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

Lejeune, Julien; Piégu, Benoît; Gouilleux-Gruart, Valérie; Ohresser, Marc; Watier, Hervé; Thibault, Gilles

doi:10.4161/mabs.22287

Cited by 15 publications

(15 citation statements)

References 24 publications

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“…The frequencies of CD32C ORF (determined by the absence of two point mutations in the FCGR2C gene, c169C.T and c798+1A.G, at the donor splice site in intron 7) and the FCGR ∼ 70-kbp deletion conditioning CD32B ectopic expression on NK cells (CD32B NK hereafter) are shown in Supplemental Table I. FCGR2C genotype frequencies approached those observed previously in whites (21,37), whereas, to our knowledge, the distribution of CD32B NK -related genotypes had never been reported. Neither CD32C ORF nor CD32B NK showed any appreciable association with herpetic susceptibility (OR =1.11 and 0.79, respectively; not significant) (Fig.…”

Section: Genetic Polymorphisms Determining Cd32b or Cd32c Expression supporting

confidence: 53%

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

Moraru

Black

Muntasell

et al. 2015

The Journal of Immunology

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HSV-1 latently infects most humans, causing a variable clinical picture that depends, in part, on host genetic factors. Both IgG and its cellular FcRs, CD16A and CD32A–C (encoded by FCGR3A and FCGR2A–C, respectively, on chromosome 1), display polymorphisms that could affect their defensive function. Of potential relevance are a FCGR3A dimorphism resulting in CD16A-valine/phenylalanine-158 allotypes with different IgG affinity, variations conditioning NK cell expression of CD32B or CD32C, and IgG1 H chain (IGHG1) and kappa-chain (IGKC) polymorphisms determining allotypes designated G1m and Km. In this study, we assessed the contribution of Ig genetic variations and their interaction with FcR polymorphism to HSV-1 susceptibility, as well as their impact on NK cell–mediated Ab-dependent cellular cytotoxicity (ADCC). Our results show an epistatic interaction between IGHG1 and FCGR3A such that the higher affinity CD16A-158V/V genotype associates with an asymptomatic course of HSV-1 infection only in homozygotes for G1m3. Furthermore, CD16A-158V and G1m3 allotypes enhanced ADCC against opsonized HSV-1–infected fibroblasts. Conversely, Km allotypes and CD32B or CD32C expression on NK cells did not significantly influence HSV-1 susceptibility or ADCC. NK cells degranulating against immune serum-opsonized HSV-1–infected fibroblasts had heterogeneous phenotypes. Yet, enhanced ADCC was observed among NK cells showing a differentiated, memory-like phenotype (NKG2CbrightNKG2A−CD57+FcRγ−), which expand in response to human CMV. These results extend our knowledge on the importance of immunogenetic polymorphisms and NK cell–Ab interplay in the host response against HSV-1 and point to the relevance of interactions between immune responses elicited during chronic coinfection by multiple herpesviruses.

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Section: Genetic Polymorphisms Determining Cd32b or Cd32c Expression supporting

confidence: 53%

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

Moraru

Black

Muntasell

et al. 2015

The Journal of Immunology

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“…NK cell ADCC capabilities can be enhanced if FCGR2C is expressed on the cell surface (26). Since NK cells can express both FCGR3A and FCGR2C, we considered whether patient outcome was influenced by the combined genotypes for FCGR3A and FCGR2C.…”

Section: Resultsmentioning

confidence: 99%

“…Our current understanding of these FCGRs is that they function primarily through engaging antigen-bound IgG, transmitting an activating signal, and inducing cellular responses, such as the induction of ADCC (by NK cells, neutrophils and monocytes/macrophages) or antibody dependent cellular phagocytosis (ADCP), and the uptake of antigens by antigen presenting cells through immobilized, bound IgG molecules, resulting in antigen processing and presentation (3, 4, 6, 8, 26). In each of these settings, an antigen-reactive antibody (either endogenous or passively administered) is needed for antibody/FCGR-facilitated ADCC, ADCP or antigen processing.…”

Section: Discussionmentioning

confidence: 99%

FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma

Erbe

Wang

Goldberg

et al. 2017

Clinical Cancer Research

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Background Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated anti-tumor responses when tumor-reactive antibodies are present. The affinity of the FCGR/antibody interaction is variable and dependent upon FCGR polymorphisms. Prior studies of cancer patients treated with immunotherapy indicate that FCGR polymorphisms can influence antitumor response for certain immunotherapies that act via therapeutically administered mAbs or via endogenous tumor-reactive antibodies induced from tumor antigen vaccines. The previously published “SELECT” trial of high-dose aldesleukin (HD-IL2) for metastatic renal cell carcinoma (mRCC) resulted in an objective response rate (ORR) of 25%. We evaluated the patients in this SELECT trial to determine whether higher affinity FCGR polymorphisms are associated with outcome. Methods Single nucleotide polymorphisms (SNPs) in FCGR2A, FCGR3A, and FCGR2C were analyzed, individually and in combination, for associations between genotype and clinical outcome. Results When higher affinity genotypes for FCGR2A, FCGR3A and FCGR2C were considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2. Conclusions While associations of higher affinity FCGR genotype with clinical outcome have been demonstrated with mAb therapy and with idiotype vaccines, to our knowledge, this is the first study to show associations of FCGR genotypes with outcome following HD-IL2 treatment. We hypothesize that endogenous anti-tumor antibodies may engage immune cells through their FCGRs, and HD-IL2 may enhance antibody-induced tumor destruction, or antibody-enhanced tumor antigen presentation, via augmented activation of innate or adaptive immune responses; this FCGR-mediated immune activity would be augmented through immunologically favorable FCGRs.

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“…Due to the close proximity of all the five different FCGR2 and FCGR3 genes, the polymorphic variants in these genes are likely to be in strong Linkage Disequilibrium (LD). However, except for some incidental reports on LD between some of the SNPs (21–24), a comprehensive analysis of LD between the functional variants at this locus has not been previously performed.…”

Section: Introductionmentioning

confidence: 99%

Extensive Ethnic Variation and Linkage Disequilibrium at the FCGR2/3 Locus: Different Genetic Associations Revealed in Kawasaki Disease

et al. 2019

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The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C -ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C -ORF haplotype showed strong LD with, among others, rs201218628 ( FCGR2A -Q27W, r 2 = 0.63). LD between these two variants was weaker ( r 2 = 0.17) in Africans, whereas the FCGR2C -ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The FCGR2C -ORF haplotype and rs1801274 ( FCGR2A -H131R) were in weak LD ( r 2 = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the FCGR2C -ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the FCGR2/3 locus with knowledge of LD and ethnic variation.

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

Cited by 15 publications

References 24 publications

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma

Extensive Ethnic Variation and Linkage Disequilibrium at the FCGR2/3 Locus: Different Genetic Associations Revealed in Kawasaki Disease

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