Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

被引：77

作者：

Martin, Jose-Ezequiel ^{[1
]}

Broen, Jasper C. ^{[2
]}

David Carmona, F. ^{[1
]}

Teruel, Maria ^{[1
]}

Simeon, Carmen P. ^{[3
]}

Vonk, Madelon C. ^{[2
]}

van 't Slot, Ruben ^{[4
]}

Rodriguez-Rodriguez, Luis ^{[5
]}

Vicente, Esther ^{[6
]}

Fonollosa, Vicente ^{[3
]}

Ortego-Centeno, Norberto ^{[7
]}

Gonzalez-Gay, Miguel A. ^{[8
]}

Garcia-Hernandez, Francisco J. ^{[9
]}

Garcia de la Pena, Paloma ^{[10
]}

Carreira, Patricia ^{[11
]}

Voskuyl, Alexandre E. ^{[12
]}

Schuerwegh, Annemie J. ^{[13
]}

van Riel, Piet L. C. M. ^{[2
]}

Kreuter, Alexander ^{[14
]}

Witte, Torsten ^{[15
]}

Riemekasten, Gabriella ^{[16
]}

Airo, Paolo ^{[17
]}

Scorza, Raffaella ^{[18
]}

Lunardi, Claudio ^{[19
]}

Hunzelmann, Nicolas ^{[20
]}

Distler, Joerg H. W. ^{[21
]}

Beretta, Lorenzo ^{[18
]}

van Laar, Jacob ^{[22
]}

Chee, Meng May ^{[23
]}

Worthington, Jane ^{[24
]}

Herrick, Ariane ^{[24
]}

Denton, Christopher ^{[25
]}

Tan, Filemon K. ^{[26
]}

Arnett, Frank C. ^{[26
]}

Assassi, Shervin ^{[26
]}

Fonseca, Carmen ^{[25
]}

Mayes, Maureen D. ^{[26
]}

Radstake, Timothy R. D. J. ^{[2
]}

Koeleman, Bobby P. C. ^{[4
]}

Martin, Javier ^{[1
]}

机构：

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

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

[3] Hosp Valle De Hebron, Med Interna Serv, Barcelona, Spain

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

[5] Hosp Clin San Carlos, Serv Reumatol, Madrid, Spain

[6] Hosp La Princesa, Serv Reumatol, Madrid, Spain

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

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

[9] Hosp Virgen Rocio, Med Interna Serv, Seville, Spain

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

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

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

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

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

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

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

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

[18] Fdn IRCCS CaGranda Osped MaRepiore Policlin & Uni, Referral Ctr Syst Autoimmune Dis, Milan, Italy

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

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

[21] Univ Erlangen Nurnberg, Inst Clin Immunol, Dept Internal Med 3, D-91054 Erlangen, Germany

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

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

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

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

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

来源：

HUMAN MOLECULAR GENETICS | 2012年 / 21卷 / 12期

关键词：

FUNCTIONAL POLYMORPHISM; KAPPA-B; SUSCEPTIBILITY; IRF5; DISEASE; PATHOGENESIS; MECHANISMS; VARIANTS; KINASES; REGION;

D O I：

10.1093/hmg/dds099

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value 5.04 10(12), odds ratio (OR) 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value 3.18 10(7), OR 1.36) and NFKB1 (P-value 1.03 10(6), OR 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.

引用

页码：2825 / 2835

页数：11

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