Understanding the genomic structure of copy number variants of the low-affinity Fcγ receptor region allows confirmation of the association of FCGR3B deletion with rheumatoid arthritis

Raheleh Rahbari, Luciana W Zuccherato, German Tischler, Belinda Chihota, Hasret Ozturk, Sara Saleem, Eduardo Tarazona-Santos, Lee Machado, Edward J Hollox

Research output: Contribution to JournalArticle

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 (IgG). In humans, five low affinity receptors are encoded by the genes FCGR2A, FCGR2B, FCGR2C, FCGR3A and FCGR3B, which are located in a 82.5kb segmental tandem duplication on chromosome 1q23.3, which shows extensive copy number variation. Deletions of FCGR3B have been suggested to increase the risk of inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we identify the deletion breakpoints of FCGR3B deletion alleles in the UK population and endogamous Native American populations, and show that some but not all alleles are likely to be identical-by-descent. We also localise a duplication breakpoint, confirming that the mechanism of CNV generation is non-allelic 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 aCGH data. Reanalysis of published aCGH data supports association of FCGR3B deletion with increased risk rheumatoid arthritis in a large cohort of 1982 cases and 3271 controls (Odds Ratio 1.61, p=2.9x10-3).
Original languageEnglish
Pages (from-to)390-399
Number of pages10
JournalHuman Mutation
Volume38
Issue number4
Early online date20 Dec 2016
DOIs
Publication statusE-pub ahead of print - 20 Dec 2016

Keywords

  • CNV
  • FCGR3B
  • Fcγ receptors
  • copy number variation
  • deletion
  • rheumatoid arthritis

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