Class II HLA interactions modulate genetic risk for multiple sclerosis

被引：256

作者：

Moutsianas, Loukas ^{[1
]}

Jostins, Luke ^{[1
]}

Beecham, Ashley H. ^{[2
]}

Dilthey, Alexander T. ^{[1
]}

Xifara, Dionysia K. ^{[1
]}

Ban, Maria ^{[3
]}

Shah, Tejas S. ^{[4
]}

Patsopoulos, Nikolaos A. ^{[5
,6
,7
,8
]}

Alfredsson, Lars ^{[9
]}

Anderson, Carl A. ^{[4
]}

Attfield, Katherine E. ^{[10
]}

Baranzini, Sergio E. ^{[11
]}

Barrett, Jeffrey ^{[4
]}

Binder, Thomas M. C. ^{[12
]}

Booth, David ^{[13
]}

Buck, Dorothea ^{[14
]}

Celius, Elisabeth G. ^{[15
]}

Cotsapas, Chris ^{[8
,16
,17
]}

D'Alfonso, Sandra ^{[18
]}

Dendrou, Calliope A. ^{[19
]}

Donnelly, Peter ^{[1
]}

Dubois, Benedicte ^{[20
]}

Fontaine, Bertrand ^{[21
,22
,23
]}

Fugger, Lars ^{[10
,19
]}

Goris, An ^{[20
]}

Gourraud, Pierre-Antoine ^{[11
]}

Graetz, Christiane ^{[24
]}

Hemmer, Bernhard ^{[14
,25
,26
]}

Hillert, Jan ^{[27
]}

Kockum, Ingrid ^{[27
]}

Leslie, Stephen ^{[28
,29
]}

Lill, Christina M. ^{[24
,30
,31
]}

Martinelli-Boneschi, Filippo ^{[32
,33
]}

Oksenberg, Jorge R. ^{[11
]}

Olsson, Tomas ^{[27
]}

Oturai, Annette ^{[34
]}

Saarela, Janna ^{[35
]}

Sondergaard, Helle Bach ^{[34
]}

Spurkland, Anne ^{[36
]}

Taylor, Bruce ^{[37
]}

Winkelmann, Juliane ^{[14
,25
,38
,39
,40
]}

Zipp, Frauke ^{[24
]}

Haines, Jonathan L. ^{[41
]}

Pericak-Vance, Margaret A. ^{[2
]}

Spencer, Chris C. A. ^{[1
]}

Stewart, Graeme ^{[13
]}

Hafler, David A. ^{[8
,16
,42
]}

Ivinson, Adrian J. ^{[43
]}

Harbo, Hanne F. ^{[15
,44
]}

Hauser, Stephen L. ^{[11
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[2] Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA

[3] Univ Cambridge, Dept Clin Neurosci, Cambridge, England

[4] Wellcome Trust Sanger Inst, Hinxton, England

[5] Brigham & Womens Hosp, Dept Neurol, Ann Romney Ctr Neurol Dis, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Boston, MA USA

[8] Broad Inst Harvard Univ & MIT, Program Med & Populat Genet, Cambridge, MA USA

[9] Karolinska Inst, Inst Environm Med IMM, Stockholm, Sweden

[10] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford OX3 9DU, England

[11] Univ Calif San Francisco, Dept Neurol, Sandler Neurosci Ctr, San Francisco, CA USA

[12] Univ Med Ctr Hamburg Eppendorf, Dept Transfus Med, HLA Lab, Hamburg, Germany

[13] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia

[14] Tech Univ Munich, Klinikum Rechts Isar, Dept Neurol, D-80290 Munich, Germany

[15] Oslo Univ Hosp, Dept Neurol, N-0450 Oslo, Norway

[16] Yale Univ, Sch Med, Dept Neurol & Immunol, New Haven, CT USA

[17] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[18] Univ Piemonte Orientale, Dept Hlth Sci, IRCAD, Novara, Italy

[19] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England

[20] Katholieke Univ Leuven, Dept Neurosci, Lab Neuroimmunol, Leuven, Belgium

[21] Univ Paris 06, INSERM, CNRS, AP HP,Dept Malad Syst Nerveux, Paris, France

[22] Pitie Salpetriere, UMRS 1127 7225, Inst Cerveau Moelle Spinal Cord, Paris, France

[23] Pitie Salpetriere, Inst Brain, Paris, France

[24] Johannes Gutenberg Univ Mainz, Med Ctr, Rhine Main Neurosci Network Rmn2, Focus Program Translat Neurosci FTN, D-55122 Mainz, Germany

[25] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[26] German Competence Network Multiple Sclerosis KKNM, Munich, Germany

[27] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden

[28] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia

[29] Univ Melbourne, Dept Math & Stat, Melbourne, Vic, Australia

[30] Univ Lubeck, Inst Neurogenet & Integrat, Platform Genome Analyt, Lubeck, Germany

[31] Univ Lubeck, Inst Expt Gen, Platform Genome Analyt, Lubeck, Germany

[32] Ist Sci San Raffaele, Lab Genet Neurol Complex Disorders, Inst Expt Neurol INSPE, Div Neurosci, I-20132 Milan, Italy

[33] Ist Sci San Raffaele, Dept Neurol, Inst Expt Neurol INSPE, Div Neurosci, I-20132 Milan, Italy

[34] Copenhagen Univ Hosp, Danish Multiple Sclerosis Ctr, Dept Neurol, Copenhagen, Denmark

[35] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[36] Univ Oslo, Inst Basic Med Sci, Oslo, Norway

[37] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas, Australia

[38] Tech Univ Munich, Inst Humangenet, D-80290 Munich, Germany

[39] Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany

[40] Stanford Univ, Ctr Sleep Sci & Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[41] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA

[42] Broad Inst Harvard Univ & MIT, Cambridge, MA USA

[43] Harvard Univ, Sch Med, Harvard NeuroDiscovery Ctr, Boston, MA USA

[44] Univ Oslo, Oslo, Norway

来源：

NATURE GENETICS | 2015年 / 47卷 / 10期

基金：

英国惠康基金; 美国国家卫生研究院; 芬兰科学院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; DISEASE; MHC; EPISTASIS; ERAP1; METAANALYSIS; POPULATION; VARIANTS; HLA-DRB1;

D O I：

10.1038/ng.3395

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.

引用

页码：1107 / +

页数：10

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