Copy number variation at theFCGRlocus includesFCGR3A, FCGR2CandFCGR3Bbut notFCGR2AandFCGR2B

Abstract

Human Fcγ receptors (FcγRs) are glycoproteins that bind the Fc region of IgG. The genes encoding the low-affinity FcγRs are located on chromosome 1q23-24. Beside single nucleotide polymorphisms (SNPs), gene copy number variation (CNV) is now being recognized as an important indicator for inter-individual differences. Recent studies on identifying CNV in the human genome suggest large areas at chromosome 1q23-24 to be involved, and CNV in this region has been associated with manifestations of systemic autoimmune disease. To study both SNPs and CNV of the low-affinity FcγRs in one assay, we have developed a Multiplex Ligation-dependent Probe Amplification (MLPA) assay. A novel CNV for FCGR3A was observed. Similar to FCGR3B and FCGR2C, a gene-dosage effect of FCGR3A was found, that seemed to correlate nicely with the FcγRIIIa expression on NK cells. Next, we delineated the approximate boundaries of CNV at the FCGR locus. Variation in co-segregation of neighboring FCGR genes was limited to four variants, with patterns of Mendelian inheritance. No CNV of the FCGR2A and FCGR2B genes was observed in over 600 individuals. In conclusion, we report a novel CNV of the FCGR3A gene that correlates with FcγRIIIa expression and function on NK cells. Only FCGR3A, FCGR2C and FCGR3B show CNV, in contrast to FCGR2A and FCGR2B.

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.…”

“…14 ) The FCGR3B CN allele distribution among the controls (CNo2 ¼ 7.6%, CN 2 ¼ 82.6% and CN42 ¼ 9.8%) is similar to that observed in other healthy Caucasian populations as determined by multiplex ligand-dependent probe amplification or paralog ratio testing (CNo2 ¼ 6.7-7.8%, CN 2 ¼ 81.1-82.2% and CN42 ¼ 9.4-11.8%). 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.…”

“…Given the complexity of the FCGR locus and the fact that deletion of FCGR3B can extend to FCGR2C and/or FCGR2B, 11,15 it is also possible that the apparent association with FCGR3B is in fact caused by variations in one of these other genes. Although FCGR2C has been associated with idiopathic thrombocytopenic purpura, 18 CN variation is unlikely to have a major biological effect; in most individuals the gene contains a premature stop codon.…”

FCGR2Cgenotyping by pyrosequencing reveals linkage disequilibrium withFCGR3AV158F andFCGR2AH131R polymorphisms in a Caucasian population

“…On the other hand, using multiplex ligation-dependent probe amplification with probes specific for coding regions, Breunis et al did not observed CNV of FCGR2A and FCGR2B in a large (> 600 individuals) control population. 19 In our pyrosequencing approach, we have also used primer pair localized in coding region of FCGR2A and FCGR2B where no CNV has been reported so far. Moreover, if the CNR2 described by Niederer et al expanded to the coding region of FCGR2A, it will be expected that 4.5% of individuals would carry 3 copies of FCGR2A.…”

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

“…14 The FCGR region on chromosome 1q23.3 shows a complex pattern of CNV and sequence homology. From the five FCGR genes within the 172-kb region, three (FCGR3A, FCGR2C and FCGR3B) have been reported to show CNV 15 although the frequency of CNV at FCGR3A is low.…”