title: Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis.
abstract: There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of ≤ 1 was a significant risk factor for SSc (OR=1.55 (1.13-2.14), P=0.007) relative to CN ≥ 2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: C
authors.initials: C
authors.lastname: McKinney
authors.forename: J C A
authors.initials: JC
authors.lastname: Broen
authors.forename: M C
authors.initials: MC
authors.lastname: Vonk
authors.forename: L
authors.initials: L
authors.lastname: Beretta
authors.forename: R
authors.initials: R
authors.lastname: Hesselstrand
authors.forename: N
authors.initials: N
authors.lastname: Hunzelmann
authors.forename: G
authors.initials: G
authors.lastname: Riemekasten
authors.forename: R
authors.initials: R
authors.lastname: Scorza
authors.forename: C P
authors.initials: CP
authors.lastname: Simeon
authors.forename: V
authors.initials: V
authors.lastname: Fonollosa
authors.forename: P E
authors.initials: PE
authors.lastname: Carreira
authors.forename: N
authors.initials: N
authors.lastname: Ortego-Centeno
authors.forename: M A
authors.initials: MA
authors.lastname: Gonzalez-Gay
authors.forename: P
authors.initials: P
authors.lastname: Airo
authors.forename: M
authors.initials: M
authors.lastname: Coenen
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.forename: T R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: T R
authors.initials: TR
authors.lastname: Merriman
mesh_terms: D001323:Autoantibodies / Q000097:blood; D001483:Base Sequence; D016022:Case-Control Studies; D002503:Centromere / Q000276:immunology; D056915:DNA Copy Number Variations; D015342:DNA Probes / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D005060:Europe; D058851:GPI-Linked Proteins / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage; D056726:Genetic Association Studies; D006801:Humans; D017452:Receptors, IgG / Q000235:genetics*; D012307:Risk Factors; D045743:Scleroderma, Diffuse / Q000235:genetics / Q000276:immunology; D045745:Scleroderma, Limited / Q000235:genetics / Q000276:immunology; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology*; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; D015342:DNA Probes; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG; D004264:DNA Topoisomerases, Type I