FcγRIIB, the only inhibitory IgG Fc receptor, functions to suppress the hyper-activation of immune cells. Numerous studies have illustrated its inhibitory function through the ITIM motif in the cytoplasmic tail of FcγRIIB. However, later studies revealed that in addition to the ITIM, the transmembrane (TM) domain of FcγRIIB is also indispensable for its inhibitory function. Indeed, recent epidemiological studies revealed that a non-synonymous single nucleotide polymorphism (rs1050501) within the TM domain of FcγRIIB, responsible for the I232T substitution, is associated with the susceptibility to systemic lupus erythematosus (SLE). In this review, we will summarize these epidemiological and functional studies of FcγRIIB-I232T in the past few years, and will further discuss the mechanisms accounting for the functional loss of FcγRIIB-I232T. Our review will help the reader gain a deeper understanding of the importance of the TM domain in mediating the inhibitory function of FcγRIIB and may provide insights to a new therapeutic target for the associated diseases.
Autoimmune Diseases ; drug therapy ; genetics ; immunology ; Humans ; Protein Domains ; Receptors, IgG ; chemistry ; immunology

ATP-Binding Cassette Transporters ; genetics ; DNA Copy Number Variations ; genetics ; Genetic Predisposition to Disease ; Gout ; genetics ; Humans ; Receptors, IgG ; genetics ; Receptors, Interleukin-17 ; genetics

BACKGROUNDTakayasu arteritis (TA) is a rare inflammatory arteriopathy of unknown etiology. The aim of this study was to investigate the genetic susceptibility to TA in a Chinese population.

METHODSFour single nucleotide polymorphisms (SNPs) those locate in the IL12B region (rs56167332), the MLX region (rs665268), the FCGR2A/FCGR3A locus (rs10919543), and the HLA-B/MICA locus (rs12524487), associated with TA in different population, were genotyped in 123 Chinese TA patients and 147 healthy controls from January 2013 to August 2014. A Chi-square test was used to test for genotype/allele frequencies variants.

RESULTSAmong the four SNPs, rs10919543 was found to be significantly associated with TA in the studied population. The GG genotype of rs10919543 at the FCGR2A/FCGR3A locus is a high risk factor (odds ratio [OR] = 6.532, 95% confidence interval [CI] = 2.402 - 17.763, P < 0.001) for TA. Among TA patients, the level of eosinophil granulocytes (Eos) in the peripheral blood was observed to be higher in the GG group of rs10919543 (n = 23, Eos = 0.11 [0.08, 0.17] ×109/L) than the GA + AA group (n = 100, Eos = 0.08 [0.05, 0.13] ×109/L, P = 0.028). No correlation between the genotypes of the other three SNPs and TA patients was observed.

CONCLUSIONSOur findings revealed unique genetic pattern in Chinese TA patients that may be partly responsible for the higher risk of TA in this population. FCGR2A/FCGR3A-related immune disorder might contribute to the etiology of TA.

Adolescent ; Adult ; Child ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Receptors, IgG ; genetics ; Takayasu Arteritis ; etiology ; genetics

OBJECTIVETo assess the association of several single nucleotide polymorphisms and haplotypes of the FCGR2A gene with ulcerative colitis (UC) among Chinese patients.

METHODSFor 198 UC patients and 356 healthy controls, the alleles and genotypes of the FCGR2A gene (rs1801274, rs10800309 and rs6696854) were detected with a multiplex SNaPshot technique. All subjects were also subjected to linkage disequilibrium and haplotype analyses.

RESULTSThe mutant homozygote (CC) of the FCGR2A gene rs1801274 polymorphism was less frequent among UC patients compared with the controls (5.56% vs. 11.80%, P=0.017, OR=0.440, 95%CI: 0.221-0.875). However, the allelic and genotypic distributions of other two SNPs did not differ significantly between the two groups (all P>0.05). Furthermore, no association of the three SNPs (rs1801274, rs10800309 and rs6696854) of the FCGR2A gene with the severity and location of the UC was found (all P>0.05). The three SNPs were shown to be in a strong linkage [rs1801274-rs10800309 (D'=0.863, r=0.634); rs1801274-rs6696854 (D'=0.753, r=0.546); rs10800309-rs6696854(D'=0.990, r=0.802)]. Moreover, the frequency of T-A-T haplotype was higher among the UC patients compared with the controls (67.40% vs. 60.93%, P=0.032, OR=1.326, 95%CI: 1.024-1.717).

CONCLUSIONOur findings suggested that the mutant homozygote (CC) of the FCGR2A gene (rs1801274) may have a protective role among Chinese patients with UC. Moreover, the T-A-T haplotype formed by rs1801274, rs10800309 and rs6696854 may confer a higher risk for UC.

Adult ; Asian Continental Ancestry Group ; genetics ; Colitis, Ulcerative ; genetics ; Female ; Genetic Predisposition to Disease ; genetics ; Haplotypes ; genetics ; Humans ; Polymorphism, Single Nucleotide ; genetics ; Receptors, IgG ; genetics

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disorder that principally attacks flexible joints and synovia. The precise pathogenesis of RA remains unclear, and genetic factors probably play an important role in its etiology. In addition to genes from human leukocyte antigen (HLA) region, such as HLA-DRB, genes from non-HLA region, such as TIM-3, PTPN22, TRAF1/C5, STAT4, CCR5, PADI4 and FCGR2A may also contribute to its susceptibility. The advance in molecular genetics research on RA is reviewed here.
Arthritis, Rheumatoid ; genetics ; Exome ; Genetic Predisposition to Disease ; HLA-DRB1 Chains ; genetics ; Hepatitis A Virus Cellular Receptor 2 ; Humans ; Membrane Proteins ; genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; genetics ; Receptors, IgG ; genetics

OBJECTIVETo evaluate the impact of Fc gamma receptor IIIa (FcγR IIIa) polymorphisms on the efficacy of rituximab (RTX) combined chemotherapy for patients with diffuse large B-cell lymphoma (DLBCL).

METHODSFcγRIIIa polymorphisms were analyzed by PCR in 122 patients and 100 healthy controls. All patients received 8(4-12) cycles of RTX combined chemotherapy.

RESULTS78(63.93%) patients with F/F, 5(4.10%) with V/V, and 39(31.97%) with V/F were identified, which were not different compared to controls. Patients with different FcγRIIIa genotypes did not have any difference in terms of gender, age, molecular subtypes, lactate dehydrogenase (LDH) or international prognostic index (IPI). The overall response rate (ORR) was 89.35% with a complete response (CR) of 80.33% and a partial response (PR) of 9.02%. The ORR was 83.33%, 100.00% and 100.00% in F/F, V/V and V/F, respectively. A higher response rate was observed in V/V and V/F as compared with F/F (P<0.05). With a median follow-up of 35 months (range: 12-62 months), 46(37.71%) patients had relapsed and 40 (32.79%) cases progressed and ended in death. The 3-year progress-free survival (PFS) rate was 41.03%, 100.00%, 100.00% in F/F, V/V and V/F, respectively. The 3-year overall survival (OS) rate was 48.72%, 100.00% and 100.00% in patients with three genotypes. The PFS and OS rate were significantly higher in V/V and V/F as compared with F/F (P<0.05).

CONCLUSIONFcγR III a polymorphisms could predict response and prognosis of RTX combined chemotherapy for patients with DLBCL.

Antibodies, Monoclonal, Murine-Derived ; administration & dosage ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Asian Continental Ancestry Group ; genetics ; Disease-Free Survival ; GPI-Linked Proteins ; Humans ; Lymphoma, Large B-Cell, Diffuse ; drug therapy ; genetics ; Polymorphism, Genetic ; Prognosis ; Receptors, IgG ; genetics ; Remission Induction ; Rituximab

Adult ; Aged ; Autoimmune Diseases ; genetics ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Receptors, IgG ; genetics ; Thrombocytopenia ; genetics ; Young Adult

OBJECTIVEKawasaki disease (KD) is a common autoimmune vasculitis. It has been regarded as the leading cause of acquired heart disease in children. This study aimed to assess the relationship between genome-wide association study (GWAS)-linked gene loci and KD.

METHODBy March of 2013, the published GWAS literatures of KD were retrieved from the databases including PubMed, MEDLINE, Web of Science, Cochrane Library, CNKI, VIP and Wanfang, and the gene loci associated with KD at genome-wide significance of P < 5.0×10(-8) were determined. For each of the gene loci, one single-nucleotide polymorphism (SNP) with strong association with KD was chosen for meta-analysis. Then the published case-control studies reporting the associations of the SNPs with KD were collected from English and Chinese databases with the same criteria. The Meta-analyses were conducted with RevMan 5.1 software after screening and evaluation.

RESULTA total of 4 gene loci including FCGR2A, BLK, CD40 and HLA were observed having association with KD at genome-wide significance of P < 5.0×10(-8) in at least one GWAS. The risk alleles of the SNPs in the gene loci were all more common in patients with KD relative to controls in the systematic reviews with 8, 4, 6 and 4 extracted case-control studies, respectively[ FCGR2A rs1801274: P < 0.001, OR = 1.40, 95% CI (1.30, 1.51); BLK rs2254546: P < 0.001, OR = 1.69, 95% CI (1.52, 1.88); CD40 rs4813003: P < 0.001, OR = 1.31, 95% CI (1.22, 1.41); HLA rs2857151: P < 0.001, OR = 1.41, 95% CI (1.27, 1.57)]. The significant publication bias was not observed in the meta-analyses.

CONCLUSIONOur results confirmed the overall association of the 4 gene loci with KD in observed populations, together with the consistent presence of the relationship between BLK or HLA and KD in the populations, suggesting that it is hopeful to find the genetic marker combination predicting the risk of KD, the formation of secondary coronary artery lesions and the resistance of intravenous immunoglobulin, by further seeking the function SNPs of the gene loci and investigating the effect on the important clinical phenotypes of KD.

Asian Continental Ancestry Group ; genetics ; Child ; Child, Preschool ; Gene Frequency ; Genetic Linkage ; Genetic Loci ; Genetic Markers ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Mucocutaneous Lymph Node Syndrome ; genetics ; Polymorphism, Single Nucleotide ; Receptors, IgG ; genetics

This study was aimed to investigate the correlation of FcγR polymorphisms with the susceptibility, severity and efficacy of immunotherapy for patients with immune thrombocytopenia (ITP). PCR and DNA sequencing were used to determine the polymorphisms of FcγRIIA, FcγRIIIA and FcγRIIB in 44 ITP patients, and in 97 healthy control subjects. The results indicated that FcγRIIIA-158V/F polymorphisms between patients and controls were statistically significantly different (P = 0.015); among FcγRIIIA genotypes, the frequency of 158V/V homotype was higher in ITP (P = 0.005). However, the FcγRIIA-131H/R or FcγRIIB-232T/I polymorphisms were not significantly different between patients and controls; there were no correlation of FcγRIIA, FcγRIIIA and FcγRIIB genotype frequencies with the platelet counts or the courses of ITP; among the 38 ITP patients who received treatments, the complete response (CR) rate was 42% (16/38), and partial response (PR) rate was 34% (13/38). The therapeutic response was significantly different between FcγRIIIA-158V/V homotype and 158F/V heterotype (P = 0.034). The CR of patients with 158V/V homotype was obviously lower than that of patients with 158F/V, but the frequencies of FcγRIIA and FcγRIIB genotypes not correlated with the responsiveness to treatment. The CR rate of 6 patients treated with rituximab was 67%, and PR rate was 17%. The overall response rate was as high as 84%, the adverse reactions were not observed. It is concluded that the polymorphism of FcγRIIIA-158V/F, but not FcγRIIA-131H/R or FcγRIIB-232T/I, correlates with the patient susceptibility and therapeutic response of ITP.
Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Murine-Derived ; therapeutic use ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Purpura, Thrombocytopenic, Idiopathic ; drug therapy ; genetics ; immunology ; Receptors, IgG ; genetics ; Risk Factors ; Rituximab ; Young Adult

BACKGROUND: Human neutrophil antigens (HNAs) are involved in autoimmune and alloimmune neutropenia and transfusion-related acute lung injury. The HNA-1 system is important in immunogenetics, and allele frequencies have been described in different populations. This study investigated the frequency of FCGR3B alleles encoding HNA-1a, HNA-1b, and HNA-1c among Thai blood donors and compared these frequencies with those previously reported for other populations. METHODS: Eight hundred DNA samples obtained from unrelated healthy blood donors at the National Blood Centre, Thai Red Cross Society, Bangkok, and the Blood Bank, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, were included. Samples were simultaneously typed for each FCGR3B allele using an in-house polymerase chain reaction with sequence-specific primer (PCR-SSP) technique. RESULTS: The frequencies of FCGR3B*1, FCGR3B*2, and FCGR3B*3 alleles in central Thai blood donors were 0.548, 0.452, and 0.004, respectively; only FCGR3B*1 and FCGR3B*2 alleles were found in northern Thai blood donors (0.68 and 0.32, respectively). Compared with other Asian populations, central Thais had higher frequencies of the FCGR3B*2 allele (P<0.001), while the frequencies of the FCGR3B*1 and FCGR3B*2 alleles in northern Thais were similar to those previously reported in Taiwanese and Japanese populations. In contrast, the frequencies of the FCGR3B*1 and FCGR3B*2 alleles in the northern Thai population were statistically different from those observed in central Thai, Korean, German, and Turkish populations. CONCLUSIONS: FCGR3B allele frequencies were significantly different between central and northern Thai blood donors. Our in-house PCR-SSP method is a simple, cost-effective, and convenient method for FCGR3B allele detection.
Asian Continental Ancestry Group/*genetics ; *Blood Donors ; DNA/analysis ; DNA Primers/chemistry/metabolism ; GPI-Linked Proteins/genetics ; Gene Frequency ; Genotype ; Humans ; Polymerase Chain Reaction ; Receptors, IgG/*genetics ; Thailand