

Zdroje

1. OpdenakkerG, RuddPM, PontingCP, DwekRA (1993) Concepts and principles of glycobiology. FASEB Journal 7: 1330–1337.

2. SkropetaD (2009) The effect of individual N-glycans on enzyme activity. Bioorg. Med.Chem 17: 2645–2653.

3. MarekKW, VijayIK, MarthJD (1999) A recessive deletion in the GlcNAc-1-phosphotransferase gene results in peri-implantation embryonic lethality. Glycobiology 9: 1263–1271.

4. JaekenJ, MatthijsG (2007) Congenital disorders of glycosylation: a rapidly expanding disease family. Annu Rev Genomics Hum Genet 8: 261–278.

5. KobataA (2008) The N-linked sugar chains of human immunoglobulin G: their unique pattern, and their functional roles. Biochim Biophys Acta 1780: 472–478.

6. JefferisR (2005) Glycosylation of recombinant antibody therapeutics. Biotechnol Prog 21: 11–16.

7. ZhuD, OttensmeierCH, DuMQ, McCarthyH, StevensonFK (2003) Incidence of potential glycosylation sites in immunoglobulin variable regions distinguishes between subsets of Burkitt's lymphoma and mucosa-associated lymphoid tissue lymphoma. Br J Haematol 120: 217–222.

8. SuttonBJ, PhillipsDC (1983) The three-dimensional structure of the carbohydrate within the Fc fragment of immunoglobulin G. Biochem Soc Trans 11: 130–132.

9. HaradaH, KameiM, TokumotoY, YuiS, KoyamaF, et al. (1987) Systematic fractionation of oligosaccharides of human immunoglobulin G by serial affinity chromatography on immobilized lectin columns. Anal Biochem 164: 374–381.

10. ParekhRB, DwekRA, SuttonBJ, FernandesDL, LeungA, et al. (1985) Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG. Nature 316: 452–457.

11. KanekoY, NimmerjahnF, RavetchJV (2006) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313: 670–673.

12. AnthonyRM, RavetchJV (2010) A novel role for the IgG Fc glycan: the anti-inflammatory activity of sialylated IgG Fcs. J Clin Immunol 30 Suppl 1: S9–14.

13. NimmerjahnF, RavetchJV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8: 34–47.

14. FerraraC, StuartF, SondermannP, BrunkerP, UmanaP (2006) The carbohydrate at FcgammaRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J Biol Chem 281: 5032–5036.

15. MizushimaT, YagiH, TakemotoE, Shibata-KoyamaM, IsodaY, et al. (2011) Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans. Genes to Cells 16: 1071–1080.

16. ShinkawaT, NakamuraK, YamaneN, Shoji-HosakaE, KandaY, et al. (2003) The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem 278: 3466–3473.

17. IidaS, MisakaH, InoueM, ShibataM, NakanoR, et al. (2006) Nonfucosylated therapeutic IgG1 antibody can evade the inhibitory effect of serum immunoglobulin G on antibody-dependent cellular cytotoxicity through its high binding to FcgammaRIIIa. Clin Cancer Res 12: 2879–2887.

18. PreithnerS, ElmS, LippoldS, LocherM, WolfA, et al. (2006) High concentrations of therapeutic IgG1 antibodies are needed to compensate for inhibition of antibody-dependent cellular cytotoxicity by excess endogenous immunoglobulin G. Mol Immunol 43: 1183–1193.

19. PucicM, KnezevicA, VidicJ, AdamczykB, NovokmetM, et al. (2011) High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations. Mol Cell Proteomics 10: M111 010090.

20. KoonerJS, SaleheenD, SimX, SehmiJ, ZhangW, et al. (2011) Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet 43: 984–989.

21. FrankeA, McGovernDP, BarrettJC, WangK, Radford-SmithGL, et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42: 1118–1125.

22. MellsGF, FloydJA, MorleyKI, CordellHJ, FranklinCS, et al. (2011) Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet 43: 329–332.

23. AouizeratBE, VittinghoffE, MusoneSL, PawlikowskaL, KwokPY, et al. (2011) GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease. BMC Cardiovasc Disord 11: 29.

24. BaranziniSE, SrinivasanR, KhankhanianP, OkudaDT, NelsonSJ, et al. (2010) Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis. Brain 133: 2603–2611.

25. DickDM, AlievF, KruegerRF, EdwardsA, AgrawalA, et al. (2011) Genome-wide association study of conduct disorder symptomatology. Mol Psychiatry 16: 800–808.

26. PivacN, KnezevicA, GornikO, PucicM, IglW, et al. (2011) Human plasma glycome in attention-deficit hyperactivity disorder and autism spectrum disorders. Mol Cell Proteomics 10: M110 004200.

27. HuffmanJE, KnezevicA, VitartV, KattlaJ, AdamczykB, et al. (2011) Polymorphisms in B3GAT1, SLC9A9 and MGAT5 are associated with variation within the human plasma N-glycome of 3533 European adults. Hum Mol Genet 20: 5000–5011.

28. OdaY, OkadaT, YoshidaH, KaufmanRJ, NagataK, et al. (2006) Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol 172: 383–393.

29. PottierN, CheokMH, YangW, AssemM, TraceyL, et al. (2007) Expression of SMARCB1 modulates steroid sensitivity in human lymphoblastoid cells: identification of a promoter SNP that alters PARP1 binding and SMARCB1 expression. Hum Mol Genet 16: 2261–2271.

30. ChambersJC, ZhangW, SehmiJ, LiX, WassMN, et al. (2011) Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 43: 1131–1138.

31. SellarsM, Reina-San-MartinB, KastnerP, ChanS (2009) Ikaros controls isotype selection during immunoglobulin class switch recombination. J Exp Med 206: 1073–1087.

32. KlugCA, MorrisonSJ, MasekM, HahmK, SmaleST, et al. (1998) Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes. Proc Natl Acad Sci U S A 95: 657–662.

33. TrevinoLR, YangW, FrenchD, HungerSP, CarrollWL, et al. (2009) Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 41: 1001–1005.

34. PapaemmanuilE, HoskingFJ, VijayakrishnanJ, PriceA, OlverB, et al. (2009) Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 41: 1006–1010.

35. Cunninghame GrahamDS, MorrisDL, BhangaleTR, CriswellLA, SyvanenAC, et al. (2011) Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus. PLoS Genet 7: e1002341 doi:10.1371/journal.pgen.1002341.

36. HanJW, ZhengHF, CuiY, SunLD, YeDQ, et al. (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 41: 1234–1237.

37. GatevaV, SandlingJK, HomG, TaylorKE, ChungSA, et al. (2009) A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41: 1228–1233.

38. DavidsonA, DiamondB (2001) Autoimmune diseases. N Engl J Med 345: 340–350.

39. SwaffordAD, HowsonJM, DavisonLJ, WallaceC, SmythDJ, et al. (2011) An allele of IKZF1 (Ikaros) conferring susceptibility to childhood acute lymphoblastic leukemia protects against type 1 diabetes. Diabetes 60: 1041–1044.

40. BarrettJC, HansoulS, NicolaeDL, ChoJH, DuerrRH, et al. (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40: 955–962.

41. GorlovaO, MartinJE, RuedaB, KoelemanBP, YingJ, et al. (2011) Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet 7: e1002178 doi:10.1371/journal.pgen.1002178.

42. JallowM, TeoYY, SmallKS, RockettKA, DeloukasP, et al. (2009) Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet 41: 657–665.

43. GaneshSK, ZakaiNA, van RooijFJ, SoranzoN, SmithAV, et al. (2009) Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet 41: 1191–1198.

44. StahlEA, RaychaudhuriS, RemmersEF, XieG, EyreS, et al. (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42: 508–514.

45. GottardoL, De CosmoS, ZhangYY, PowersC, PrudenteS, et al. (2008) A polymorphism at the IL6ST (gp130) locus is associated with traits of the metabolic syndrome. Obesity (Silver Spring) 16: 205–210.

46. BirmannBM, TamimiRM, GiovannucciE, RosnerB, HunterDJ, et al. (2009) Insulin-like growth factor-1- and interleukin-6-related gene variation and risk of multiple myeloma. Cancer Epidemiol Biomarkers Prev 18: 282–288.

47. BarrettJC, LeeJC, LeesCW, PrescottNJ, AndersonCA, et al. (2009) Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat. Genet 41: 1330–1334.

48. SilverbergMS, ChoJH, RiouxJD, McGovernDP, WuJ, et al. (2009) Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 41: 216–220.

49. McGovernDP, GardetA, TorkvistL, GoyetteP, EssersJ, et al. (2010) Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42: 332–337.

50. AndersonCA, BoucherG, LeesCW, FrankeA, D'AmatoM, et al. (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43: 246–252.

51. AsanoK, MatsushitaT, UmenoJ, HosonoN, TakahashiA, et al. (2009) A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 41: 1325–1329.

52. KamioT, TokiT, KanezakiR, SasakiS, TandaiS, et al. (2003) B-cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs. Blood 102: 3317–3322.

53. GrantSF, QuHQ, BradfieldJP, MarchandL, KimCE, et al. (2009) Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes. Diabetes 58: 290–295.

54. CooperJD, SmythDJ, SmilesAM, PlagnolV, WalkerNM, et al. (2008) Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 40: 1399–1401.

55. BarrettJC, ClaytonDG, ConcannonP, AkolkarB, CooperJD, et al. (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41: 703–707.

56. PlagnolV, HowsonJM, SmythDJ, WalkerN, HaflerJP, et al. (2011) Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS Genet 7: e1002216 doi:10.1371/journal.pgen.1002216.

57. ChuX, PanCM, ZhaoSX, LiangJ, GaoGQ, et al. (2011) A genome-wide association study identifies two new risk loci for Graves' disease. Nat Genet 43: 897–901.

58. DuboisPC, TrynkaG, FrankeL, HuntKA, RomanosJ, et al. (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42: 295–302.

59. SawcerS, HellenthalG, PirinenM, SpencerCC, PatsopoulosNA, et al. (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476: 214–219.

60. MatsuiT, LeungD, MiyashitaH, MaksakovaIA, MiyachiH, et al. (2010) Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464: 927–931.

61. IglW, PolasekO, GornikO, KnezevicA, PucicM, et al. (2011) Glycomics meets lipidomics-associations of N-glycans with classical lipids, glycerophospholipids, and sphingolipids in three European populations. Mol Biosyst 7: 1852–1862.

62. CozenW, LiD, BestT, Van Den BergDJ, GourraudPA, et al. (2012) A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32. Blood 119: 469–475.

63. ChungSA, TaylorKE, GrahamRR, NitithamJ, LeeAT, et al. (2011) Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet 7: e1001323 doi:10.1371/journal.pgen.1001323.

64. HorH, KutalikZ, DauvilliersY, ValsesiaA, LammersGJ, et al. (2010) Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet 42: 786–789.

65. Celestino-SoperPB, ShawCA, SandersSJ, LiJ, MurthaMT, et al. (2011) Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE. Hum Mol Genet 20: 4360–4370.

66. YashinAI, WuD, ArbeevKG, UkraintsevaSV (2010) Joint influence of small-effect genetic variants on human longevity. Aging (Albany NY) 2: 612–620.

67. PrasadRB, HoskingFJ, VijayakrishnanJ, PapaemmanuilE, KoehlerR, et al. (2010) Verification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood 115: 1765–1767.

68. SouabniA, CobaledaC, SchebestaM, BusslingerM (2002) Pax5 promotes B lymphopoiesis and blocks T cell development by repressing Notch1. Immunity 17: 781–793.

69. MolokhiaM, McKeigueP (2006) Systemic lupus erythematosus: genes versus environment in high risk populations. Lupus 15: 827–832.

70. KunduS, AulchenkoYS, van DuijnCM, JanssensAC (2011) PredictABEL: an R package for the assessment of risk prediction models. Eur J Epidemiol 26: 261–264.

71. LaucG, EssafiA, HuffmanJE, HaywardC, KneževićA, et al. (2010) Genomics meets glycomics - The first GWAS study of human N-glycome identifies HNF1alpha as a master regulator of plasma protein fucosylation. PLoS Genet 6: e1001256 doi:10.1371/journal.pgen.1001256.

72. FukutaK, AbeR, YokomatsuT, OmaeF, AsanagiM, et al. (2000) Control of bisecting GlcNAc addition to N-linked sugar chains. J Biol Chem 275: 23456–23461.

73. Van DammeJ, OpdenakkerG, SimpsonRJ, RubiraMR, CayphasS, et al. (1987) Identification of the human 26-kD protein, interferon beta 2 (IFN-beta 2), as a B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. J Exp Med 165: 914–919.

74. ShieldsRL, LaiJ, KeckR, O'ConnellLY, HongK, et al. (2002) Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem 277: 26733–26740.

75. AlbertH, CollinM, DudziakD, RavetchJV, NimmerjahnF (2008) In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner. Proc Natl Acad Sci U S A 105: 15005–15009.

76. BaudinoL, Azeredo da SilveiraS, NakataM, IzuiS (2006) Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies. Springer Semin Immunopathol 28: 175–184.

77. SivakumaranS, AgakovF, TheodoratouE, PrendergastJG, ZgagaL, et al. (2011) Abundant pleiotropy in human complex diseases and traits. Am J Hum Genet 89: 607–618.

78. YouingsA, ChangSC, DwekRA, ScraggIG (1996) Site-specific glycosylation of human immunoglobulin G is altered in four rheumatoid arthritis patients. Biochem J 314(Pt 2): 621–630.

79. WormaldMR, RuddPM, HarveyDJ, ChangSC, ScraggIG, et al. (1997) Variations in oligosaccharide-protein interactions in immunoglobulin G determine the site-specific glycosylation profiles and modulate the dynamic motion of the Fc oligosaccharides. Biochemistry 36: 1370–1380.

80. MimuraY, AshtonPR, TakahashiN, HarveyDJ, JefferisR (2007) Contrasting glycosylation profiles between Fab and Fc of a human IgG protein studied by electrospray ionization mass spectrometry. J Immunol Methods 326: 116–126.

81. WangJ, BalogCI, StavenhagenK, KoelemanCA, SchererHU, et al. (2011) Fc-glycosylation of IgG1 is modulated by B-cell stimuli. Mol Cell Proteomics 10: M110 004655.

82. VitartV, RudanI, HaywardC, GrayNK, FloydJ, et al. (2008) SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 40: 437–442.

83. ZemunikT, BobanM, LaucG, JankovicS, RotimK, et al. (2009) Genome-wide association study of biochemical traits in Korcula Island, Croatia. Croat Med J 50: 23–33.

84. McQuillanR, LeuteneggerAL, Abdel-RahmanR, FranklinCS, PericicM, et al. (2008) Runs of homozygosity in European populations. Am J Hum Genet 83: 359–372.

85. SchoenmakerM, de CraenAJ, de MeijerPH, BeekmanM, BlauwGJ, et al. (2006) Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur J Hum Genet 14: 79–84.

86. RuhaakLR, UhHW, BeekmanM, KoelemanCA, HokkeCH, et al. (2010) Decreased levels of bisecting GlcNAc glycoforms of IgG are associated with human longevity. PLoS ONE 5: e12566 doi:10.1371/journal.pone.0012566.

87. AulchenkoYS, RipkeS, IsaacsA, van DuijnCM (2007) GenABEL: an R library for genome-wide association analysis. Bioinformatics 23: 1294–1296.

88. Pe'erI, YelenskyR, AltshulerD, DalyMJ (2008) Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol 32: 381–385.

89. PruimRJ, WelchRP, SannaS, TeslovichTM, ChinesPS, et al. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26: 2336–2337.

90. UhHW, DeelenJ, BeekmanM, HelmerQ, RivadeneiraF, et al. (2011) How to deal with the early GWAS data when imputing and combining different arrays is necessary. Eur J Hum Genet 20: 572–576.

91. TanEM, CohenAS, FriesJF, MasiAT, McShaneDJ, et al. (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25: 1271–1277.