FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity

Fanciulli, Manuela; Norsworthy, Penny J.; Petretto, Enrico; Dong, Rong; Harper, Lorraine; Kamesh, Lavanya; Heward, J. M.; Gough, Stephen; Smith, Adam J. de; Blakemore, Alexandra I. F.; Froguel, Philippe; Owen, Catherine J.; Pearce, Simon H. S.; Teixeira, Luis; Guillevin, Loı̈c; Graham, Deborah S. Cunninghame; Pusey, Charles D.; Cook, H. Terence; Vyse, Timothy J.; Aitman, Timothy J.

doi:10.1038/ng2046

Cited by 424 publications

(403 citation statements)

References 16 publications

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“…[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.…”

Section: Discussionmentioning

confidence: 58%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…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).…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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. In order to evaluate this hypothesis, we tested for association between FCGR3B gene dosage and SSc in a Caucasian case-control sample set under the specific hypothesis that deletion of FCGR3B is a risk factor in comparison with diploid and increased CN.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of p1 was a significant risk factor for SSc (OR ¼ 1.55 (1.13-2.14), P ¼ 0.007) relative to CNX2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.

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A Survey of Copy‐Number Variation Detection Tools Based on High‐Throughput Sequencing Data

Lee

Park

2012

CP Human Genetics

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Copy-number variation (CNV) is a major class of genomic variation with potentially important functional consequences in both normal and diseased populations. Remarkable advances in development of next-generation sequencing (NGS) platforms provide an unprecedented opportunity for accurate, high-resolution characterization of CNVs. In this unit, we give an overview of available computational tools for detection of CNVs and discuss comparative advantages and disadvantages of different approaches.

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FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity

Abstract: Naturally occurring variation in gene copy number is increasingly recognized as a heritable source of susceptibility to genetically complex diseases. Here we report strong association between FCGR3B copy number and risk of systemic lupus erythematosus (P = 2.7 × 10 -8 ), microscopic

Cited by 424 publications

References 16 publications

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

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

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

A Survey of Copy‐Number Variation Detection Tools Based on High‐Throughput Sequencing Data

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