Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans

Abstract

Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis

“…It has been hypothesised that the primary effect of deletion in the FCGR3B gene is a reduced uptake of IgG complexes, leading to tissue deposition of IC. 5,6,12,15 Our results, however, suggest that this may not be the only explanation for the observed associations. Although SLE and SSc are characterised by the presence of autoantibodies, the absence of IgG deposits in SSc is one of the major differences between SLE and SSc.…”

“…8,12,13,15,16 The influence of possessing o2 copies of FCGR3B on SSc risk was tested under the hypothesis that any association of FCGR3B with disease would be similar to that evident in SLE, where CNo2 is a risk factor. [5][6][7][8][9][10] There was significant evidence that possessing fewer than two copies of FCGR3B is a risk factor for SSc (odds ratio (OR) ¼ 1.55 (1.13-2.14), P ¼ 0.007) ( We tested for association between FCGR3B CNo2 and limited cutaneous or diffuse cutaneous SSc, and the presence or absence of anti-topoisomerase I and anti-centromere antibodies. There was no significant association of CNo2 with any of these stratifications (Supplementary Table 1).…”

“…Copy number (CN) variation in FCGR3B has been associated with a variety of autoimmune disorders, including rheumatoid arthritis, 2-4 ulcerative colitis 5 and glomerular disease. 6,7 In particular, CNo2 has been reported to be a risk factor for SLE in a number of studies. [7][8][9][10][11][12][13] Given the evidence for shared genetic susceptibility between SSc and SLE, we hypothesised that copy-number variation in FCGR3B has a role in the pathology of SSc.…”

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

“…[35][36][37][38][39][40][41][42][43] Within our associated region, a segmental duplication is reported, 44 which is situated between the two associated regions on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background and caused a 223-kb gap not genotyped in our study. This segmental duplication has, to our knowledge, not been studied regarding human diseases.…”

“…Structural variations and copy number alterations have recently been found to influence the risk of complex diseases, for example, a copy number variation in the FCGR3B gene was recently found to be associated with systemic lupus erythematosus. 39,40 Hence, the possible involvement of the segmental duplication in our associated region should be further investigated.…”