title: Evidence for both copy number and allelic (NA1/NA2) risk at the FCGR3B locus in systemic lupus erythematosus.
abstract: The Fcgamma-receptor locus on chromosome 1q23 shows copy-number variation (CNV), and it has previously been shown that individuals with reduced numbers of copies of the Fcgamma-receptor-IIIB gene (FCGR3B) have an increased risk of developing systemic lupus erythematosus (SLE). It is not understood whether the association arises from FCGR3B (CD16b) itself, is observed because of linkage disequilibrium with actual causal alleles and/or is an effect of CNV on flanking FCGR genes. Thus, we extended this previous work by genotyping the FCGR3B alleles NA1/NA2 and re-assaying CNV using a paralogue ratio test assay in a family study (365 families). We have developed a novel case/pseudo-control approach to analyse family data, as the phase of copy number (CN) is not known in parents and cannot always be inferred in offspring. The results, obtained by fitting logistic regression models, confirm the association of low CN of FCGR3B with SLE (P=0.04). The risk conferred by low copies (<2) was contingent on FCGR3B allotype, being greater for deletion of NA1 than the for lower-affinity NA2. The simpler model with just CN was rejected in favour of the biallelic-CN model (P=0.03). We observed a correlation (R(2)=0.75, P<0.0001) between FCGR3B CNV and neutrophil expression in both healthy controls and patients with SLE. Our results suggest that one mechanism by which CNV at this locus confers disease risk is directly as a result of reduced FcgammaRIIIb function, either because of reduced expression (related to CNV) or because of reduced affinity for its ligand (NA1/NA2 allotype).
authors.affiliation: Section of Rheumatology, Hammersmith Hospital, Imperial College London, London, UK.
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
authors.forename: Amy L
authors.initials: AL
authors.lastname: Roberts
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Witherden
authors.forename: Ruth
authors.initials: R
authors.lastname: Tarzi
authors.forename: Paula
authors.initials: P
authors.lastname: Barros
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.forename: Terence H
authors.initials: TH
authors.lastname: Cook
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
mesh_terms: D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D017452:Receptors, IgG / Q000235:genetics*; D012307:Risk Factors
chemical_list: D017931:DNA Primers; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG