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

Jose-Ezequiel Martin*, Jasper C. Broen, F. David Carmona, Maria Teruel, Carmen P. Simeon, Madelon C. Vonk, Ruben van 't Slot, Luis Rodriguez-Rodriguez, Esther Vicente, Vicente Fonollosa, Norberto Ortego-Centeno, Miguel A. Gonzalez-Gay, Francisco J. Garcia-Hernandez, Paloma Garcia de la Pena, Patricia Carreira, Alexandre E. Voskuyl, Annemie J. Schuerwegh, Piet L. C. M. van Riel, Alexander Kreuter, Torsten WitteGabriella Riemekasten, Paolo Airo, Raffaella Scorza, Claudio Lunardi, Nicolas Hunzelmann, Joerg H. W. Distler, Lorenzo Beretta, Jacob van Laar, Meng May Chee, Jane Worthington, Ariane Herrick, Christopher Denton, Filemon K. Tan, Frank C. Arnett, Shervin Assassi, Carmen Fonseca, Maureen D. Mayes, Timothy R. D. J. Radstake, Bobby P. C. Koeleman, Javier Martin,

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)2825-2835
Number of pages11
JournalHuman Molecular Genetics
Issue number12
Publication statusPublished - 2012


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