Journal Article

Copy number, linkage disequilibrium and disease association in the <i>FCGR</i> locus

Heather A. Niederer, Lisa C. Willcocks, Tim F. Rayner, Wanling Yang, Yu Lung Lau, Thomas N. Williams, J. Anthony G. Scott, Britta C. Urban, Norbert Peshu, Sarah J. Dunstan, Tran Tinh Hien, Nguyen Hoan Phu, Leonid Padyukov, Iva Gunnarsson, Elisabet Svenungsson, Caroline O. Savage, Richard A. Watts, Paul A. Lyons, David G. Clayton and Kenneth G.C. Smith

in Human Molecular Genetics

Volume 19, issue 16, pages 3282-3294
Published in print August 2010 | ISSN: 0964-6906
Published online May 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq216

Show Summary Details

Preview

The response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcγRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcγR genomic locus is complex, containing regions of copy number variation (CNV) which can alter receptor expression and leukocyte responses to IgG. Combined paralogue ratio tests (PRTs) were used to distinguish three intervals within the FCGR locus which undergo CNV, and to determine FCGR gene copy number (CN). There were significant differences in FCGR3B and FCGR3A CNV profiles between Caucasian, East Asian and Kenyan populations. A previously noted association of low FCGR3B CN with SLE in Caucasians was supported [OR = 1.57 (1.08–2.27), P = 0.018], and replicated in Chinese [OR = 1.65 (1.25–2.18), P = 4 × 10−4]. There was no association of FCGR3B CNV with vasculitis, nor with malarial or bacterial infection. Linkage disequilibrium (LD) between multi-allelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus was defined for the first time. Despite LD between FCGR3B CNV and a variant in FcγRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcγRIIB-232T allele were individually strongly associated with SLE risk. Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Further interpretations of contributions to pathogenesis by FcγRs must be made in the context of LD involving CNV regions.

Journal Article.  8678 words.  Illustrated.

Subjects: Genetics and Genomics

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.