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Evidence for both copy number and allelic (NA1/NA2) risk at the FCGR3B locus in systemic lupus erythematosus

Research output: Contribution to journalArticle

David L Morris, Amy L Roberts, Abigail S Witherden, Ruth Tarzi, Paula Barros, John C Whittaker, Terence H Cook, Timothy J Aitman, Timothy J Vyse

Original languageEnglish
Pages (from-to)1027-1031
Number of pages5
JournalEuropean Journal of Human Genetics
Volume18
Issue number9
DOIs
Published10 Sep 2010

King's Authors

Abstract

The Fc gamma-receptor locus on chromosome 1q23 shows copy-number variation (CNV), and it has previously been shown that individuals with reduced numbers of copies of the Fc gamma-receptor-IIIB gene (FCGR3B) have an increased risk of developing systemic lupus erythematosus (SLE). It is not understood whether the association arises from FCGR3B (CD16b) itself, is observed because of linkage disequilibrium with actual causal alleles and/or is an effect of CNV on flanking FCGR genes. Thus, we extended this previous work by genotyping the FCGR3B alleles NA1/NA2 and re-assaying CNV using a paralogue ratio test assay in a family study (365 families). We have developed a novel case/pseudo-control approach to analyse family data, as the phase of copy number (CN) is not known in parents and cannot always be inferred in offspring. The results, obtained by fitting logistic regression models, confirm the association of low CN of FCGR3B with SLE (P=0.04). The risk conferred by low copies (<2) was contingent on FCGR3B allotype, being greater for deletion of NA1 than the for lower-affinity NA2. The simpler model with just CN was rejected in favour of the biallelic-CN model (P=0.03). We observed a correlation (R-2=0.75, P<0.0001) between FCGR3B CNV and neutrophil expression in both healthy controls and patients with SLE. Our results suggest that one mechanism by which CNV at this locus confers disease risk is directly as a result of reduced Fc gamma RIIIb function, either because of reduced expression (related to CNV) or because of reduced affinity for its ligand (NA1/NA2 allotype). European Journal of Human Genetics (2010) 18, 1027-1031; doi:10.1038/ejhg.2010.56; published online 5 May 2010

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