title: Systematic candidate gene investigations in the SPA2 locus (9q32) show an association between TNFSF8 and susceptibility to spondylarthritis.
abstract: OBJECTIVE
  Our group previously identified a new susceptibility region linked to spondylarthritis (SpA) on chromosome 9q31-34. Fine mapping of this SPA2 locus allowed us to refine the peak of linkage to a 1.3-Mb interval. The objective of this study was to resequence most positional candidate genes lying in that region, to identify polymorphisms, and to examine their association with SpA.
  
  
  METHODS
  Variants screening was performed in 30 independent patients with SpA from families with a high linkage score to the SPA2 locus and 30 control subjects. The coding regions, intron-exon boundaries, and 5'- and 3'-flanking regions of ZNF618, A1L4R1_HUMAN (AF495724), AMBP, KIF12, ORM1, ORM2, C9ORF91, ENSESTG000000230601, and TNFSF8 were resequenced to identify polymorphisms. Selected variants were genotyped in an extended French cohort (442 patients and 268 control subjects overall). Replication was performed in a combined Belgian and Portuguese cohort (433 patients and 299 control subjects).
  
  
  RESULTS
  Variants screening allowed us to identify 98 polymorphisms, 5 of which were selected for further studies, based on statistical significance. The rare intronic single-nucleotide polymorphism (SNP) rs3181357, located in TNFSF8, was significantly associated with SpA in the French and the replication cohorts (odds ratio [OR] 2.03, P = 0.009 and OR 2.26, P = 0.0014, respectively) and in the pooled analysis (OR 2.14, P = 0.0001).
  
  
  CONCLUSIONS
  Positional candidate gene screening in the SPA2 locus allowed us to identify and replicate an association between a rare SNP located in TNFSF8 and SpA. This new finding appears to be independent of an association with a haplotype near TNFSF15, which we recently reported.
authors.affiliation: Institut Cochin, Paris Descartes University, CNRS (UMR 8104), Paris, France.
authors.forename: Elena
authors.initials: E
authors.lastname: Zinovieva
authors.forename: Amir
authors.initials: A
authors.lastname: Kadi
authors.forename: Franck
authors.initials: F
authors.lastname: Letourneur
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Brigitte
authors.initials: B
authors.lastname: Izac
authors.forename: Agathe
authors.initials: A
authors.lastname: Vigier
authors.forename: Roula
authors.initials: R
authors.lastname: Said-Nahal
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.forename: Kurt
authors.initials: K
authors.lastname: de Vlam
authors.forename: Fernando
authors.initials: F
authors.lastname: Pimentel-Santos
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
authors.forename: Maxime
authors.initials: M
authors.lastname: Breban
mesh_terms: D000328:Adult; D000483:Alleles; D053285:CD30 Ligand / Q000235:genetics*; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D025241:Spondylarthritis / Q000235:genetics*
chemical_list: D053285:CD30 Ligand; C505774:TNFSF8 protein, human