Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

被引：87

作者：

Acosta-Herrera, Marialbert ^{[1
]}

Kerick, Martin ^{[1
]}

Gonzalez-Serna, David ^{[1
]}

Wijmenga, Cisca ^{[2
]}

Franke, Andre ^{[3
]}

Gregersen, Peter K. ^{[4
]}

Padyukov, Leonid ^{[5
,6
]}

Worthington, Jane ^{[7
]}

Vyse, Timothy James ^{[8
,9
]}

Eugenia Alarcon-Riquelme, Marta ^{[10
]}

Mayes, Maureen D. ^{[11
]}

Martin, Javier ^{[1
]}

Miller, Frederick W. ^{[12
]}

Chen, Wei ^{[13
]}

O'Hanlon, Terrance P. ^{[12
]}

Cooper, Robert G. ^{[14
]}

Vencovsky, Jiri ^{[15
]}

Rider, Lisa G. ^{[12
]}

Danko, Katalin ^{[16
]}

Wedderburn, Lucy R. ^{[17
]}

Lundberg, Ingrid E. ^{[18
]}

Pachman, Lauren M. ^{[19
]}

Reed, Ann M. ^{[20
]}

Ytterberg, Steven R. ^{[20
]}

Selva-O'Callaghan, Albert ^{[21
]}

Radstake, Timothy R. ^{[22
,23
]}

Isenberg, David A. ^{[24
]}

Chinoy, Hector ^{[25
]}

Ollier, William E. R. ^{[26
]}

Scheet, Paul ^{[13
]}

Peng, Bo ^{[13
]}

Lee, Annette ^{[27
]}

Lamb, Janine A. ^{[26
]}

Amos, Christopher I. ^{[28
]}

Denton, Christopher ^{[29
]}

Hilton-Jones, David ^{[30
]}

Plotz, Paul H. ^{[31
]}

Varsani, Hemlata ^{[32
]}

Radstake, Timothy R. D. J. ^{[33
]}

Gorlova, Olga ^{[34
]}

Rueda, Blanca ^{[35
]}

Martin, Jose-Ezequiel ^{[35
]}

Alizadeh, Behrooz Z. ^{[36
]}

Palomino-Morales, Rogelio ^{[35
]}

Coenen, Marieke J. ^{[37
]}

Vonk, Madelon C. ^{[33
]}

Voskuyl, Alexandre E. ^{[38
]}

Scheurwegh, Annemie J. ^{[39
]}

Broen, Jasper C. ^{[33
]}

van Riel, Piet L. C. M. ^{[33
]}

机构：

[1] PTS Granada, CSIC, IPBLN, Granada, Spain

[2] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[3] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

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

[5] Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden

[6] Karolinska Univ Hosp, Stockholm, Sweden

[7] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester NIHR Biomed Res Ctr, Manchester, Lancs, England

[8] Kings Coll London, Div Genet & Mol Med, London, England

[9] Kings Coll London, Div Immunol Infect & Inflammatory Dis, London, England

[10] Univ Granada, Andalusian Reg Govt, Pfizer, Ctr Genom & Oncol Res GENYO, Granada, Spain

[11] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Rheumatol, Houston, TX 77030 USA

[12] NIEHS, NIH, Bethesda, MD USA

[13] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[14] Univ Liverpool, MRC ARUK Inst Ageing & Chron Dis, Liverpool, Merseyside, England

[15] Charles Univ Prague, Inst Rheumatol, Prague, Czech Republic

[16] Univ Debrecen, Dept Internal Med 3, Div Immunol, Debrecen, Hungary

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

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

[19] Northwestern Univ, Feinberg Sch Med, Dept Pediat Rheumatol, Chicago, IL 60611 USA

[20] Mayo Clin, Rochester, MN USA

[21] Vall dHebron Gen Hosp, Barcelona, Spain

[22] Univ Utrecht, Med Ctr, Lab Translat Immunol, Dept Rheumatol & Clin Immunol, Utrecht, Netherlands

[23] Nijmegen Ctr Mol Life Sci, Nijmegen, Netherlands

[24] UCL, Div Med, London, England

[25] Univ Manchester, Ctr Musculoskeletal Res, Natl Inst Hlth Res Manchester Musculoskeletal Bio, Manchester, Lancs, England

[26] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Integrated Genom Med Res, Manchester, Lancs, England

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

[28] Dartmouth Coll, Dept Community & Family Med, Hanover, NH 03755 USA

[29] Royal Free Hosp, Ctr Rheumatol, London, England

[30] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England

[31] NIAMSD, NIH, Bethesda, MD 20892 USA

[32] UCL, London, England

[33] Radboud Univ Nijmegen, Med Ctr, Dept Rheumatol, Nijmegen, Netherlands

[34] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[35] CSIC, Inst Parasitol Biomed Lopez Neyra, Granada, Spain

[36] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[37] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands

[38] Vrije Univ Amsterdam Med Ctr, Dept Rheumatol, Amsterdam, Netherlands

[39] Leiden Univ, Dept Rheumatol, Leiden, Netherlands

[40] UCLA Ctr Neurobehav Genet, Los Angeles, CA USA

[41] Charite, Dept Rheumatol & Clin Immunol, Berlin, Germany

[42] Univ Cologne, Dept Dermatol, Cologne, Germany

[43] Hosp Valle de Hebron, Serv Med Interna, Barcelona, Spain

[44] Hosp Clin Univ, Serv Med Interna, Granada, Spain

[45] Hosp Marques de Valdecilla, Serv Reumatol, Santander, Spain

[46] Hosp Virgen del Rocio, Serv Inmunol, Seville, Spain

[47] Univ Brescia, Brescia, Italy

[48] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England

[49] Univ Manchester, Manchester, Lancs, England

[50] Lund Univ, Lund, Sweden

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2019年 / 78卷 / 03期

关键词：

ASSOCIATION; VARIANTS; ARTHRITIS; SCLEROSIS; MULTIPLE; PROTEIN; PATHOGENESIS; GENETICS; COMPLEX; COMMON;

D O I：

10.1136/annrheumdis-2018-214127

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective I mmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. Methods We meta-analysed similar to 6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. Results Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. Conclusions We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.

引用

页码：311 / 319

页数：9

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