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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.

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posted on 27.03.2017, 10:41 by Raheleh Rahbari, Luciana W. Zuccherato, German Tischler, Belinda Chihota, Hasret Ozturk, Sara Saleem, Eduardo Tarazona-Santos, Lee R. Machado, Edward J. Hollox
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) ).

Funding

Wellcome Trust. Grant Number: 087663

History

Citation

Human Mutation, 2016, 38, pp. 390–399.

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Department of Genetics

Version

VoR (Version of Record)

Published in

Human Mutation

Publisher

Wiley for Human Genome Variation Society

issn

1059-7794

eissn

1098-1004

Acceptance date

14/12/2016

Copyright date

2016

Available date

27/03/2017

Publisher version

http://onlinelibrary.wiley.com/doi/10.1002/humu.23159/abstract

Notes

Novel variants have been submitted to dbVAR (accession number nstd142) (https://www.ncbi.nlm.nih.gov/dbvar).

Language

en