title: Understanding the Genomic Structure of Copy-Number Variation of the Low-Affinity Fcγ Receptor Region Allows Confirmation of the Association of FCGR3B Deletion with Rheumatoid Arthritis.
abstract: Fcγ receptors are a family of cell-surface receptors that are expressed by a host of different innate and adaptive immune cells, and mediate inflammatory responses by binding the Fc portion of immunoglobulin G. In humans, five low-affinity receptors are encoded by the genes FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B, which are located in an 82.5-kb segmental tandem duplication on chromosome 1q23.3, which shows extensive copy-number variation (CNV). Deletions of FCGR3B have been suggested to increase the risk of inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis (RA). In this study, we identify the deletion breakpoints of FCGR3B deletion alleles in the UK population and endogamous native American population, and show that some but not all alleles are likely to be identical-by-descent. We also localize a duplication breakpoint, confirming that the mechanism of CNV generation is nonallelic homologous recombination, and identify several alleles with gene conversion events using fosmid sequencing data. We use information on the structure of the deletion alleles to distinguish FCGR3B deletions from FCGR3A deletions in whole-genome array comparative genomic hybridization (aCGH) data. Reanalysis of published aCGH data using this approach supports association of FCGR3B deletion with increased risk of RA in a large cohort of 1,982 cases and 3,271 controls (odds ratio 1.61, P = 2.9×10-3).
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.|Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Raheleh
authors.initials: R
authors.lastname: Rahbari
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.|Departmento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Luciana W
authors.initials: LW
authors.lastname: Zuccherato
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: German
authors.initials: G
authors.lastname: Tischler
authors.affiliation: School of Health, University of Northampton, Northampton, United Kingdom.
authors.forename: Belinda
authors.initials: B
authors.lastname: Chihota
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Hasret
authors.initials: H
authors.lastname: Ozturk
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Saleem
authors.affiliation: Departmento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tarazona-Santos
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.|School of Health, University of Northampton, Northampton, United Kingdom.
authors.forename: Lee R
authors.initials: LR
authors.lastname: Machado
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hollox
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization / Q000379:methods; D056915:DNA Copy Number Variations; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D059765:Homologous Recombination; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D017384:Sequence Deletion
chemical_list: C496124:FCGR3A protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG
keywords: CNV; FCGR3B; Fcγ receptors; copy-number variation; deletion; rheumatoid arthritis