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. González-Gay, Francisco J. García-Hernández, Paloma García de la Peña, Patricia Carreira, Alexandre E. Voskuyl, Annemie J. Schuerwegh, Piet L C M van Rie, Alexander Kreuter, Torsten WitteGabriella Riemekasten, Paolo Airo, Raffaella Scorza, Claudio Lunardi, Nicolas Hunzelmann, Jörg 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

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

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 5.04 3 10-12, odds ratio (OR) 5 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value 5 3.18 3 10-7, OR 5 1.36) and NFKB1 (P-value 5 1.03 3 10-6, OR5 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
Article numberdds099
Pages (from-to)2825-2835
Number of pages11
JournalHuman Molecular Genetics
Volume21
Issue number12
DOIs
Publication statusPublished - Jun 2012

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Systemic Scleroderma
Genome-Wide Association Study
Single Nucleotide Polymorphism
Odds Ratio
Genetic Loci
Connective Tissue
Autoimmune Diseases
Meta-Analysis
Genome
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Martin, J. E., Broen, J. C., David Carmona, F., Teruel, M., Simeon, C. P., Vonk, M. C., ... Martin, J. (2012). Identification of CSK as a systemic sclerosis genetic risk factor through genome wide association study follow-up. Human Molecular Genetics, 21(12), 2825-2835. [dds099]. https://doi.org/10.1093/hmg/dds099

Identification of CSK as a systemic sclerosis genetic risk factor through genome wide association study follow-up. / Martin, Jose Ezequiel; Broen, Jasper C.; David Carmona, F.; Teruel, Maria; Simeon, Carmen P.; Vonk, Madelon C.; Slot, Ruben van t; Rodriguez-Rodriguez, Luis; Vicente, Esther; Fonollosa, Vicente; Ortego-Centeno, Norberto; González-Gay, Miguel A.; García-Hernández, Francisco J.; de la Peña, Paloma García; Carreira, Patricia; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; van Rie, Piet L C M; Kreuter, Alexander; Witte, Torsten; Riemekasten, Gabriella; Airo, Paolo; Scorza, Raffaella; Lunardi, Claudio; Hunzelmann, Nicolas; Distler, Jörg H W; Beretta, Lorenzo; van Laar, Jacob; Chee, Meng May; Worthington, Jane; Herrick, Ariane; Denton, Christopher; Tan, Filemon K.; Arnett, Frank C.; Assassi, Shervin; Fonseca, Carmen; Mayes, Maureen D.; Radstake, Timothy R D J; Koeleman, Bobby P C; Martin, Javier.

In: Human Molecular Genetics, Vol. 21, No. 12, dds099, 06.2012, p. 2825-2835.

Research output: Contribution to journalArticle

Martin, JE, Broen, JC, David Carmona, F, Teruel, M, Simeon, CP, Vonk, MC, Slot, RVT, Rodriguez-Rodriguez, L, Vicente, E, Fonollosa, V, Ortego-Centeno, N, González-Gay, MA, García-Hernández, FJ, de la Peña, PG, Carreira, P, Voskuyl, AE, Schuerwegh, AJ, van Rie, 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 2012, 'Identification of CSK as a systemic sclerosis genetic risk factor through genome wide association study follow-up', Human Molecular Genetics, vol. 21, no. 12, dds099, pp. 2825-2835. https://doi.org/10.1093/hmg/dds099
Martin, Jose Ezequiel ; Broen, Jasper C. ; David Carmona, F. ; Teruel, Maria ; Simeon, Carmen P. ; Vonk, Madelon C. ; Slot, Ruben van t ; Rodriguez-Rodriguez, Luis ; Vicente, Esther ; Fonollosa, Vicente ; Ortego-Centeno, Norberto ; González-Gay, Miguel A. ; García-Hernández, Francisco J. ; de la Peña, Paloma García ; Carreira, Patricia ; Voskuyl, Alexandre E. ; Schuerwegh, Annemie J. ; van Rie, Piet L C M ; Kreuter, Alexander ; Witte, Torsten ; Riemekasten, Gabriella ; Airo, Paolo ; Scorza, Raffaella ; Lunardi, Claudio ; Hunzelmann, Nicolas ; Distler, Jörg H W ; Beretta, Lorenzo ; van Laar, Jacob ; Chee, Meng May ; Worthington, Jane ; Herrick, Ariane ; Denton, Christopher ; Tan, Filemon K. ; Arnett, Frank C. ; Assassi, Shervin ; Fonseca, Carmen ; Mayes, Maureen D. ; Radstake, Timothy R D J ; Koeleman, Bobby P C ; Martin, Javier. / Identification of CSK as a systemic sclerosis genetic risk factor through genome wide association study follow-up. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 12. pp. 2825-2835.
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abstract = "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 5.04 3 10-12, odds ratio (OR) 5 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value 5 3.18 3 10-7, OR 5 1.36) and NFKB1 (P-value 5 1.03 3 10-6, OR5 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.",
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AU - Martin, Jose Ezequiel

AU - Broen, Jasper C.

AU - David Carmona, F.

AU - Teruel, Maria

AU - Simeon, Carmen P.

AU - Vonk, Madelon C.

AU - Slot, Ruben van t

AU - Rodriguez-Rodriguez, Luis

AU - Vicente, Esther

AU - Fonollosa, Vicente

AU - Ortego-Centeno, Norberto

AU - González-Gay, Miguel A.

AU - García-Hernández, Francisco J.

AU - de la Peña, Paloma García

AU - Carreira, Patricia

AU - Voskuyl, Alexandre E.

AU - Schuerwegh, Annemie J.

AU - van Rie, Piet L C M

AU - Kreuter, Alexander

AU - Witte, Torsten

AU - Riemekasten, Gabriella

AU - Airo, Paolo

AU - Scorza, Raffaella

AU - Lunardi, Claudio

AU - Hunzelmann, Nicolas

AU - Distler, Jörg H W

AU - Beretta, Lorenzo

AU - van Laar, Jacob

AU - Chee, Meng May

AU - Worthington, Jane

AU - Herrick, Ariane

AU - Denton, Christopher

AU - Tan, Filemon K.

AU - Arnett, Frank C.

AU - Assassi, Shervin

AU - Fonseca, Carmen

AU - Mayes, Maureen D.

AU - Radstake, Timothy R D J

AU - Koeleman, Bobby P C

AU - Martin, Javier

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