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The response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcgammaRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcgammaR genomic locus is complex, containing regions of copy number variation (CNV) which can alter receptor expression and leukocyte responses to IgG. Combined paralogue ratio tests (PRTs) were used to distinguish three intervals within the FCGR locus which undergo CNV, and to determine FCGR gene copy number (CN). There were significant differences in FCGR3B and FCGR3A CNV profiles between Caucasian, East Asian and Kenyan populations. A previously noted association of low FCGR3B CN with SLE in Caucasians was supported [OR = 1.57 (1.08-2.27), P = 0.018], and replicated in Chinese [OR = 1.65 (1.25-2.18), P = 4 x 10(-4)]. There was no association of FCGR3B CNV with vasculitis, nor with malarial or bacterial infection. Linkage disequilibrium (LD) between multi-allelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus was defined for the first time. Despite LD between FCGR3B CNV and a variant in FcgammaRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcgammaRIIB-232T allele were individually strongly associated with SLE risk. Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Further interpretations of contributions to pathogenesis by FcgammaRs must be made in the context of LD involving CNV regions.

Objective: Recent genome-wide association studies have identified multiple novel loci associated with obesity in Europeans. We hypothesized that these genetic variants may be associated with obesity and type 2 diabetes (T2D) in Chinese., Research Design and Methods: We examined 14 associated single-nucleotide polymorphisms at 12 loci (NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15) in 605 healthy adults, 1087 healthy adolescents and 6013 T2D patients from Hong Kong., Results: The European at-risk alleles at five loci including GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 were significantly associated with increased body mass index (BMI), waist circumference (4.5 x 10(-8) < P < 0.024), and/or obesity risk (odds ratio 1.14-1.22, 2.0 x 10(-5) < P < 0.002) in our Chinese populations. The former four loci as well as LIN7C/BDNF were also modestly associated with T2D risk (odds ratio 1.09-1.22, 0.008 < P < 0.041), but the associations were lost after adjustment for BMI, suggesting their roles in T2D risk are mediated through modulation of adiposity. Joint effect analyses of the five adiposity loci revealed an increase of about 0.29 kg/m(2) in BMI with each additional copy of at-risk allele (P(trend) = 4.2 x 10(-12))., Conclusions: Our findings support the important contribution of GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 in the regulation of adiposity, which in turn affects T2D risk in Chinese.

Copy number variation (CNV) is common in genomic regions encoding immune-related genes and can impact polygenic autoimmunity. FCGR3B CNV is associated with susceptibility to systemic autoimmunity in Caucasian populations. In this study, we examined FCGR3B CNV in patients with the autoimmune disease lupus nephritis (LN) in a Chinese population. The study includes 202 patients with histologically verified LN and 146 geographically matched healthy controls. To identify CNV at the FCGRB locus, quantitative polymerase chain reaction (PCR) was done with TaqMan( TM) probes and relative copy number was estimated with relative quantitative 2(-DeltaDeltaCt) method. The distribution of FCGR3B relative copy number did not differ significantly between the LN patients and the controls (1.17 +/- 0.42 for LN; 1.15 +/- 0.37 for controls; p = 0.627). The difference was still not significant when the data were stratified by gender. There was no significant difference when the LN patients were divided by pathological phenotype (proliferative LN compared with non-proliferative p = 0.511; AI < 12 compared with AI > or = 12, p = 0.401; and chronicity index (CI) < 4 compared with CI > or = 4, p = 0.058) or lupus disease activity index (SLEDAI < or = 10 compared with SLEDAI > 10, p = 0.996). The data suggest that FCGR3B CNV was not associated with LN development or progression in this Chinese population. These results were surprising given the strong in a Caucasian population.

Anti-glomerular basement membrane antibody disease (anti-GBM disease) is a rare disorder characteristic of universally poor outcome. Fcgamma receptors (FcgammaRs) play important roles in anti-GBM disease based on evidence from animal models. Copy number variation (CNV) influences disease susceptibility. The FcgammaRs genes show CNV, and CNV of the FCGR3B gene is associated with glomerulonephritis in systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody-associated small vasculitis. Here, we investigated CNV of three FCGR genes, including two (FCGR3A and FCGR3B) for activating FcgammaRs and one (FCGR2B) for inhibitory FcgammaR by duplex quantitative real-time PCR. Copy numbers were analyzed by Applied Biosystems CopyCaller Software v1.0. We first demonstrated the distribution of CNV of FCGR3A, FCGR3B and no CNV of FCGR2B in Chinese population (including 47 anti-GBM patients and 146 healthy controls). The frequency of CNV of FCGR3A was observed to be significantly higher than matched healthy controls (27.7 versus 12.3%, P = 0.013, odds ratio 1.21-6.10). Considering previous report about gene knock-out animal models and CNV effect of FCGR3A, we thus propose that CNV in members of FCGR family should have different roles in the pathogenesis of human anti-GBM disease.

Background: The Fcgamma receptors play important roles in anti-glomerular basement membrane antibody disease (anti-GBM disease) in animal models, and FCGR gene polymorphisms have been reported to be associated with numerous human autoimmune diseases. We aimed to clarify the genetic association of FCGR gene polymorphisms with anti-GBM disease in Chinese patients., Methods: A total of 48 patients with anti-GBM disease and 225 geographically and ethnically matched healthy controls were involved. Genotyping of the previously identified polymorphisms FCGR2A131H/R (rs1801274), FCGR2B 232I/T (rs1050501) and FCGR3A176F/V (rs396991) were detected by the TaqMan genotyping assay and FCGR3B NA1/2 by the PCR-sequence specific primer (SSP). Allele type, genotype and haplotype of identified polymorphisms were analysed between patients and controls., Results: Our results revealed that FCGR2A131H/R, FCGR3A176F/V and FCGR3B NA1/2 were not associated with anti-GBM disease. The frequency of the FCGR2B 232T allele (30.2% versus 15.6%, corrected P = 0.00028, 95% CI: 1.42-3.89) and genotypes of I232T (60.4% versus 31.1%, corrected P = 0.0004, 95% CI: 1.78-6.43) was significantly increased in patients compared with controls., Conclusion: The present study demonstrates the genetic association of polymorphism of FCGR2B (I232T) with susceptibility to anti-GBM disease in Chinese.

Several studies have identified FcgRIIIb (Fcgr3b) polymorphisms that determine susceptibility to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The objective of the study was to clarify whether Fcgr3b allele polymorphism influence susceptibility to immunoglobulin A nephropathy (IgAN), clinical features or severity in patients with IgAN. Deoxyribonucleic acid (DNA) fragments were amplified by polymerase chain reaction (PCR) using genomic DNA from 172 unrelated, healthy blood donors and 128 IgAN patients in our Kidney Disease Centre. The present findings showed that Fcgr3b genotype influenced the disease susceptibility and severity of IgAN, although Fcgr3b polymorphism did not affect the age of the disease onset. We found that the genotype frequency of Fcgr3b heterozygote NA1/NA2 in IgAN patients in Chinese significantly higher than that of healthy donors. Furthermore, higher genotype frequency of NA1/NA2 was found also in IgAN patients with glomerulosclerosis or crescent formation than those without it. NA1/NA2 heterozygote of Fcgr3b is a risk factor for progression of IgA nephropathy in Chinese., ((c) 2007 Wiley-Liss, Inc.)

Fc gamma RIIIb receptor is expressed primarily on neutrophils as three polymorphic antigens (HNA-1a, HNA-1b, and HNA-1c) that are encoded by alleles FCGR3B*1, FCGR3B*2, and FCGR3B*3, respectively. These antigens play an important role in immune neutropenia; their absence predisposes individuals who lack them to life-threatening infections. This study investigated the FCGR3B gene frequencies in three ethnic Chinese populations: Han, She, and Tajik. FCGR3B*1, FCGR3B*2, and FCGR3B*3 were genotyped by PCR using sequence specific primers (PCR-SSP). The results showed the gene frequencies were 0.55 for FCGR3B*1 and 0.45 for FCGR3B*2 in 177 Han individuals, 0.69 for FCGR3B*1 and 0.31 for FCGR3B*2 in 87 She individuals, and 0.35 for FCGR3B*1 and 0.65 for FCGR3B*2 in 99 Tajik individuals, respectively. The FCGR3Bnull genotype was not found, but the FCGR3B*3 allele was identified in only three individuals in the Tajik population. DNA clone and sequencing confirmed that these individuals had the C ==>A mutation at position 266 on exon 3. This study found that the gene frequencies in Han and She ethnic groups were similar to those previously reported in the Asian population, but the FCGR3B allele frequencies in the Tajik population were more similar to that of Caucasians.

Objective: To investigate the FCGR3B gene frequencies and FCGR3 variants in a Chinese population from Zhejiang Province., Methods: DNA was extracted from the blood specimens of 487 healthy blood donors from Zhejiang Province. The FCGR3B gene frequencies were determined by polymerase chain reaction with sequence-specific primers (PCR-SSP). The 19 specimens with 3 different FCGR3B genotypes underwent FCGR3 gene cloning and sequencing., Results: The gene frequencies of FCGR3B(*1), FCGR3B(*2), and FCGR3B(*3) in these 487 individuals were 0.564, 0.429, and 0.000 respectively. The genotype frequency of FCGR3B(null) was 0.62% (3/487). Sequencing of FCGR3 revealed that in 7 out of the 19 Chinese individuals variants caused by single nucleotide exchanges at one or more of the polymorphic positions 141, 147, 227, 266 and 277 in exon 3 also existed in this Chinese population., Conclusion: FCGR3B(*1) gene is more frequent in a Chinese population from Zhejiang Province than the FCGR3B(*2) gene, and the FCGR3B(*3) gene seems to be absent. Gene variants caused by single nucleotide exchanges are found in addition to the well known forms, but the reason for this remains unclear.

The human neutrophil antigens HNA-1a, -1b and -1c play an important role in immune neutropenia. The frequencies of the coding FCGR3B genes were determined in different populations. New FCGR3B variants were also found in some populations. This study investigated the FCGR3B gene frequencies and FCGR3 variants in a Chinese population compared with the results of Northern Germans and African Blacks (Uganda). Our results show that the gene frequencies in 413 healthy Chinese individuals from Zhejiang Province were 0.565 for FCGR3B*1, 0.430 for FCGR3B*2 and 0.00 for FCGR3B*3. The genotype frequency of FCGR3B(null) was 0.48% (2/413). Sequencing of FCGR3 revealed that in seven out of 19 Chinese individuals, cloned and sequenced DNA fragments that exhibited variants caused by single nucleotide exchanges at one or more of the polymorphic positions 141, 147, 227, 266 and 277 in exon 3 also existed in this Chinese population. From the present study, it is concluded that the FCGR3B*1 gene is more frequent in a Chinese population from Zhejiang Province than the FCGR3B*2 gene, and the FCGR3B*3 gene seems to be absent, which is in contrast to studies in the white populations. Gene variants caused by single nucleotide exchanges were found in addition to the well-known forms, but the reason for this remains unclear.