title: Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis.
abstract: OBJECTIVE
  To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found.
  
  
  METHODS
  Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry.
  
  
  RESULTS
  In multivariable analysis, low copy number of CNR1 (including FCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23), FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype of FCGR2B (OR 1.59; 95% CI: 1.13, 2.24), but not FCGR2C open reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcγRIIb on neutrophils and monocytes.
  
  
  CONCLUSIONS
  This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcγRII and FcγRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcγRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcγRs in the pathogenesis of SLE and LN.
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and immunology Center, VU University Medical Center, m.tsangasjoe@vumc.nl.
authors.forename: Michel W P
authors.initials: MW
authors.lastname: Tsang-A-Sjoe
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, University of Amsterdam.
authors.forename: Sietse Q
authors.initials: SQ
authors.lastname: Nagelkerke
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and immunology Center, VU University Medical Center.
authors.forename: Irene E M
authors.initials: IE
authors.lastname: Bultink
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, University of Amsterdam.
authors.forename: Judy
authors.initials: J
authors.lastname: Geissler
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center.
authors.forename: Michael W T
authors.initials: MW
authors.lastname: Tanck
authors.affiliation: Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carline E
authors.initials: CE
authors.lastname: Tacke
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Department of Paediatrics, University of Melbourne, VIC, Australia.
authors.forename: Justine A
authors.initials: JA
authors.lastname: Ellis
authors.affiliation: Department of General Paediatrics, Medical University of Graz, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Zenz
authors.affiliation: Department of Internal Medicine and Rheumatology, Martini Hospital, Groningen.
authors.forename: Marc
authors.initials: M
authors.lastname: Bijl
authors.affiliation: Division of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Berden
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen and.
authors.forename: Karina
authors.initials: K
authors.lastname: de Leeuw
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Derksen
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, University of Amsterdam, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and immunology Center, VU University Medical Center.
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008181:Lupus Nephritis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics*
chemical_list: C000609718:FCGR2C protein, human; D017452:Receptors, IgG
keywords: Caucasian; Fc-gamma receptor; FcγRIIb; FcγRIIc; gene polymorphisms; lupus nephritis; systemic lupus erythematosus