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

McKinney, Cushla; Broen, Jasper; Vonk, Madelon C.; Beretta, Lorenzo; Hesselstrand, Roger; Hunzelmann, Nicolas; Riemekasten, Gabriela; Scorza, Raffaella; Simeón, Carmen P.; Fonollosa, V.; Carreira, Patrícia; Ortego-Centeno, Norbérto; Airò, Paolo; Coenen, Marieke J. H.; Martín, Javier; Radstake, Timothy R. D. J.; Merriman, Tony R.

doi:10.1038/gene.2012.15

Cited by 29 publications

(16 citation statements)

References 21 publications

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“…Amongst these, an association between FCGR3B and a risk of autoimmunity has been the most intensively investigated to date. FCGR3B copy number deficiency is associated with a number of different autoimmune diseases, including SLE (11-15), Sjogren's syndrome (16) and systemic sclerosis (17). Although a low FCGR3B copy number is reportedly associated with SLE susceptibility in Afro-Caribbean and Caucasian populations, to the best of our knowledge, no information is available regarding the Henan population in China.…”

Section: Introductionmentioning

confidence: 83%

Low copy number of FCGR3B is associated with lupus nephritis in a Chinese population

Zheng

Gao

et al. 2017

Exp Ther Med

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Abstract. Lupus nephritis (LN) is a polygenic disease caused by an interaction between hereditary and environmental factors. Numerous gene copy number variations have been identified to contribute to this disease. Previously, immunoglobulin (Ig)G Fcγ receptor 3B (FCGR3B) copy number variation (CNV) was reported to be associated with LN in the Caucasian population. However, the effect of FCGR3B CNV on LN in the Chinese population remains unknown. The present study aimed to investigate whether CNVs of FCGR3B are associated with LN in the Henan Chinese population. FCGR3B CNVs were determined in 142 LN patients and 328 healthy controls. A modified methodology based on competitive polymerase chain reaction, a Multiplex AccuCopy™ kit was used to detect FCGR3B copy number. Clinical and laboratory data was collected retrospectively from medical records. To evaluate associations between FCGR3B CNVs and LN susceptibility, the present study calculated the odds ratios using a logistic regression analysis. The current study identified that the distribution of FCGR3B copy number was significantly different between LN and healthy controls (P=0.031). A low copy number (<2) of FCGR3B was significantly enriched in LN patients (P= 0.042), and was a risk factor for LN (odds ratio=2.059; 95% confidence interval, 1.081-3.921; P=0.028). However, a high copy number (>2) had no effect on LN. There were no associations between FCGR3B CNV and clinical phenotypes of LN. The results from the present study demonstrate that a low copy number of FCGR3B is a risk factor for LN in a Chinese population.

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Section: Introductionmentioning

confidence: 83%

Low copy number of FCGR3B is associated with lupus nephritis in a Chinese population

Zheng

Gao

et al. 2017

Exp Ther Med

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“…In some cases, studies using real-time QPCR have systematically removed uncertain data that fails to cluster around integer values in an attempt to reduce the impact of measurement error [26, 27]. However, calling samples with only a high degree of certainty may result in bias, as the failure to cluster is unlikely to be independent of genotype [28].…”

Section: Discussionmentioning

confidence: 99%

Technical considerations for genotyping multi-allelic copy number variation (CNV), in regions of segmental duplication

et al. 2014

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BackgroundIntrachromosomal segmental duplications provide the substrate for non-allelic homologous recombination, facilitating extensive copy number variation in the human genome. Many multi-copy gene families are embedded within genomic regions with high levels of sequence identity (>95%) and therefore pose considerable analytical challenges. In some cases, the complexity involved in analyzing such regions is largely underestimated. Rapid, cost effective analysis of multi-copy gene regions have typically implemented quantitative approaches, however quantitative data are not an absolute means of certainty. Therefore any technique prone to degrees of measurement error can produce ambiguous results that may lead to spurious associations with complex disease.ResultsIn this study we have focused on testing the accuracy and reproducibility of quantitative analysis techniques. With reference to the C-C Chemokine Ligand-3-like-1 (CCL3L1) gene, we performed analysis using real-time Quantitative PCR (QPCR), Multiplex Ligation-dependent Probe Amplification (MLPA) and Paralogue Ratio Test (PRT). After controlling for potential outside variables on assay performance, including DNA concentration, quality, preparation and storage conditions, we find that real-time QPCR produces data that does not cluster tightly around copy number integer values, with variation substantially greater than that of the MLPA or PRT systems. We find that the method of rounding real-time QPCR measurements can potentially lead to mis-scoring of copy number genotypes and suggest caution should be exercised in interpreting QPCR data.ConclusionsWe conclude that real-time QPCR is inherently prone to measurement error, even under conditions that would seem favorable for association studies. Our results indicate that potential variability in the physicochemical properties of the DNA samples cannot solely explain the poor performance exhibited by the real-time QPCR systems. We recommend that more robust approaches such as PRT or MLPA should be used to genotype multi-allelic copy number variation in disease association studies and suggest several approaches which can be implemented to ensure the quality of the copy number typing using quantitative methods.

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“…In patients with giantcell arteritis, an association was observed with the FCGR2A-FCGR3A 131R-158F haplotype (Morgan et al, 2006). However, no association between FCGR3A-158 and systemic sclerosis was described (McKinney et al, 2012). Homozygosity for the higher-affinity V allele has also been shown to be associated with susceptibility to antibody-positive RA (Robinson et al, 2010;Thabet et al, 2009).…”

Section: Introductionmentioning

confidence: 94%

Association of theFCGR3A-158F/V Gene Polymorphism with the Response to Rituximab Treatment in Spanish Systemic Autoimmune Disease Patients

Robledo

Márquez

Dávila-Fajardo

et al. 2012

DNA and Cell Biology

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Rituximab is being used as treatment for systemic autoimmune diseases. The objective of this study was to determine whether the genetic variant in the Fc gamma-receptor III a (FCGR3A) gene, 158F/V, contributes to the observed variation in response to rituximab in patients with systemic autoimmune diseases. DNA samples from 132 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for FCGR3A-158F/V (rs396991) gene polymorphism using the TaqMan(®) allelic discrimination technology. Six months after infusion with rituximab we evaluated the response to the drug: 61% of the patients showed a complete response, partial 27% and 12% did not respond to the treatment. A statistically significant difference was observed in V allele frequency between responder (38%) and nonresponder (16%) patients (p=0.01; odds ratio [OR]=3.24, 95% confidence interval [CI] 1.17-11.1). Rituximab was also more effective in V allele carriers (94%) than in homozygous FF patients (81%): p=0.02; OR=3.96, 95% CI 1.10-17.68. These results suggest that FCGR3A-158F/V (rs396991) gene polymorphism play a role in the response to rituximab in autoimmune diseases. Validation of these findings in independent cohorts is warranted.

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

Cited by 29 publications

References 21 publications

Low copy number of FCGR3B is associated with lupus nephritis in a Chinese population

Low copy number of FCGR3B is associated with lupus nephritis in a Chinese population

Technical considerations for genotyping multi-allelic copy number variation (CNV), in regions of segmental duplication

Association of theFCGR3A-158F/V Gene Polymorphism with the Response to Rituximab Treatment in Spanish Systemic Autoimmune Disease Patients

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