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.
authors.affiliation: Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain. cebercoto@ipb.csic.es
authors.forename: Jose-Ezequiel
authors.initials: JE
authors.lastname: Martin
authors.forename: Jasper C
authors.initials: JC
authors.lastname: Broen
authors.forename: F David
authors.initials: FD
authors.lastname: Carmona
authors.forename: Maria
authors.initials: M
authors.lastname: Teruel
authors.forename: Carmen P
authors.initials: CP
authors.lastname: Simeon
authors.forename: Madelon C
authors.initials: MC
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authors.forename: Ruben
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authors.lastname: van 't Slot
authors.forename: Luis
authors.initials: L
authors.lastname: Rodriguez-Rodriguez
authors.forename: Esther
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authors.lastname: Vicente
authors.forename: Vicente
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authors.lastname: Fonollosa
authors.forename: Norberto
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authors.lastname: Ortego-Centeno
authors.forename: Miguel A
authors.initials: MA
authors.lastname: González-Gay
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: García-Hernández
authors.forename: Paloma García
authors.initials: PG
authors.lastname: de la Peña
authors.forename: Patricia
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authors.lastname: Carreira
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
authors.forename: Annemie J
authors.initials: AJ
authors.lastname: Schuerwegh
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
authors.forename: Alexander
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authors.lastname: Kreuter
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.forename: Gabriella
authors.initials: G
authors.lastname: Riemekasten
authors.forename: Paolo
authors.initials: P
authors.lastname: Airo
authors.forename: Raffaella
authors.initials: R
authors.lastname: Scorza
authors.forename: Claudio
authors.initials: C
authors.lastname: Lunardi
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hunzelmann
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Beretta
authors.forename: Jacob
authors.initials: J
authors.lastname: van Laar
authors.forename: Meng May
authors.initials: MM
authors.lastname: Chee
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Ariane
authors.initials: A
authors.lastname: Herrick
authors.forename: Christopher
authors.initials: C
authors.lastname: Denton
authors.forename: Filemon K
authors.initials: FK
authors.lastname: Tan
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.forename: Carmen
authors.initials: C
authors.lastname: Fonseca
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D015331:Cohort Studies; D005060:Europe; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D015201:Meta-Analysis as Topic; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000235:genetics*; D028961:beta Karyopherins / Q000235:genetics; D019061:src-Family Kinases; D000099185:Interferon Regulatory Factor-8
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D050835:Interferon Regulatory Factors; D052002:NF-kappa B p50 Subunit; D011505:Protein-Tyrosine Kinases; D028961:beta Karyopherins; D019061:src-Family Kinases; D000099185:Interferon Regulatory Factor-8; C431713:IRF5 protein, human; C489548:NFKB1 protein, human; C546476:TNPO3 protein, human; C000631346:CSK protein, human