FCGR2A Polymorphisms Research Articles

Correlations of FCGR2A 131R/H and FCGR3A 158V/F Polymorphisms with the Susceptibility of Peri-implantitis in Chinese Han Population.

The purpose of the study is to investigate the relationship of peri-implantitis (PI) with FCGR2A and FCGR3A gene polymorphisms. One hundred and forty-four patients with PI and 136 patients without PI infection were selected. Gingival crevicular fluid samples were collected from the two groups. The FCGR2A and FCGR3A polymorphism in the two groups were measured. All volunteers were evaluated for periodontal status. The effect of polymorphisms on PI susceptibility was investigated by chi-square analysis and logistic regression. The frequency of FCGR2A rs1801274 GG genotype of PI group was higher than that of the control group, while the GA and AA genotype carriers were less in PI group. After adjusting for other clinical indicators, rs1801274 GA genotype, AA genotype, and the A allele were still negatively correlated with the onset of PI. FCGR3A rs396991 polymorphism was not associated with PI. FCGR2A rs1801274 polymorphism was significantly associated with PI in the Chinese Han population, and GG genotype might be a genetic risk factor for PI.

Genetic biomarkers for diagnosis and treatment of spondyloarthropathies in Moroccan population

BackgroundThe spondyloarthropathies (SpA) are inflammatory rheumatologic diseases whose pathogenesis comes from interaction between genetic and environmental factors. MethodsThis is a case-control analysis that aims to explore in Moroccan population the relationship of some allelic polymorphisms of the CTLA-4 CT60, FCGR3A-158G/T SNPs and HLA-B locus with SpA disease. Eighty-four Spa patients grouped according to pain site and 95 healthy individuals from Morocco were typed by sequence-based-typing methods. ResultsThe CTLA-4 CT60 investigation showed a significantly increased frequency of rs11571319 A allele in male patients with sacroiliitis (pcorr.=0.048, OR=2.756) and a protective role of A/G genotype in SPA patients with thoracic spine (pcorr.=0.016, OR=0.055) and peripheral joints pain (pcorr.=0.036 OR=0.068), compared to controls. Furthermore, a significant increase of A/A in rs3087243 was shown in male patients with peripheral joints pain (p = 0.035 OR = 4.45). Data from FCGR3A-158 analysis evidenced a reduction of T/T (F/F) genotype in patients with thoracic spine pain (p = 0.030, OR = 0.09) and a higher frequency of G/T (F/V) (p = 0.038 OR = 5.045) towards controls. With regard to HLA-B locus, we noticed a protective role of HLA-B*45:01 (pcorr. = 0.033,OR = 0.041) and an increased frequency of HLA-B*51 alleles (51:01, 51:02, 51:08, 51:09, 51:29) and B*52:01:01 (p = 0.041,OR = 2.714), in addition to HLA-B*27 alleles (p = 0.028, OR = 2.593) commonly associated with AS pathologies. ConclusionsOur data suggest the role of some additional CTLA-4, FCGR3A and HLA-B gene polymorphisms in SPA pathogenesis of Moroccan population, useful as new diagnostic biomarkers and targets for immunotherapy.

Inebilizumab reduces neuromyelitis optica spectrum disorder risk independent of FCGR3A polymorphism.

Inebilizumab, a humanized, glycoengineered, IgG1 monoclonal antibody that depletes CD19+ B-cells, is approved to treat aquaporin 4 (AQP4) IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab is afucosylated and engineered for enhanced affinity to Fc receptor III-A (FCGR3A) receptors on natural killer cells to maximize antibody-dependent cellular cytotoxicity. Previously, the F allele polymorphism at amino acid 158 of the FCGR3A gene (F158) was shown to decrease IgG-binding affinity and reduce rituximab (anti-CD20) efficacy for NMOSD attack prevention. In contrast, our current findings from inebilizumab-treated NMOSD patients indicate similar clinical outcomes between those with F158 and V158 allele genotypes.

Comparative Analysis of FCGR Gene Polymorphism in Pulmonary Sarcoidosis and Tuberculosis.

The clinical outcome of sarcoidosis (SA) is very similar to tuberculosis (TB); however, they are treated differently and should not be confused. In search for their biomarkers, we have previously revealed changes in the phagocytic activity of monocytes in sarcoidosis and tuberculosis. On these monocytes we found a higher expression of receptors for the Fc fragment of immunoglobulin G (FcγR) in SA and TB patients vs. healthy controls. FcγRs are responsible for the binding of immune complexes (ICs) to initiate an (auto)immune response and for ICs clearance. Surprisingly, our SA patients had a high blood level of ICs, despite the abundant presence of FcγRs. It pointed to FcγR disfunction, presumably caused by the polymorphism of their (FCGR) genes. Therefore, we present here an analysis of the occurrence of FCGR2A, FCGR2B, FCGR2C, FCGR3A and FCGR3B variants in Caucasian SA and TB patients, and healthy individuals with the use of polymerase chain reaction (PCR) and real-time PCR. The presented data point to a possibility of supporting the differential diagnosis of SA and TB by analyzing FCGR2C, FCGR3A and FCGR3B polymorphism, while for severe stages of SA also by studying FCGR2A variants. Additionally, the genotyping of FCGR2A and FCGR3B might serve as a marker of SA progression.

Analysis of FCGR3A-p.176Val variants in women with recurrent pregnancy loss and the association with CD16a expression and anti-HLA antibody status

Natural Killer (NK) cells have been implicated in recurrent pregnancy loss (RPL). The p.Val176Phe (or Val158Phe) Single Nucleotide Polymorphism (SNP) in the FCGR3A gene encoding the FcγRIIIA or CD16a receptor has been associated with an enhanced affinity for IgG and stronger NK-mediated antibody-dependent cellular cytotoxicity. We hypothesized that the presence of at least one p.176Val variant associates with RPL and increased CD16a expression and alloantibodies e.g., against paternal human leukocyte antigen (HLA). In 50 women with RPL, we studied frequencies of the p.Val176Phe FCGR3A polymorphisms. Additionally, CD16a expression and anti-HLA antibody status were analyzed by flowcytometry and Luminex Single Antigens. In woman with RPL, frequencies were: 20% (VV), 42% (VF) and 38% (FF). This was comparable to frequencies from the European population in the NCBI SNP database and in an independent Dutch cohort of healthy women. NK cells from RPL women with a VV (22,575 [18731-24607]) and VF (24,294 [20157-26637]) polymorphism showed a higher expression of the CD16a receptor than NK cells from RPL women with FF (17,367 [13257-19730]). No difference in frequencies of the FCGR3A-p.176 SNP were detected when comparing women with or without class I and class II anti-HLA antibodies. Our study does not provide strong evidence for an association between the p.Val176Phe FCGR3A SNP and RPL.

Impact of FCGR2A R131H, FCGR3A F158V and FCGR3B NA1/NA2 polymorphisms on response to fc-containing TNF inhibitors in Tunisian rheumatoid arthritis patients.

Single nucleotid polymorphisms (SNPs) of Fc-gamma receptors (FcgRs), by inducing a variation of their affinity to the Fc-region of immunoglobulins, might influence the efficacy of Fc-containing biologics prescribed in rheumatoid arthritis (RA). Our aim was to investigate associations of FCGR2A, FCGR3A and FCGR3B SNPs with TNF-inhibitors (TNFi)' response in Tunisian RA patients. A cross-sectional, observational and analytic multicentric cohort study was conducted in a group of 47 Tunisian RA patients treated with (etanercept [ETA], adalimumab [ADL] and infliximab [IFX]). Treatment outcome was evaluated after 6months. R131H-FCGR2A, F158V-FCGR3A and NA1/NA2-FCGR3B SNPs were genotyped. The analytic study including all types of TNFi showed that FCGR3A-F/F low-affinity receptor was associated with a greater decrease of DAS28, while FCGR3B-NA1/NA1 high-affinity receptor was associated with a lower decrease of DAS28 in ADL group. Furthermore, both of high affinity receptors FCGR3B-NA1/NA1 and FCGR3A-V/V were more prevalent in non-responders to ADL, according to EULAR criteria. Identifying reliable biomarkers of response to biologics in RA is necessary to improve responsiveness, preserve joints' functions and structure, and reduce treatment's cost. Our study showed that FCGR3A and FCGR3B polymorphisms might have an impact on TNFis' response in RA Tunisian patients since bad response was more frequent in homozygous carriers of high affinity alleles FCGR3A-V and FCGR3B-NA1.

Prediction of response to anti-TNF treatment using laboratory biomarkers in patients with rheumatoid arthritis: a systematic review

ObjectivesIn this systematic review, we aim to identify laboratory biomarkers that predict response to tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA).MethodsEMBASE, PubMed and Cochrane Library (CENTRAL)...

Adoptive immunotherapy overcomes genetic susceptibility to bloodstream infections due to fc-gamma receptor polymorphisms after liver transplantation

Single nucleotide polymorphisms (SNPs) in FCGR3A can predict the susceptibility of liver transplant (LT) recipients to bloodstream infections (BSI) and clinical outcomes following living-donor LT (LDLT). Here, we retrospectively analyzed the relationship of adoptive immunotherapy with activated natural killer (NK) cells from perfusate effluents of liver allografts against BSI following LDLT. Higher BSI incidence and lower survival were observed in LT recipients with FcγRIIIa (158F/F or F/V) (n=81) who did not receive adoptive immunotherapy (n=55) than in those who did (n=26) (BSI frequency, 36.4% vs. 11.5%; p =.033; log-rank p =.047). After matching patient background using propensity score, similar results were obtained (BSI ratio, 41.7% vs. 12.5%; p =.049; log-rank p=.039). The predominant BSI pathogens in patients who did and did not receive adoptive immunotherapy were gram-negative rods (n=3, 100%) and gram-positive cocci (GPC) (n=15, 65.2%), respectively. The proportion of NK cells administered to patients with BSI was significantly lower than that administered to patients without BSI (Number: 80.3 (29.9-239.2)× 106 cells vs. 37.1 (35.6-50.4)× 106 ; p=.033, percentage; 14.1 (13.3-17.8)% vs. 34.6 (16.5-47)%, p=.0078). Therefore, adoptive immunotherapy with NK cells was associated with the reduced post-transplant BSI related to GPCs due to FcγRIIIa SNP in LT recipients.

FCGR3A gene duplication, FcγRIIb-232TT and FcγRIIIb-HNA1a associate with an increased risk of vertical acquisition of HIV-1.

BackgroundSome mother-to-child transmission (MTCT) studies suggest that allelic variations of Fc gamma receptors (FcγR) play a role in infant HIV-1 acquisition, but findings are inconsistent. To address the limitations of previous studies, the present study investigates the association between perinatal HIV-1 transmission and FcγR variability in three cohorts of South African infants born to women living with HIV-1.MethodsThis nested case-control study combines FCGR genotypic data from three perinatal cohorts at two hospitals in Johannesburg, South Africa. Children with perinatally-acquired HIV-1 (cases, n = 395) were compared to HIV-1-exposed uninfected children (controls, n = 312). All study participants were black South Africans and received nevirapine for prevention of MTCT. Functional variants were genotyped using a multiplex ligation-dependent probe amplification assay, and their representation compared between groups using logistic regression analyses.ResultsFCGR3A gene duplication associated with HIV-1 acquisition (OR = 10.27; 95% CI 2.00–52.65; P = 0.005) as did the FcγRIIb-232TT genotype even after adjusting for FCGR3A copy number and FCGR3B genotype (AOR = 1.72; 95%CI 1.07–2.76; P = 0.024). The association between FcγRIIb-232TT genotype and HIV-1 acquisition was further strengthened (AOR = 2.28; 95%CI 1.11–4.69; P = 0.024) if adjusted separately for FCGR2C c.134-96C>T. Homozygous FcγRIIIb-HNA1a did not significantly associate with HIV-1 acquisition in a univariate model (OR = 1.42; 95%CI 0.94–2.16; P = 0.098) but attained significance after adjustment for FCGR3A copy number and FCGR2B genotype (AOR = 1.55; 95%CI 1.01–2.38; P = 0.044). Both FcγRIIb-232TT (AOR = 1.83; 95%CI 1.13–2.97; P = 0.014) and homozygous FcγRIIIb-HNA1a (AOR = 1.66; 95%CI 1.07–2.57; P = 0.025) retained significance when birthweight and breastfeeding were added to the model. The common FCGR2A and FCGR3A polymorphisms did not associate with HIV-1 acquisition.ConclusionsCollectively, our findings suggest that the FcγRIIb-232TT genotype exerts a controlling influence on infant susceptibility to HIV-1 infection. We also show a role for less studied variants–FCGR3A duplication and homozygous HNA1a. These findings provide additional insight into a role for FcγRs in HIV-1 infection in children.

Abstract 31 Testing of Cord Blood Units for Non-Hematopoietic Markers

IntroductionCord blood units (CBU) are tested at banking for markers relevant to donor safety (infectious disease markers) and hematopoietic stem cell transplantation (cellularity and HLA typing). As CBUs are being increasingly used for new, non-transplant purposes, additional markers are sometimes needed for CBU selection.ObjectiveWe describe here our procedure for testing CBU, looking for specific NK cell characteristics: KIR haplotype B (associated with more activating KIRs), and Fc gamma receptor III A (FCGR3A) 158 V/V (presence of a homozygous valine in position 158) polymorphism (which has a higher affinity for IgG), as requested by some of our clients for non-transplant studies.MethodsFirst, a list of eligible CBUs was established, based on the order specifications. Testing was requested from an outside lab (Histogenetics, Ossining, New York). As CBU DNA is a precious resource, we wanted to limit the number of new samples to be sent by first testing leftover samples from HLA typing, then sending additional samples to the lab, to reach the required number of CBUs. Testing was done sequentially (Figure 1): first, KIR typing, then FCGR3A polymorphism on the CBU with KIR B haplotype.ResultsA total of 216 samples were selected for KIR testing (130 from stored DNA and 86 from newly sent DNA); 154 (71%) were found to have at least one B haplotype receptor. For those, FCGR3A polymorphism was tested; 60 samples (39%) were F/F, 70 (46%) F/V, and 23 (15%) V/V (Figure 1), in line with expected frequencies from the literature. Average TAT for KIR testing was 13 days and an additional 18 days for FCGRA3.Figure 1.Testing protocol.DiscussionPerforming additional testing can easily be integrated into a bank’s routine and help select CBU for purposes other than transplantation. When several markers are needed, sequential testing is an efficient and cost-saving method.

To Determine the Genotyping of Fc-gamma Receptor FCGR2A Polymorphism as Genetic Susceptibility to Neonatal Sepsis: A Study from a Tertiary Center of North India.

Neonatal sepsis term is an infection of newborns <28 days of age. It is a common cause of death in developing countries. The receptor-gamma receptor FCGR2A has been shown to be associated with neonatal sepsis. It is an activating receptor found in many cell types such as monocytes, neutrophils, macrophages, platelets, and others. The receptor has a polymorphism (single-nucleotide polymorphism rs1801274) in its gene (FCGR2A) that encodes either a histidine (H) or arginine (R) at amino acid position 131. There are many studies showing the impact of these FCGR2A polymorphisms on sepsis. Our study aims to determine the prevalence of Fc-gamma receptor FCGR2A (rs1801274) polymorphism in neonatal sepsis and control in Eastern UP populations. We conducted a cross-sectional descriptive study of 590 patients (310 healthy individuals and 280 sepsis patients) to determine polymorphisms in the CD32A coding region in neonates. All individuals were genotyped for a variant at position 131 of the FcγRIIA gene. In our study, the prevalence of FcγRIIa polymorphism is more in neonates with sepsis than in noninfected neonates. It was observed that the heterozygous allele (AG) were significantly increased in septic neonates when compared to the normal. Our data indicate that FcγRIIA genotyping can be used as a marker of genetic susceptibility to sepsis.

Impact of FcγR variants on the response to alemtuzumab in multiple sclerosis.

Allelic variants of genes encoding for the Fc gamma receptors IIIA and IIA have been associated with the clinical response to cell‐depleting antibodies in lymphoma patients. Here, we tested the hypothesis that FCGR3A and FCGR2A high‐affinity polymorphisms predict clinical outcomes to alemtuzumab therapy in 85 patients with relapsing‐remitting multiple sclerosis. No differences in clinical and MRI‐based efficacy parameters, the development of severe infusion‐associated reactions and secondary autoimmune diseases during a 2 year follow‐up was observed based on FCGR3A or FCGR2A polymorphisms. This study does not support the use of FCGR genetic variants to predict clinical outcomes to alemtuzumab.

Decline in Left Ventricular Ejection Fraction Following Anthracyclines Predicts Trastuzumab Cardiotoxicity

ObjectivesThe aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC). BackgroundCardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results. MethodsA total of 222 patients with early-stage human epidermal growth factor receptor 2–positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%. ResultsTRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a “low-risk TRC score” to identify patients with low TRC incidence. ConclusionsLow baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039)

FCGR3A and FCGR2A Genotypes Differentially Impact Allograft Rejection and Patients' Survival After Lung Transplant.

Fc gamma receptors (FcγRs) play a major role in the regulation of humoral immune responses. Single-nucleotide polymorphisms (SNPs) of FCGR2A and FCGR3A can impact the expression level, IgG affinity and function of the CD32 and CD16 FcγRs in response to their engagement by the Fc fragment of IgG. The CD16 isoform encoded by FCGR3A [158V/V] controls the intensity of antibody-dependent cytotoxic alloimmune responses of natural killer cells (NK) and has been identified as a susceptibility marker predisposing patients to cardiac allograft vasculopathy after heart transplant. This study aimed to investigate whether FCGR2A and FCGR3A polymorphisms can also be associated with the clinical outcome of lung transplant recipients (LTRs). The SNPs of FCGR2A ([131R/H], rs1801274) and FCGR3A ([158V/F], rs396991) were identified in 158 LTRs and 184 Controls (CTL). The corresponding distribution of genotypic and allelic combinations was analyzed for potential links with the development of circulating donor-specific anti-HLA alloantibodies (DSA) detected at months 1 and 3 after lung transplant (LTx), the occurrence of acute rejection (AR) and chronic lung allograft dysfunction (CLAD), and the overall survival of LTRs. The FCGR3A [158V/V] genotype was identified as an independent susceptibility factor associated with higher rates of AR during the first trimester after LTx (HR 4.8, p < 0.0001, 95% CI 2.37–9.61), but it could not be associated with the level of CD16- mediated NK cell activation in response to the LTR's DSA, whatever the MFI intensity and C1q binding profiles of the DSA evaluated. The FCGR2A [131R/R] genotype was associated with lower CLAD-free survival of LTRs, independently of the presence of DSA at 3 months (HR 1.8, p = 0.024, 95% CI 1.08–3.03). Our data indicate that FCGR SNPs differentially affect the clinical outcome of LTRs and may be of use to stratify patients at higher risk of experiencing graft rejection. Furthermore, these data suggest that in the LTx setting, specific mechanisms of humoral alloreactivity, which cannot be solely explained by the complement and CD16-mediated pathogenic effects of DSA, may be involved in the development of acute and chronic lung allograft rejection.

Prognostic Impact of Germ-Line FCGR2A (H131R), FCGR3A (F158V), and FCGR2B (I232T) Single Nucleotide Polymorphisms in Lymphoma Patients Treated with Obinutuzumab or Rituximab in Combination with Chemotherapy: Results from the Phase III GALLIUM and GOYA Clinical Trials

Prognostic Impact of Germ-Line FCGR2A (H131R), FCGR3A (F158V), and FCGR2B (I232T) Single Nucleotide Polymorphisms in Lymphoma Patients Treated with Obinutuzumab or Rituximab in Combination with Chemotherapy: Results from the Phase III GALLIUM and GOYA Clinical Trials

A comprehensive overview of FCGR3A gene variability by full-length gene sequencing including the identification of V158F polymorphism

The FCGR3A gene encodes for the receptor important for antibody-dependent natural killer cell-mediated cytotoxicity. FCGR3A gene polymorphisms could affect the success of monoclonal antibody therapy. Although polymorphisms, such as the FcγRIIIA-V158F and -48L/R/H, have been studied extensively, an overview of other polymorphisms within this gene is lacking. To provide an overview of FCGR3A polymorphisms, we analysed the 1000 Genomes project database and found a total of 234 polymorphisms within the FCGR3A gene, of which 69%, 16%, and 15% occur in the intron, UTR, and exon regions respectively. Additionally, only 16% of all polymorphisms had a minor allele frequency (MAF) > 0.01. To facilitate (full-length) analysis of FCGR3A gene polymorphism, we developed a FCGR3A gene-specific amplification and sequencing protocol for Sanger sequencing and MinION (Nanopore Technologies). First, we used the Sanger sequencing protocol to study the presence of the V158F polymorphism in 76 individuals resulting in frequencies of 38% homozygous T/T, 7% homozygous G/G and 55% heterozygous. Next, we performed a pilot with both Sanger sequencing and MinION based sequencing of 14 DNA samples which showed a good concordance between Sanger- and MinION sequencing. Additionally, we detected 13 SNPs listed in the 1000 Genome Project, from which 11 had MAF > 0.01, and 10 SNPs were not listed in 1000 Genome Project. In summary, we demonstrated that FCGR3A gene is more polymorphic than previously described. As most novel polymorphisms are located in non-coding regions, their functional relevance needs to be studied in future functional studies.

A Case-Control Study on Association of Ulcerative Colitis with FCGR2A Gene Polymorphisms in Chinese Patients.

The Fc gamma receptor IIa (FcγRIIa), encoded by FCGR2A gene, has been suggested to play a crucial role in immunity by linking immunoglobulin G antibody-mediated responses with cellular effector and regulatory functions. Polymorphisms in FCGR2A have been shown to affect FcγRIIa/antibody interactions and have been potentially implicated in several autoimmune and inflammatory conditions. This study was designed to analyze the association between ulcerative colitis (UC) and FCGR2A polymorphisms in the Chinese population. A total of 422 patients with UC and 710 unaffected controls were recruited. Five single nucleotide polymorphisms of FCGR2A (rs1801274, rs10800309, rs4657039, rs511278, and rs6696854) were genotyped by SNaPshot. Analyses for linkage disequilibrium (LD) and haplotype studies of FCGR2A were performed for all study subjects. The frequency of the minor homozygote (CC) of the rs1801274 SNP of FCGR2A was shown to be significantly lower in patients with UC than in controls (7.1% vs. 12.1%, p = 0.008). Two haplotype blocks, formed by FCGR2A (rs4657039, rs6696854, and rs10800309) and FCGR2A (rs1801274 and rs511278), respectively, were observed in the subsequent LD analysis. The TC haplotype constructed by the major allele of FCGR2A (rs1801274 and rs511278) was more prevalent in UC patients compared with controls (65.2% vs. 60.2%, p = 0.017). The minor homozygote (CC) of FCGR2A (rs1801274) may contribute to decrease the susceptibility to UC and the TC haplotype formed by FCGR2A (rs1801274 and rs511278) may increase the risk of UC in the Chinese population.

Polymorphism of FCGR3A gene in chronic beryllium disease.

Previously we showed that alveolar macrophages(AMs) from patients with chronic beryllium disease(CBD) and beryllium sensitization(BeS) demonstrated significantly greater cell surface CD16(encoded by the FCGR3A gene) than controls. We hypothesized that these differences were related to polymorphisms in the FCGR3A gene. This study was to determine the association between FCGR3A polymorphisms in CBD, BeS versus controls as well as clinical data, providing potential information about disease pathogenesis, risk and activity. 189 CBD/154 BeS /150 controls (92 Be-exposed-non-diseased and 58 healthy controls) were included in this study. Sequence specific primers polymerase chain reaction(PCR-SSP) was used to determine FCGR3A 158V/F polymorphisms. We found significantly higher frequencies of the 158V allele (OR:1.60 (CI: 1.17-2.19),p=0.004) and 158VV homozygotes (OR:2.97 (CI:1.48-5.97) p=0.007) in CBD versus controls. No differences were found in the frequencies of FCGR3A alleles or genotypes between BeS versus controls and CBD versus BeS. Average changes in exercise testing maximum workload(Wlm),maximum oxygen consumption(VO2m) and diffusion capacity of carbon monoxide(DLCO) demonstrated greater decline over time in those CBD cases with the 158VV gene, modelled between 10 and 40 years from first beryllium exposure. The FCGR3A V158F polymorphism is associated with CBD compared to BeS and controls and may impact lung function in CBD.

Infliximab Biosimilars in the Age of Personalized Medicine

Structural and functional differences between REMICADE and its two FDA-approved biosimilars appear to have clinical implications. We suggest a personalized biosimilar substitution approach based on prescribed indication, biosimilar afucosylation level, and a patient's FCGR3A polymorphism. We also advocate for establishing glycosylation variation limits for biosimilar approvals.

The Association of FCGR2A and FCGR3A polymorphisms with outcomes in cetuximab treated metastatic colorectal cancer patients: CCTG and AGITG CO.20 trial analysis.

633 Background: We previously reported that the Fc-gamma receptor (FCGR) germline polymorphism in the FCGR2A gene (rs1801274; His (H) to Arg (R) substitution) but not FCGR3A (rs396991; Phe (F) to Val (V)) was associated with cetuximab benefit on overall survival (OS) in metastatic colorectal cancer patients (CCTG CO.17 trial). We performed a validation of these results in CO.20, a randomized trial of cetuximab+placebo vs. cetuximab+brivanib for metastatic, chemotherapy refractory, wild type K-RAS colorectal cancer. Methods: After genotyping DNA extracted from whole blood, the polymorphism relationships with OS and progression-free survival (PFS) were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. Results: Of 592/725 (82%) K-RAS wild type patients with available DNA and genotyping, those carrying the higher affinity FCGR2A H/H genotype (N = 165; 28%) had improved OS (HR 0.53; 95%CI:0.41-0.68) and PFS (HR 0.65; 95%CI:0.51-0.83) compared to those carrying the lower affinity R/R genotype (N = 128; 22%), corresponding to median absolute benefits of 3.7 (OS) and 3.3 months (PFS). The H/R genotype (N = 299; 50%) had intermediate outcomes. No significant associations were found between FCGR3A genotype and OS or PFS. No interaction between FCGR polymorphisms and treatment arm was observed. Patients carrying the double wild type combination of FCGR2A H/H and FCGR3A F/F genotypes (N = 45; 7.6%) had significantly better outcomes than other patients, particularly those carrying the rare (N = 11; 2%) R/R+ V/V genotype combination, corresponding to median absolute benefits of 12.5 (OS; HR 0.33 95%CI:0.16-0.68) and 4.5 (PFS; HR 0.45 95%CI:0.22-0.92) months. There were no significant associations between FCGR polymorphisms and either any grade of 3/4 toxicity or skin rash. Conclusions: In KRAS-wild type, cetuximab-treated patients, FCGR2A polymorphism was independently replicated to be associated with clinical outcome without affecting toxicity profiles. Additionally, in this large dataset, FCGR3A appears to modulate the relationship between FCGR2A polymorphism and outcome.