title: 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.
abstract: 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 meta analysis 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)].
  
  
  CONCLUSIONS
  We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype.
authors.affiliation: Université Paris Descartes, Rhumatologie A, INSERM U1016, Hôpital Cochin, APHP, Paris, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Coustet
authors.forename: Matthieu
authors.initials: M
authors.lastname: Bouaziz
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.forename: Mickael
authors.initials: M
authors.lastname: Guedj
authors.forename: Lara
authors.initials: L
authors.lastname: Bossini-Castillo
authors.forename: Sandeep
authors.initials: S
authors.lastname: Agarwal
authors.forename: Timothy
authors.initials: T
authors.lastname: Radstake
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Pravitt
authors.initials: P
authors.lastname: Gourh
authors.forename: Muriel
authors.initials: M
authors.lastname: Elhai
authors.forename: Eugénie
authors.initials: E
authors.lastname: Koumakis
authors.forename: Jérôme
authors.initials: J
authors.lastname: Avouac
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruiz
authors.forename: Maureen
authors.initials: M
authors.lastname: Mayes
authors.forename: Frank
authors.initials: F
authors.lastname: Arnett
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Diot
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Cracowski
authors.forename: Kiet
authors.initials: K
authors.lastname: Tiev
authors.forename: Jean
authors.initials: J
authors.lastname: Sibilia
authors.forename: Luc
authors.initials: L
authors.lastname: Mouthon
authors.forename: Camille
authors.initials: C
authors.lastname: Frances
authors.forename: Zahir
authors.initials: Z
authors.lastname: Amoura
authors.forename: Patrick
authors.initials: P
authors.lastname: Carpentier
authors.forename: Anne
authors.initials: A
authors.lastname: Cosnes
authors.forename: Olivier
authors.initials: O
authors.lastname: Meyer
authors.forename: André
authors.initials: A
authors.lastname: Kahan
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
mesh_terms: D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics*; D002503:Centromere / Q000235:genetics / Q000276:immunology; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D053278:OX40 Ligand / Q000235:genetics* / Q000276:immunology; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D044465:White People / Q000235:genetics
chemical_list: D053278:OX40 Ligand; C089251:TNFSF4 protein, human