• J Rheumatol · May 2012

    Meta Analysis

    Independent replication and meta analysis of association studies establish TNFSF4 as a susceptibility gene preferentially associated with the subset of anticentromere-positive patients with systemic sclerosis.

    • Baptiste Coustet, Matthieu Bouaziz, Philippe Dieudé, Mickael Guedj, Lara Bossini-Castillo, Sandeep Agarwal, Timothy Radstake, Javier Martin, Pravitt Gourh, Muriel Elhai, Eugénie Koumakis, Jérôme Avouac, Barbara Ruiz, Maureen Mayes, Frank Arnett, Eric Hachulla, Elisabeth Diot, Jean-Luc Cracowski, Kiet Tiev, Jean Sibilia, Luc Mouthon, Camille Frances, Zahir Amoura, Patrick Carpentier, Anne Cosnes, Olivier Meyer, André Kahan, Catherine Boileau, Gilles Chiocchia, and Yannick Allanore.
    • Université Paris Descartes, Rhumatologie A, INSERM U1016, Hôpital Cochin, APHP, Paris, France.
    • J Rheumatol. 2012 May 1; 39 (5): 997-1003.

    ObjectiveIndependent 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.MethodsKnown 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 meta analysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry.ResultsAllelic 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)].ConclusionWe confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype.

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