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

Lookup NU author(s): Professor Jaap Van Laar


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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.

Publication metadata

Author(s): Martin JE, Broen JC, Carmona FD, Teruel M, Simeon CP, Vonk MC, van 't Slot R, Rodriguez-Rodriguez L, Vicente E, Fonollosa V, Ortego-Centeno N, Gonzalez-Gay MA, Garcia-Hernandez FJ, de la Pena PG, Carreira P, Voskuyl AE, Schuerwegh AJ, van Riel PLCM, Kreuter A, Witte T, Riemekasten G, Airo P, Scorza R, Lunardi C, Hunzelmann N, Distler JHW, Beretta L, van Laar J, Chee MM, Worthington J, Herrick A, Denton C, Tan FK, Arnett FC, Assassi S, Fonseca C, Mayes MD, Radstake TRDJ, Koeleman BPC, Martin J, Spanish Schleroderma Grp

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2012

Volume: 21

Issue: 12

Pages: 2825-2835

Print publication date: 09/03/2012

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/dds099


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Funder referenceFunder name
Fondo Europeo de Desarrollo Regional (FEDER)
GEN-FER from the Spanish Society of Rheumatology
Raynaud's and Scleroderma Association
Redes Tematicas de Investigacion Cooperativa Sanitaria Program
VIDI laureate from the Dutch Association of Research (NWO)
European League Against Rheumatism (EULAR)
Scleroderma Society
1P50AR054144NIH Center of Research Translation in Scleroderma
2008.40.001Dutch Diabetes Research Foundation
CTS-4977Junta de Andalucia (Spain)
N01-AR-0-2251NIH Scleroderma Family Registry and DNA Repository
PI-0590-2010Consejeria de Salud, Junta de Andalucia, Spain
NR 09-1-408Dutch Arthritis Foundation
RD08/0075Instituto de Salud Carlos III (ISCIII, Spain)
W81XWH-07-01-0111Department of Defense
WI 1031/6-1DFG
RO1- AR055258NIH
SAF2009-11110Spanish Ministry of Science