title: Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura.
abstract: Gene copy number variation (CNV) and single nucleotide polymorphisms (SNPs) count as important sources for interindividual differences, including differential responsiveness to infection or predisposition to autoimmune disease as a result of unbalanced immunity. By developing an FCGR-specific multiplex ligation-dependent probe amplification assay, we were able to study a notoriously complex and highly homologous region in the human genome and demonstrate extensive variation in the FCGR2 and FCGR3 gene clusters, including previously unrecognized CNV. As indicated by the prevalence of an open reading frame of FCGR2C, Fcgamma receptor (FcgammaR) type IIc is expressed in 18% of healthy individuals and is strongly associated with the hematological autoimmune disease idiopathic thrombocytopenic purpura (ITP) (present in 34.4% of ITP patients; OR 2.4 (1.3-4.5), P < .009). FcgammaRIIc acts as an activating IgG receptor that exerts antibody-mediated cellular cytotoxicity by immune cells. Therefore, we propose that the activating FCGR2C-ORF genotype predisposes to ITP by altering the balance of activating and inhibitory FcgammaR on immune cells.
authors.affiliation: Department of Pediatric Hematology, Immunology and Infectious Disease, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Willemijn B
authors.initials: WB
authors.lastname: Breunis
authors.forename: Edwin
authors.initials: E
authors.lastname: van Mirre
authors.forename: Marrie
authors.initials: M
authors.lastname: Bruin
authors.forename: Judy
authors.initials: J
authors.lastname: Geissler
authors.forename: Martin
authors.initials: M
authors.lastname: de Boer
authors.forename: Marjolein
authors.initials: M
authors.lastname: Peters
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
authors.forename: Masja
authors.initials: M
authors.lastname: de Haas
authors.forename: Harry R
authors.initials: HR
authors.lastname: Koene
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006262:Health; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D005810:Multigene Family / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000235:genetics* / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism*