PT - JOURNAL ARTICLE AU - Baptiste Coustet AU - Matthieu Bouaziz AU - Philippe Dieudé AU - Mickael Guedj AU - Lara Bossini-Castillo AU - Sandeep Agarwal AU - Timothy Radstake AU - Javier Martin AU - Pravitt Gourh AU - Muriel Elhai AU - Eugénie Koumakis AU - Jérôme Avouac AU - Barbara Ruiz AU - Maureen Mayes AU - Frank Arnett AU - Eric Hachulla AU - Elisabeth Diot AU - Jean-Luc Cracowski AU - Kiet Tiev AU - Jean Sibilia AU - Luc Mouthon AU - Camille Frances AU - Zahir Amoura AU - Patrick Carpentier AU - Anne Cosnes AU - Olivier Meyer AU - André Kahan AU - Catherine Boileau AU - Gilles Chiocchia AU - Yannick Allanore TI - 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 AID - 10.3899/jrheum.111270 DP - 2012 Mar 15 TA - The Journal of Rheumatology PG - jrheum.111270 4099 - http://www.jrheum.org/content/early/2012/03/10/jrheum.111270.short 4100 - http://www.jrheum.org/content/early/2012/03/10/jrheum.111270.full AB - 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 intracohort 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.