title: C8orf13-BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: results from a large french cohort and meta-analysis.
abstract: OBJECTIVE
  Accumulating evidence suggests that B cells are involved in systemic sclerosis (SSc). BANK1 has been reproducibly reported to be associated with diffuse cutaneous SSc (dcSSc). BLK encodes another B cell signal transducer, and a functional variant at the C8orf13-BLK locus has been found to be associated with SSc in Caucasians. However, no independent replication has been reported, and there are discrepancies in the genotype-phenotype correlation between these studies in Caucasians and another study performed in the Japanese population. Therefore, in a large cohort of French Caucasians and using a meta-analysis of the available data, this study was undertaken to determine whether the C8orf13-BLK locus is associated with SSc, and to assess the possibility of interaction between BLK and BANK1 in SSc.
  
  
  METHODS
  The C8orf13-BLK rs13277113 genotype was determined in 1,031 patients with SSc and 1,014 control subjects for whom BANK1 genotypes were available. Meta-analysis of the 3 available data sets (6,078 individuals) was also performed.
  
  
  RESULTS
  Minor allele frequencies for rs13277113 revealed an association restricted to the dcSSc subtype (P = 0.012, odds ratio [OR] 1.29) in the French sample. Meta-analysis of the combined Caucasian populations showed an association of this genotype with both SSc (P = 0.0013, OR 1.16, 95% confidence interval [95% CI] 1.06-1.26) and dcSSc (P = 0.0012, OR 1.23, 95% CI 1.08-1.39). Inclusion of the Japanese population confirmed the overall association with the disease, with the strongest association observed with dcSSc (P = 3.27 × 10⁻⁵, OR 1.27). Secondary analysis in the French sample revealed additive effects between C8orf13-BLK and BANK1, mainly in the dcSSc subset.
  
  
  CONCLUSIONS
  These results confirm C8orf13-BLK as an SSc risk locus. The strongest effects, and particularly additive effects, were observed in the interaction between C8orf13-BLK and BANK1 in the dcSSc subset.
authors.affiliation: INSERM U1016, Université Paris Descartes, Paris, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Coustet
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.forename: Mickael
authors.initials: M
authors.lastname: Guedj
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bouaziz
authors.forename: Jerome
authors.initials: J
authors.lastname: Avouac
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruiz
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: Andre
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: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D016009:Chi-Square Distribution; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C447641:BANK1 protein, human; D008565:Membrane Proteins; D011505:Protein-Tyrosine Kinases