Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

被引：189

作者：

Gorlova, Olga ^{[1
]}

Martin, Jose-Ezequiel ^{[2
]}

Rueda, Blanca ^{[2
]}

Koeleman, Bobby P. C. ^{[3
]}

Ying, Jun ^{[1
]}

Teruel, Maria ^{[2
]}

Diaz-Gallo, Lina-Marcela ^{[2
]}

Broen, Jasper C. ^{[4
]}

Vonk, Madelon C. ^{[4
]}

Simeon, Carmen P. ^{[5
]}

Alizadeh, Behrooz Z. ^{[6
]}

Coenen, Marieke J. H. ^{[7
]}

Voskuyl, Alexandre E. ^{[8
]}

Schuerwegh, Annemie J. ^{[9
]}

van Riel, Piet L. C. M. ^{[4
]}

Vanthuyne, Marie ^{[10
]}

van't Slot, Ruben ^{[3
]}

Italiaander, Annet ^{[3
]}

Ophoff, Roel A. ^{[3
]}

Hunzelmann, Nicolas ^{[11
]}

Fonollosa, Vicente ^{[5
]}

Ortego-Centeno, Norberto ^{[12
]}

Gonzalez-Gay, Miguel A. ^{[13
]}

Garcia-Hernandez, Francisco J. ^{[14
]}

Gonzalez-Escribano, Maria F. ^{[15
]}

Airo, Paolo ^{[16
,17
]}

van Laar, Jacob ^{[18
]}

Worthington, Jane ^{[19
]}

Hesselstrand, Roger ^{[20
]}

Smith, Vanessa ^{[21
]}

de Keyser, Filip ^{[21
]}

Houssiau, Fredric ^{[10
]}

Chee, Meng May ^{[22
]}

Madhok, Rajan ^{[22
]}

Shiels, Paul G. ^{[23
]}

Westhovens, Rene ^{[24
]}

Kreuter, Alexander ^{[25
]}

de Baere, Elfride ^{[26
]}

Witte, Torsten ^{[27
]}

Padyukov, Leonid ^{[28
]}

Nordin, Annika ^{[28
]}

Scorza, Raffaella ^{[29
,30
]}

Lunardi, Claudio ^{[31
]}

Lie, Benedicte A. ^{[32
]}

Hoffmann-Vold, Anna-Maria ^{[33
]}

Palm, Oyvind ^{[33
]}

Garcia de la Pena, Paloma ^{[34
]}

Carreira, Patricia ^{[35
]}

Varga, John ^{[36
]}

Hinchcliff, Monique ^{[36
]}

机构：

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

[2] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain

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

[4] Radboud Univ Nijmegen, Med Ctr, Dept Rheumatol, NL-6525 ED Nijmegen, Netherlands

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

[6] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9713 AV Groningen, Netherlands

[7] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[8] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands

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

[10] Catholic Univ Louvain, Clin Univ St Luc, B-1200 Brussels, Belgium

[11] Univ Cologne, Dept Dermatol, D-5000 Cologne, Germany

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

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

[14] Hosp Virgen del Rocio, Med Interna Serv, Seville, Spain

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

[16] Univ Brescia, Rheumatol Unit, Spedali Civili, Brescia, Italy

[17] Univ Brescia, Spedali Civili, Rheumatol Chair, Brescia, Italy

[18] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[19] Univ Manchester, Manchester Acad Hlth Sci Ctr, Dept Rheumatol & Epidemiol, Manchester, Lancs, England

[20] Lund Univ, Div Rheumatol, Dept Clin Sci, Lund, Sweden

[21] Univ Ghent, B-9000 Ghent, Belgium

[22] Glasgow Royal Infirm, Ctr Rheumat Dis, Glasgow G4 0SF, Lanark, Scotland

[23] Univ Glasgow, Western Infirm Glasgow, Dept Surg, Glasgow, Lanark, Scotland

[24] Katholieke Univ Leuven, Louvain, Belgium

[25] Ruhr Univ Bochum, Josefs Hosp, Dept Dermatol, Bochum, Germany

[26] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium

[27] Hannover Med Sch, D-3000 Hannover, Germany

[28] Karolinska Inst, Ctr Mol Med, Stockholm, Sweden

[29] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Referral Ctr Syst Autoimmune Dis, Milan, Italy

[30] Univ Milan, Milan, Italy

[31] Univ Verona, Dept Med, Policlin GB Rossi, I-37100 Verona, Italy

[32] Univ Oslo, Rikshosp, Oslo Univ Hosp, Inst Immunol, N-0027 Oslo, Norway

[33] Oslo Univ Hosp, Rikshosp, Dept Rheumatol, Oslo, Norway

[34] Hosp Ramon & Cajal, Serv Reumatol, E-28034 Madrid, Spain

[35] Hosp 12 Octubre, E-28041 Madrid, Spain

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

[37] Feinstein Inst Med Res, Manhasset, NY USA

[38] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA

[39] Johns Hopkins Univ, Med Ctr, Baltimore, MD 21218 USA

[40] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

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

[42] Royal Free & Univ Coll Sch, Ctr Rheumatol, London, England

来源：

PLOS GENETICS | 2011年 / 7卷 / 07期

关键词：

FUNCTIONAL POLYMORPHISM; RISK-FACTOR; SUSCEPTIBILITY; IRF5; REPLICATION; REGION; STAT4; MANIFESTATIONS; CLASSIFICATION; PATHWAYS;

D O I：

10.1371/journal.pgen.1002178

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (IcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

引用

页数：11

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