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. Chem otkritj fajl sii. 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).

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Introduction 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) [Nimmerjahn and Ravetch, ]. They can be divided into low‐ and high‐affinity receptors, based on their affinity for IgG. Low‐affinity receptors are unable to bind monomeric IgG and instead bind to polymeric IgG in the form of antigen–antibody immune complexes. IgG binding can either activate or inhibit downstream cellular responses depending on the particular ITAM or ITIM containing Fcγ receptor that is engaged. Dysregulation of Fcγ receptors is important in a number of different inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Kawasaki disease [Niederer et al.,; McKinney and Merriman,; Hargreaves et al., ].

Furthermore, not only are Fcγ receptors critical for disease etiology but also for successful immunotherapy of patients with hematological and solid cancers by mediating the effector functions of therapeutic monoclonal antibodies [Dahal et al., ]. In humans, there are five low‐affinity receptors FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb encoded by the genes FCGR2A (MIM# 146790), FCGR2B (MIM# 604590), FCGR2C (MIM# 612169), FCGR3A (MIM# 146740), and FCGR3B (MIM# 610665).

All five genes are encoded within or surrounding an 82.5‐kb tandemly arranged segmental duplication on chromosome 1q23.3 (Fig. There is substantial single‐nucleotide variation within and between the duplicated paralogs, and extensive copy‐number variation involving FCGR3A, FCGR3B, and FCGR2C [Aitman et al.,; Hollox et al.,; Machado et al.,; Mueller et al., ]. The extent of variation has made dissecting the genomic structure of this region particularly challenging. It is now generally accepted that copy‐number variation is a result of more or fewer copies of the full 82.5 kb segmental duplication, resulting in the deletion or duplication of FCGR3A and FCGR2C together, or FCGR3B and FCGR2C together, but not FCGR2A or FCGR2B, which fall outside the CNV region [Breunis et al.,; Hollox et al.,; Mueller et al., ]. The mechanism generating FCGR deletions and duplications has been shown to be mediated by nonallelic homologous recombination (NAHR) between the two segmental duplications with the location of the breakpoint determining whether FCGR3A or FCGR3B genes are deleted, and whether fusion FCGR2A/C genes are generated [Machado et al.,; Nagelkerke et al., ]. The breakpoints of several deletion alleles have been determined and, although resolution to the exact nucleotide is not possible, breakpoints cluster at two points: breakpoint A [Machado et al., ], generating CNR3 [Nagelkerke et al., ]; and breakpoint B, generating CNR1. Rarer breakpoints, termed CNR2 and CNR4, have also been observed, and generate FCGR2B pseudogenes and FCGR2C/A fusion genes [Machado et al.,; Nagelkerke et al., ].