1. Copy number, linkage disequilibrium and disease association in the FCGR locus
- Author
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David Clayton, Iva Gunnarsson, Kenneth G. C. Smith, Nguyen Hoan Phu, Sarah J. Dunstan, Paul A. Lyons, Yu-Lung Lau, Heather A. Niederer, Norbert Peshu, Tim F. Rayner, Wanling Yang, Lisa C. Willcocks, Britta C. Urban, J. Anthony G. Scott, Caroline O. S. Savage, Elisabet Svenungsson, Tran Tinh Hien, Leonid Padyukov, Thomas N. Williams, Richard A. Watts, Lyons, Paul [0000-0001-7035-8997], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository
- Subjects
China ,Linkage disequilibrium ,Genotype ,Receptor expression ,Receptors, IgG - genetics ,Gene Dosage ,Black People ,Single-nucleotide polymorphism ,Locus (genetics) ,FCGR2B ,Biology ,GPI-Linked Proteins ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,White People ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Gene Frequency ,African Continental Ancestry Group - genetics ,Genetics ,Humans ,Lupus Erythematosus, Systemic ,Genetic Predisposition to Disease ,Allele ,Genetic Predisposition to Disease - ethnology - genetics ,Molecular Biology ,Alleles ,Genetics (clinical) ,030304 developmental biology ,Sweden ,0303 health sciences ,Chi-Square Distribution ,Receptors, IgG ,Association Studies Articles ,FCGR3A ,General Medicine ,FCGR3B ,Kenya ,United Kingdom ,3. Good health ,Vietnam ,Immunology ,030215 immunology - Abstract
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 FcgR 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. © The Author 2010. Published by Oxford University Press. All rights reserved., published_or_final_version
- Published
- 2010