Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to analyze in families with SLE for the presence of linkage and the structure and transmission of haplotypes containing alleles for the low-affinity Fcgamma receptors. The Fcgamma receptor polymorphisms FcgammaRIIA-131R/H, FcgammaRIIIA-176F/V and FcgammaRIIIB-NA1/2 and a polymorphism in the FcgammaRIIB gene were genotyped with RFLP, allele-specific PCR or pyrosequencing. Individual SNPs and haplotypes were tested for linkage in multicase families and for association using contingency tables, transmission disequilibrium test and affected family-based control groups in Swedish and Mexican single-case families. No linkage or association could be detected using the FcgammaR polymorphisms in the multicase families. However, an association was found for both FcgammaRIIA-131R and IIIA-176F alleles in the single-case families, but not for IIIB or IIB. Allelic association to SLE was found for a haplotype that included both risk alleles, but not in haplotypes where only one or the other was present. We propose that FcgammaRIIA-131R and FcgammaRIIIA-176F are both risk alleles for SLE transmitted primarily, but not exclusively on a single major haplotype that behaves functionally in a situation similar to that of compound heterozygozity.
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PMID:Both risk alleles for FcgammaRIIA and FcgammaRIIIA are susceptibility factors for SLE: a unifying hypothesis. 1473 97

FcgammaRIIb, the immunoreceptor tyrosine-based inhibitory motif-containing receptor for IgG (Mendelian Inheritance in Man no. 604590), plays an important role in maintaining the homeostasis of immune responses. We have identified 10 novel single-nucleotide polymorphisms in the promoter region of human FCGR2B gene and characterized two functionally distinct haplotypes in its proximal promoter. In luciferase reporter assays, the less frequent promoter haplotype leads to increased expression of the reporter gene in both B lymphoid and myeloid cell lines under constitutive and stimulated conditions. Four independent genome-wide scans support linkage of the human FcgammaR region to the systemic lupus erythematosus (SLE; Online Mendelian Inheritance in Man no. 152700) phenotype. Our case-control study in 600 Caucasians indicates a significant association of the less frequent FCGR2B promoter haplotype with the SLE phenotype (odds ratio = 1.65; p = 0.0054). The FCGR2B haplotype has no linkage disequilibrium with previously identified FCGR2A and FCGR3A polymorphisms, and after adjustment for FCGR2A and FCGR3A, FCGR2B showed a persistent association with SLE (odds ratio = 1.72; p = 0.0083). These results suggest that an expression variant of FCGR2B is a risk factor for human lupus and implicate FCGR2B in disease pathogenesis.
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PMID:A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. 1515 43

Our knowledge about the role of human Fc receptors for IgG (FcgammaR) has increased considerably within the last several years. These receptors vary in their affinity for IgG, their preferences for IgG subclasses, the cell type-specific expression patterns, and the intracellular signals that they elicit. Additional FcgammaR heterogeneity is introduced by the presence of well characterized genetic polymorphisms. Allelic variants of FcgammaR genes may influence phagocyte biologic activity, providing a basis for inherited predisposition to disease. Recent evidence suggests that certain FcgammaR alleles are genetic risk factors for systemic autoimmune diseases and the development of major manifestations of these diseases. The FcgammaRIIA-R/H131 polymorphism is an important determinant of predisposition to systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). FcgammaRIIA-R131, the low-binding IgG2 allele, seems to confer risk for APS under a recessive model, whereas its effect on SLE susceptibility probably has a dose-response character. The population-attributable fraction of lupus cases due to the R131 allele is 13% and for APS cases is at least 10%, in subjects of European descent. The FcgammaRIIIA-V/F158 polymorphism has a significant impact on renal involvement in lupus patients. The proportion of nephritis cases that could be attributed to the low-binding IgG1 and IgG3 F158 allele is approximately 10-14%. These genetic associations have been well documented in meta-analyses including a large number of studies. Besides the epidemiologic and pathophysiologic interest, this knowledge may be of use in the future in designing novel therapeutic interventions.
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PMID:The role of FcgammaRIIA and IIIA polymorphisms in autoimmune diseases. 1519 64

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immunological hyperactivity and multi-system organ damage. A complex genetic trait involving multiple genes, with both genetic heterogeneity and a threshold effect for disease expression, SLE involves abnormalities of both the innate and adaptive immune systems. Recognition of an 'interferon signature' in SLE leukocytes, of the role of B cells in promoting disease activity, and of FCGR3A alleles as a biomarker of end organ damage, provide important insights into disease pathogenesis. Nonetheless, coordinated studies in humans and model systems hold promise for an even more rapid advance in understanding pathways of disease development and strategies for intervention. More effective markers of disease risk, disease activity, severity of organ damage and outcomes would facilitate earlier diagnosis and guide appropriately targeted treatment.
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PMID:SLE: challenges and candidates in human disease. 1616 9

The capacity to locate polymorphisms on a virtually complete map of the human genome coupled with the ability to accurately evaluate large numbers (by historical standards) of genetic markers has led to gene identification in complex diseases, such as systemic lupus erythematosus (SLE or lupus). While this is a phenotype with enormous clinical variation, the twin studies and the observed familial aggregation, along with the genetic effects now known, suggest a strong genetic component. Unlike type 1 diabetes, lupus genetics is not dominated by the powerful effect of a single locus. Instead, there are at least six known genetic association effects in lupus of smaller magnitude (odds ratio <2), and at least 17 robust linkages (established and arguably confirmed independently) defining potentially responsible genes that largely remain to be discovered. The more convincing genetic associations include the human leukocyte antigen region (with multiple genes), C1q, PTPN22, PDCD1, Fc receptor-like 3, FcgammaRIIA, FcgammaRIIIA, interferon regulatory factor 5, and others. How they contribute to disease risk remains yet to be clarified, beyond the obvious speculation derived from what has previously been learned about these genes. Certainly, they are expected to contribute to lupus risk independently and in combination with each other, with genes not yet identified, and with the environment. A substantial number of genes (>10) are expected to be identified to contribute to lupus or in its many subsets defined by clinical and laboratory features.
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PMID:Unraveling the genetics of systemic lupus erythematosus. 1702 21

The objective of this study was to determine risk factors predicting seizures and damage caused by seizures in a multi-ethnic systemic lupus erythematosus cohort (PROFILE) that includes systemic lupus erythematosus patients (n = 1295) from five different US institutions. Only patients with seizures after systemic lupus erythematosus diagnosis (incident) were included in the analyses of clinical seizures (80/1295, 6.2%), but all patients (prevalent and incident) were included in the analyses of damage caused by seizures (51/1295, 3.9%). We examined socioeconomic-demographic, clinical, and genetic variables predictive of clinical seizures and damage from seizures by Cox proportional hazard ratios (HR) and 95% confidence intervals (CI). Independent predictors of a shorter time to the occurrence of clinical seizures were younger age (HR = 1.0; 95% CI 0.9-1.0), having Hispanic-Texan ethnicity (HR = 2.7; 95% CI 1.3-5.7) or African-American ethnicity (HR = 1.8; 95% CI 1.0-3.1), and the previous occurrence of a cerebrovascular accident (HR = 3.3; 95% CI 1.6-7.1) or an episode of psychosis (HR = 2.4; 95% CI 1.1-5.0), whereas the previous occurrence of photosensitivity (HR = 0.5; 95% CI 0.3-0.9) was the only independent predictor of a longer time to the occurrence of clinical seizures. Independent predictors of a shorter time to the occurrence of damage caused by seizures were younger age (HR = 1.0; 95% CI 0.9-1.0), male gender (HR = 2.4; 95% CI 1.1-5.4), and the occurrence of a previous cerebrovascular accident (HR = 2.7; 95% CI 1.0-7.0) or an episode of psychosis (HR = 4.7; 95% CI 2.3-9.9). No allele from the candidate genes examined (HLA-DRB1, HLA-DQB1, FCGR2A, FCGR3A, or FCG3B) predicted clinical seizures or damage caused by seizures.
Lupus 2008 Mar
PMID:Time to seizure occurrence and damage in PROFILE, a multi-ethnic systemic lupus erythematosus cohort. 1837 57

The objective of this study is to understand the role of FcgammaRIIB and FcgammaRIIIA gene in susceptibility to systemic lupus erythematosus (SLE), and to examine possible susceptible haplotypes between two genes. A total of 119 patients with SLE from 95 nuclear families, aged from 14 to 78 years, were selected according to 1997 criteria of American College of Rheumatology. In addition, 316 family members of these patients were also genotyped. A family-based association study was used to explore the relationship between gene polymorphism and SLE. We studied 13 single-nucleotide polymorphisms (SNPs) encoding non-synonymous substitution in the FcgammaRIIB and FcgammaRIIIA gene (four SNPs in the FcgammaRIIB gene and nine SNPs in the FcgammaRIIIA gene) with respect to genetic susceptibility to SLE. All SNPs were genotyped by restriction fragment length polymorphism method. Among 13 SNPs, univariate (single-marker) family-based association tests showed that variant alleles at only four SNPs (rs10917661 and rs1050501, in exon 2 and exon 5 of FcgammaRIIB gene, rs403016 and rs428888, in exon3 of FcgammaRIIIA gene respectively) were significantly associated with genetic susceptibility to SLE. Furthermore, the haplotype-specific FBATs showed 50Ter-225Thr (34.1%, in FcgammaRIIB gene) and 72Arg-118Asn (40%, in the FcgammaRIIIA gene) haplotype were more frequently transmitted in SLE than other haplotypes (Z = 3.539, P = 0.00042; Z = 2.678, P = 0.007412 respectively). But haplotypes were not found between FcgammaRIIB and FcgammaRIIIA gene Our results suggest that there were meaningful haplotype in FcgammaRIIIA and FcgammaRIIB gene respectively. FcgammaRIIIA and FcgammaRIIB genes in the pathogenesis of SLE may play an independent role in Chinese population.
Lupus 2008 Aug
PMID:Genetic susceptibility and haplotype analysis between Fcgamma receptor IIB and IIIA gene with systemic lupus erythematosus in Chinese population. 1862 51

Using a targeted peptide-centric proteomics approach, we performed in vitro protease substrate profiling of the apoptotic serine protease granzyme B resulting in the delineation of more than 800 cleavage sites in 322 human and 282 mouse substrates, encompassing the known substrates Bid, caspase-7, lupus La protein, and fibrillarin. Triple SILAC (stable isotope labeling by amino acids in cell culture) further permitted intra-experimental evaluation of species-specific variations in substrate selection by the mouse or human granzyme B ortholog. For the first time granzyme B substrate specificities were directly mapped on a proteomic scale and revealed unknown cleavage specificities, uncharacterized extended specificity profiles, and macromolecular determinants in substrate selection that were confirmed by molecular modeling. We further tackled a substrate hunt in an in vivo setup of natural killer cell-mediated cell death confirming in vitro characterized granzyme B cleavages next to several other unique and hitherto unreported proteolytic events in target cells.
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PMID:Analysis of protein processing by N-terminal proteomics reveals novel species-specific substrate determinants of granzyme B orthologs. 1883 77

Copy number variation (CNV) is an important source of genomic diversity in humans, and influences disease susceptibility. The immunoglobulin-receptor genes FCGR3A and FCGR3B on chromosome 1q23.3 show CNV, and CNV of the FCGR3B gene is associated with glomerulonephritis in systemic lupus erythematosus and organ-specific autoimmunity. Large-scale case-control association studies of CNV require technologies that are amenable to high-throughput analysis with low error rates. Here we propose an integrated suite of five assays, four of them duplexed to reduce DNA usage, that assays for CNV at FCGR3A and FCGR3B, and genotype the polymorphic neutrophil antigen HNA1. We show how a maximum-likelihood (ML) approach to combining the results from these five assays allows estimation of statistical confidence for each individual copy number, and therefore an appropriate significance threshold to be set, controlling the error rate. This approach results in a high-throughput copy number genotyping system, with demonstrable precision and accuracy, that can be applied to large case-control cohort studies. We demonstrate Mendelian inheritance of this CNV, variation in frequency between Europeans and East Asians, and a lack of strong association between the CNV and flanking SNP genotypes, with important consequences for genome-wide association studies.
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PMID:An integrated approach for measuring copy number variation at the FCGR3 (CD16) locus. 1914 32

The NKG2D receptor stimulates natural killer cell and T cell responses upon engagement of ligands associated with malignancies and certain autoimmune diseases. However, conditions of persistent NKG2D ligand expression can lead to immunosuppression. In cancer patients, tumor expression and shedding of the MHC class I-related chain A (MICA) ligand of NKG2D drives proliferative expansions of NKG2D(+)CD4(+) T cells that produce interleukin-10 (IL-10) and transforming growth factor-beta, as well as Fas ligand, which inhibits bystander T cell proliferation in vitro. Here, we show that increased frequencies of functionally equivalent NKG2D(+)CD4(+) T cells are inversely correlated with disease activity in juvenile-onset systemic lupus erythematosus (SLE), suggesting that these T cells may have regulatory effects. The NKG2D(+)CD4(+) T cells correspond to a normally occurring small CD4 T cell subset that is autoreactive, primed to produce IL-10, and clearly distinct from proinflammatory and cytolytic CD4 T cells with cytokine-induced NKG2D expression that occur in rheumatoid arthritis and Crohn's disease. As classical regulatory T cell functions are typically impaired in SLE, it may be clinically significant that the immunosuppressive NKG2D(+)CD4(+) T cells appear functionally uncompromised in this disease.
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PMID:Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus. 1928 77


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