Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups

被引：119

作者：

Rothwell, Simon ^{[1
]}

Cooper, Robert G. ^{[2
]}

Lundberg, Ingrid E. ^{[3
]}

Miller, Frederick W. ^{[4
]}

Gregersen, Peter K. ^{[5
]}

Bowes, John ^{[1
]}

Vencovsky, Jiri ^{[6
,7
]}

Danko, Katalin ^{[8
]}

Limaye, Vidya ^{[9
,10
]}

Selva-O'Callaghan, Albert ^{[11
]}

Hanna, Michael G. ^{[12
]}

Machado, Pedro M. ^{[12
]}

Pachman, Lauren M. ^{[13
,14
]}

Reed, Ann M. ^{[15
]}

Rider, Lisa G. ^{[4
]}

Cobb, Joanna ^{[16
]}

Platt, Hazel ^{[17
]}

Molberg, Oyvind ^{[18
]}

Benveniste, Olivier ^{[19
]}

Mathiesen, Pernille ^{[20
]}

Radstake, Timothy ^{[21
]}

Doria, Andrea ^{[22
]}

De Bleecker, Jan ^{[23
]}

De Paepe, Boel ^{[23
]}

Maurer, Britta ^{[24
,25
]}

Ollier, William E. ^{[17
]}

Padyukov, Leonid ^{[3
]}

O'Hanlon, Terrance P. ^{[4
]}

Lee, Annette ^{[5
]}

Amos, Christopher I. ^{[26
]}

Gieger, Christian ^{[27
]}

Meitinger, Thomas ^{[28
,29
]}

Winkelmann, Juliane ^{[30
,31
]}

Wedderburn, Lucy R. ^{[32
,33
]}

Chinoy, Hector ^{[34
]}

Lamb, Janine A. ^{[17
]}

机构：

[1] Univ Manchester, Arthrit Res UK, Ctr Genet & Genom, Manchester M13 9PT, Lancs, England

[2] Univ Liverpool, Inst Ageing & Chron Dis, Dept Musculoskeletal Biol, Liverpool, Merseyside, England

[3] Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden

[4] NIEHS, Environm Autoimmun Grp, Clin Res Branch, NIH, Bethesda, MD USA

[5] Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY USA

[6] Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic

[7] Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic

[8] Univ Debrecen, Dept Internal Med, Div Clin Immunol, Debrecen, Hungary

[9] Royal Adelaide Hosp, Adelaide, SA, Australia

[10] Univ Adelaide, Adelaide, SA, Australia

[11] Vall dHebron Hosp, Dept Internal Med, Barcelona, Spain

[12] UCL Inst Neurol, MRC Ctr Neuromuscular Dis, London, England

[13] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

[14] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA

[15] Duke Univ, Dept Pediat, Durham, NC 27706 USA

[16] Univ Manchester, NIHR Manchester Musculoskeletal Biomed Res Unit, Cent Manchester NHS Fdn Trust, Arthrit Res UK,Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England

[17] Univ Manchester, Ctr Integrated Genom Med Res, Manchester, Lancs, England

[18] Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway

[19] Univ Paris 06, Pitie Salpetriere Hosp, APHP, Paris, France

[20] Naestved Hosp, Dept Paediat, Naestved, Denmark

[21] Univ Med Ctr Utrecht, Dept Rheumatol & Clin Immunol, Utrecht, Netherlands

[22] Univ Padua, Dept Med, Padua, Italy

[23] Ghent Univ Hosp, Dept Neurol, Neuromuscular Reference Ctr, Ghent, Belgium

[24] Univ Zurich Hosp, Dept Rheumatol, Zurich, Switzerland

[25] Univ Zurich Hosp, Ctr Expt Rheumatol, Zurich, Switzerland

[26] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA

[27] Helmholtz Zentrum Munchen, Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Neuherberg, Germany

[28] Tech Univ Munich, Inst Human Genet, Munich, Germany

[29] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[30] Tech Univ Munich, Klinikum Rechts Isar, Neurol Klin & Poliklin, Munich, Germany

[31] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Neurogen, Neuherberg, Germany

[32] UCL, Arthrit Res UK Ctr Adolescent Rheumatol, London, England

[33] UCL, Inst Child Hlth, London, England

[34] Univ Manchester, Ctr Musculoskeletal Res, Manchester Musculoskeletal Biomed Res Unit, Natl Inst Hlth Res, Manchester, Lancs, England

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2016年 / 75卷 / 08期

基金：

英国惠康基金; 美国国家卫生研究院; 瑞典研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; INCLUSION-BODY MYOSITIS; SUSCEPTIBILITY LOCI; TYROSINE-PHOSPHATASE; VARIANTS; POLYMYOSITIS; JUVENILE; INNATE; COMMON;

D O I：

10.1136/annrheumdis-2015-208119

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objectives The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. Results The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5x10(-8)). Nine regions were associated at a significance level of p<2.25x10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. Conclusions This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.

引用

页码：1558 / 1566

页数：9

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