title: Evidence for caveolin-1 as a new susceptibility gene regulating tissue fibrosis in systemic sclerosis.
abstract: OBJECTIVE
  Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis and has been implicated in the pathogenesis of systemic sclerosis (SSc). The aim of the study was to analyse the possible association of CAV1 gene single nucleotide polymorphisms (SNP) with SSc.
  
  
  METHODS
  A total population of 3974 individuals (1355 SSc patients, 2619 controls) was studied. Genotype data for 23 SNP spanning the CAV1-CAV2 gene locus were obtained from a genome-wide scan conducted in a French population (564 SSc patients, 1776 controls). Three CAV1 SNP (rs926198, rs959173, rs9920) displaying the most significant associations with SSc and/or clinical phenotypes were then genotyped in an Italian population (791 SSc patients, 843 controls). CAV1 protein expression in skin biopsies was investigated by immunohistochemistry and western blotting.
  
  
  RESULTS
  In the French population, the CAV1 rs959173 C minor allele showed a significant protective association with susceptibility to SSc (OR 0.71, 95% CI 0.59 to 0.86, p(adjusted)=0.009), and with the subset of patients with limited cutaneous SSc (OR 0.71, 95% CI 0.56 to 0.89, p(adjusted)=0.018). The association was replicated in the Italian population and strengthened in the combined populations through Cochran-Mantel-Haenszel meta-analysis (SSc: pooled OR 0.81, 95% CI 0.71 to 0.92, p=0.0018; limited cutaneous SSc: pooled OR 0.80, 95% CI 0.69 to 0.93, p=0.0053). Genotype/protein expression correlations revealed that the rs959173 C protective allele was associated with increased CAV1 protein expression.
  
  
  CONCLUSIONS
  These results add CAV1 to the list of SSc susceptibility genes and provide further evidence for the contribution of this pathway in the fibrotic process that characterises SSc pathogenesis.
authors.affiliation: Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy. mirkomanetti@yahoo.it
authors.forename: Mirko
authors.initials: M
authors.lastname: Manetti
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.forename: Mohamad
authors.initials: M
authors.lastname: Saad
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fatini
authors.forename: Vanessa
authors.initials: V
authors.lastname: Cohignac
authors.forename: Serena
authors.initials: S
authors.lastname: Guiducci
authors.forename: Eloisa
authors.initials: E
authors.lastname: Romano
authors.forename: Paolo
authors.initials: P
authors.lastname: Airó
authors.forename: Paola
authors.initials: P
authors.lastname: Caramaschi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Tinazzi
authors.forename: Valeria
authors.initials: V
authors.lastname: Riccieri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Della Rossa
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
authors.forename: Roberto
authors.initials: R
authors.lastname: Caporali
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cuomo
authors.forename: Guido
authors.initials: G
authors.lastname: Valesini
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Cracowski
authors.forename: Kiet
authors.initials: K
authors.lastname: Tiev
authors.forename: Luc
authors.initials: L
authors.lastname: Letenneur
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez
authors.forename: Lidia
authors.initials: L
authors.lastname: Ibba-Manneschi
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci-Cerinic
mesh_terms: D000328:Adult; D000368:Aged; D051242:Caveolin 1 / Q000235:genetics*; D051243:Caveolin 2 / Q000235:genetics; D002874:Chromosome Mapping; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000473:pathology*; D012867:Skin / Q000473:pathology; D044465:White People / Q000235:genetics
chemical_list: C495540:CAV1 protein, human; C495544:CAV2 protein, human; D051242:Caveolin 1; D051243:Caveolin 2