Independent Replication and Metaanalysis of Association Studies Establish TNFSF4 as a Susceptibility Gene Preferentially Associated with the Subset of Anticentromere-positive Patients with Systemic Sclerosis - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Journal of Rheumatology Année : 2012

Independent Replication and Metaanalysis of Association Studies Establish TNFSF4 as a Susceptibility Gene Preferentially Associated with the Subset of Anticentromere-positive Patients with Systemic Sclerosis

Baptiste Coustet
  • Fonction : Auteur
Mickael Guedj
  • Fonction : Auteur
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Muriel Elhai
  • Fonction : Auteur
Eugenie Koumakis
  • Fonction : Auteur
Jerome Avouac
  • Fonction : Auteur
Barbara Ruiz
  • Fonction : Auteur
Luc Mouthon
  • Fonction : Auteur
Camille Frances
  • Fonction : Auteur
Olivier Meyer
  • Fonction : Auteur
André Kahan
  • Fonction : Auteur
Gilles Chiocchia
  • Fonction : Auteur

Résumé

Objective. Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk. Methods. Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and metaanalysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry. Results. Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12-1.66)], with significant intra-cohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15-1.54) and TT genotype p = 0.00046; OR 2.02 (1.36-2.98)]. Conclusion. We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype. (First Release March 15 2012; J Rheumatol 2012;39:997-1003; doi:10.3899/jrheum.111270)

Dates et versions

hal-02652557 , version 1 (29-05-2020)

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Baptiste Coustet, Matthieu Bouaziz, Philippe Dieudé, Mickael Guedj, Lara Bossini-Castillo, et al.. Independent Replication and Metaanalysis of Association Studies Establish TNFSF4 as a Susceptibility Gene Preferentially Associated with the Subset of Anticentromere-positive Patients with Systemic Sclerosis. Journal of Rheumatology, 2012, 39 (5), pp.997 - 1003. ⟨10.3899/jrheum.111270⟩. ⟨hal-02652557⟩
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