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 Witte; Gabriella 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

doi:10.1093/hmg/dds099

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 journal › Article › Academic › peer-review

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 5.04 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 language	English
Pages (from-to)	2825-2835
Number of pages	11
Journal	Human Molecular Genetics
Volume	21
Issue number	12
DOIs	https://doi.org/10.1093/hmg/dds099
Publication status	Published - 2012

Keywords

LUPUS-ERYTHEMATOSUS
FUNCTIONAL POLYMORPHISM
INFLAMMATORY DISEASES
KAPPA-B
SUSCEPTIBILITY
IRF5
SCLERODERMA
POPULATION
PATHOGENESIS
MECHANISMS

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10.1093/hmg/dds099

http://www.ncbi.nlm.nih.gov/pubmed?term=22407130

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Martin, J.-E., Broen, J. C., David Carmona, F., Teruel, M., Simeon, C. P., Vonk, M. C., van 't Slot, R., Rodriguez-Rodriguez, L., Vicente, E., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M. A., Garcia-Hernandez, F. J., Garcia de la Pena, P., Carreira, P., Voskuyl, A. E., Schuerwegh, A. J., van Riel, P. L. C. M., Kreuter, A. (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. https://doi.org/10.1093/hmg/dds099

@article{581cbdc57bfb4298966d926f2d150709,

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

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 5.04 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.",

keywords = "LUPUS-ERYTHEMATOSUS, FUNCTIONAL POLYMORPHISM, INFLAMMATORY DISEASES, KAPPA-B, SUSCEPTIBILITY, IRF5, SCLERODERMA, POPULATION, PATHOGENESIS, MECHANISMS",

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

year = "2012",

doi = "10.1093/hmg/dds099",

language = "English",

volume = "21",

pages = "2825--2835",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "12",

}

Martin, J-E, Broen, JC, David Carmona, F, 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, Garcia de la Pena, P, 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 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, pp. 2825-2835. https://doi.org/10.1093/hmg/dds099

TY - JOUR

T1 - Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

AU - Martin, Jose-Ezequiel

AU - Broen, Jasper C.

AU - David Carmona, F.

AU - Teruel, Maria

AU - Simeon, Carmen P.

AU - Vonk, Madelon C.

AU - van 't Slot, Ruben

AU - Rodriguez-Rodriguez, Luis

AU - Vicente, Esther

AU - Fonollosa, Vicente

AU - Ortego-Centeno, Norberto

AU - Gonzalez-Gay, Miguel A.

AU - Garcia-Hernandez, Francisco J.

AU - Garcia de la Pena, Paloma

AU - Carreira, Patricia

AU - Voskuyl, Alexandre E.

AU - Schuerwegh, Annemie J.

AU - van Riel, 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, Joerg 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

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - LUPUS-ERYTHEMATOSUS

KW - FUNCTIONAL POLYMORPHISM

KW - INFLAMMATORY DISEASES

KW - KAPPA-B

KW - SUSCEPTIBILITY

KW - IRF5

KW - SCLERODERMA

KW - POPULATION

KW - PATHOGENESIS

KW - MECHANISMS

U2 - 10.1093/hmg/dds099

DO - 10.1093/hmg/dds099

M3 - Article

C2 - 22407130

SN - 0964-6906

VL - 21

SP - 2825

EP - 2835

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 12

ER -

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

Abstract

Keywords

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