Objective. To determine the relationship between FCGR3B gene copy number variation (CNV) and biopsy proven giant cell arteritis (GCA). Methods. FCGR3B CNV was determined in 139 Australian biopsy proven GCA patients and 162 population matched controls, using a duplex qPCR assay and RNase P as the reference gene. Copy number was determined using Copy Caller software (v.1.0, Applied Biosystems, USA). CNV genotypes were classified into 3 groups (<2, 2, 3+) for analysis purposes, and analysis was performed using logistic regression. Results. All GCA patients had a positive temporal artery biopsy, and the most common presenting symptoms were visual disturbance and temporal headache. The mean age of patients at biopsy was 74 years (range 51–94) and 88/139 (63%) were female. The frequency of low (<2) FCGR3B copy number was comparable between GCA patients ( %) and controls ( %), as was the frequency of high (3+) FCGR3B copy number (15/130 (10.8%) in GCA patients versus 13/162 (8.0%) in controls). Overall there was no evidence that FCGR3B CNV frequencies differed between GCA patients and controls ( , , ). Conclusion. FCGR3B CNV is not associated with GCA; however, replicate studies are required. 1. Introduction Giant cell arteritis (GCA), also known as temporal arteritis, is a systemic inflammatory vasculitis which primarily affects medium to large extracranial arteries of the head and neck and can result in stroke and blindness. GCA typically affects people aged over 50 years and incidence rates increase with advancing age, peaking around 80 years of age [1]. GCA is 2-3 times more likely to affect females and is more commonly diagnosed in Caucasians than in any other ethnic background with the highest incidence observed in populations of Scandinavian descent [2]. The pathogenesis of GCA is not understood, although environmental, infectious, and genetic risk factors have been implicated. Familial aggregation and established associations with HLA-DR4 provide evidence for a genetic component to GCA [3–5]. Multiple genetic association studies have been performed on a number of immune response genes. However, the majority of these studies have been performed on a single GCA cohort from north-western Spain and, to date, have failed to confirm any additional genetic associations. One gene of interest is Fc gamma receptor 3B (FCGR3B) which exhibits gene copy number variation (CNV), an important source of quantitative genetic variation. Copy number variation is a departure from the normal diploid number of genes ( ) which may arise through gene duplication and deletion
References
[1]
A. T. Borchers and M. E. Gershwin, “Giant cell arteritis: a review of classification, pathophysiology, geoepidemiology and treatment,” Autoimmunity Reviews, vol. 11, no. 6-7, pp. A544–A554, 2012.
[2]
P. Ghosh, F. A. Borg, and B. Dasgupta, “Current understanding and management of giant cell arteritis and polymyalgia rheumatica,” Expert Review of Clinical Immunology, vol. 6, no. 6, pp. 913–928, 2010.
[3]
E. Liozon, B. Ouattara, K. Rhaiem et al., “Familial aggregation in giant cell arteritis and polymyalgia rheumatica: a comprehensive literature review including 4 new families,” Clinical and Experimental Rheumatology, vol. 27, no. 1, pp. S89–S94, 2009.
[4]
C. M. Weyand and J. J. Goronzy, “Functional domains on HLA-DR molecules: implications for the linkage of HLA-DR genes to different autoimmune diseases,” Clinical Immunology and Immunopathology, vol. 70, no. 2, pp. 91–98, 1994.
[5]
C. M. Weyand, K. C. Hicok, G. G. Hunder, and J. J. Goronzy, “The HLA-DRB1 locus as a genetic component in giant cell arteritis. Mapping of a disease-linked sequence motif to the antigen binding site of the HLA-DR molecule,” Journal of Clinical Investigation, vol. 90, no. 6, pp. 2355–2361, 1992.
[6]
P. Stankiewicz and J. R. Lupski, “Structural variation in the human genome and its role in disease,” Annual Review of Medicine, vol. 61, pp. 437–455, 2010.
[7]
F. Nimmerjahn and J. V. Ravetch, “Fcγ receptors as regulators of immune responses,” Nature Reviews Immunology, vol. 8, no. 1, pp. 34–47, 2008.
[8]
L. C. Willcocks, P. A. Lyons, M. R. Clatworthy et al., “Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake,” Journal of Experimental Medicine, vol. 205, no. 7, pp. 1573–1582, 2008.
[9]
M. Fanciulli, P. J. Norsworthy, E. Petretto et al., “FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity,” Nature Genetics, vol. 39, no. 6, pp. 721–723, 2007.
[10]
M. Mamtani, J.-M. Anaya, W. He, and S. K. Ahuja, “Association of copy number variation in the FCGR3B gene with risk of autoimmune diseases,” Genes and Immunity, vol. 11, no. 2, pp. 155–160, 2010.
[11]
J. C. Nossent, M. Rischmueller, and S. Lester, “Low copy number of the Fc-γ receptor 3B gene FCGR3B is a risk factor for primary Sjogren's syndrome,” The Journal of Rheumatology, vol. 39, no. 11, pp. 2142–2147, 2012.
[12]
S. W. Graf, S. Lester, J. C. Nossent et al., “Low copy number of the FCGR3B gene and rheumatoid arthritis: a case-control study and meta-analysis,” Arthritis Research and Therapy, vol. 14, no. 1, article R28, 2012.
[13]
C. McKinney, M. Fanciulli, M. E. Merriman et al., “Association of variation in Fcγ receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples,” Annals of the Rheumatic Diseases, vol. 69, no. 9, pp. 1711–1716, 2010.
[14]
C. McKinney, J. C. A. Broen, M. C. Vonk et al., “Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis,” Genes and Immunity, vol. 13, pp. 458–460, 2012.
[15]
M. Phillipson and P. Kubes, “The neutrophil in vascular inflammation,” Nature Medicine, vol. 17, no. 11, pp. 1381–1390, 2011.
[16]
C. McKinney and T. R. Merriman, “Meta-analysis confirms a role for deletion in FCGR3B in autoimmune phenotypes,” Human Molecular Genetics, vol. 21, no. 10, Article ID dds039, pp. 2370–2376, 2012.
[17]
R. Black, S. Lester, E. Dunstan et al., “Fc-gamma receptor 3B copy number variation is not a risk factor for Behcet's disease,” International Journal of Rheumatology, vol. 2012, Article ID 167096, 4 pages, 2012.
[18]
H. A. Niederer, L. C. Willcocks, T. F. Rayner et al., “Copy number, linkage disequilibrium and disease association in the FCGR locus,” Human Molecular Genetics, vol. 19, no. 16, pp. 3282–3294, 2010.
[19]
W. B. Breunis, E. Van Mirre, J. Geissler et al., “Copy number variation at the FCGR locus includes FCGR3A, FCGR2C and FCGR3B but not FCGR2A and FCGR2B,” Human Mutation, vol. 30, no. 5, pp. E640–E650, 2009.
[20]
X.-J. Zhou, J.-C. Lv, D.-F. Bu et al., “Copy number variation of FCGR3A rather than FCGR3B and FCGR2B is associated with susceptibility to anti-GBM disease,” International Immunology, vol. 22, no. 1, Article ID dxp113, pp. 45–51, 2009.
[21]
H. A. Niederer, M. R. Clatworthy, L. C. Willcocks, and K. G. Smith, “FcgammaRIIB, FcgammaRIIIB, and systemic lupus erythematosus,” Annals of the New York Academy of Sciences, vol. 1183, pp. 69–88, 2010.
[22]
C. C. Khor, S. Davila, W. B. Breunis et al., “Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease,” Nature Genetics, vol. 43, no. 12, pp. 1241–1246, 2011.
[23]
A. W. Morgan, J. I. Robinson, J. H. Barrett et al., “Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis,” Arthritis Research and Therapy, vol. 8, no. 4, article R109, 2006.
