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 Witte; Gabriella 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

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. 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

^*Corresponding author for this work

Clinic of Rheumatology

68 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 language	English
Article number	dds099
Journal	Human Molecular Genetics
Volume	21
Issue number	12
Pages (from-to)	2825-2835
Number of pages	11
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/dds099
Publication status	Published - 06.2012

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/hmg/dds099

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Martin, J. E., Broen, J. C., David Carmona, F., Teruel, M., Simeon, C. P., Vonk, M. C., Slot, R. V. T., Rodriguez-Rodriguez, L., Vicente, E., Fonollosa, V., Ortego-Centeno, N., González-Gay, M. A., García-Hernández, F. J., de la Peña, P. G., Carreira, P., Voskuyl, A. E., Schuerwegh, A. J., van Rie, P. L. C. M., Kreuter, A., ... 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. Article dds099. https://doi.org/10.1093/hmg/dds099

@article{3625883775714805acd6b46d5aa2dc5b,

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 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.",

author = "Martin, {Jose Ezequiel} and Broen, {Jasper C.} and {David Carmona}, F. and Maria Teruel and Simeon, {Carmen P.} and Vonk, {Madelon C.} and Slot, {Ruben van t.} and Luis Rodriguez-Rodriguez and Esther Vicente and Vicente Fonollosa and Norberto Ortego-Centeno and Gonz{\'a}lez-Gay, {Miguel A.} and Garc{\'i}a-Hern{\'a}ndez, {Francisco J.} and {de la Pe{\~n}a}, {Paloma Garc{\'i}a} and Patricia Carreira and Voskuyl, {Alexandre E.} and Schuerwegh, {Annemie J.} and {van Rie}, {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, {J{\"o}rg 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",

month = jun,

doi = "10.1093/hmg/dds099",

language = "English",

volume = "21",

pages = "2825--2835",

journal = "Human Molecular Genetics",

issn = "0964-6906",

number = "12",

}

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

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 - 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

PY - 2012/6

Y1 - 2012/6

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 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.

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 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.

UR - http://www.scopus.com/inward/record.url?scp=84861727232&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds099

DO - 10.1093/hmg/dds099

M3 - Journal articles

C2 - 22407130

AN - SCOPUS:84861727232

SN - 0964-6906

VL - 21

SP - 2825

EP - 2835

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 12

M1 - dds099

ER -

Identification of CSK as a systemic sclerosis genetic risk factor through genome wide association study follow-up

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