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 PHYTOHEMAGGLUTININ (PHA) RESPONSE OF LYMPHOCYTES FROM UNTREATED PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) WAS STUDIED USING HIGHLY PURIFIED SUBPOPULATIONS OF CELLS INVOLVED IN THE TRANSFORMATION RESPONSE: T lymphocytes, B lymphocytes, and monocytes. Cell transformation was quantitated using both tritiated thymidine ([(3)H]-TdR) incorporation into DNA and cytofluorographic determination of cellular DNA content. Dose-response curves using six concentrations of PHA and five concentrations of cells over 0-5 days revealed a decrease in [(3)H]TdR by stimulated lymphocytes from some SLE patients. This decrease in [(3)H]TdR was paralleled by a decreased percentage of cells in S, G(2), and M phases of the cell cycle. However, abnormal response occurred entirely in those SLE patients who were hypocomplementemic. The etiology of the impaired response was further examined. Lymphocyte receptors for concanavalin A were studied using cytofluorography of lymphocytes stained with fluorescein-conjugated concanavalin A. The frequency distribution of concanavalin A receptors was similar in the normocomplementemic and hypocomplementemic lupus patients and in normals. The latex phagocytic activity of lupus macrophages was similar to normals when allogeneic normal plasma was used in the culture medium. Phagocytic activity became abnormal in the presence of SLE plasma. However, there was no difference in the [(3)H]TdR response or the percentage of cells in S, G(2), and M phases when T lymphocytes from the hypocomplementemic patients were stimulated on either autologous or normal allogeneic monocyte monolayers. Likewise, normal lymphocytes incorporated similar amounts of [(3)H]TdR and had similar percentages of cells in S, G(2), and M phases whether their T lymphocytes were stimulated on autologous or SLE monocyte monolayers. Highly purified subpopulations of B and T lymphocytes were obtained by density sedimentation or Fenwal Leuko-Pak passage of lymphocyte populations. The response to PHA by lymphocytes from the hypocomplementemic lupus patients could be seen to involve at least two abnormalities. One, in reference to normal lymphocytes, SLE T lymphocytes plus monocytes had an impaired response; two, SLE B lymphocytes plus SLE T lymphocytes plus SLE monocytes had an impaired response. Two patients in the hypocomplementemic group were treated with steroids. 5 days after steroid treatment was initiated, the percentage of cells in S, G(2), and M phases and the [(3)H]TdR response of PHA-stimulated lymphocytes returned to normal. The normalization of the [(3)H]TdR response was explained both by a return of purified T cells plus monocytes, purified B cells plus monocytes, and whole lymphocyte populations to normal responsiveness. These studies suggest that a steroid-correctable defect exists in T and B lymphocytes in SLE.
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PMID:Phytohemagglutinin response in systemic lupus erythematosus. Reconstitution experiments using highly purified lymphocyte subpopulations and monocytes. 33 May 65

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance. In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 x 10(-10); OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Delta2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell-receptor signaling and B-cell hyperactivity characteristic of this disease.
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PMID:Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. 1822 69

Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T-cell, B-cell and accessory cell functions. B cells are hyperactive in SLE patients. An adapter protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study was to assess the BANK1 genotype-phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected P-value=1.97 x 10(-5), odds ratio (OR)=1.22, 95% CI 1.12-1.34) and rs10516487 (corrected P-value=2.59 x 10(-5), OR=1.22, 95% CI 1.11-1.34). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus.
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PMID:Replication of the BANK1 genetic association with systemic lupus erythematosus in a European-derived population. 1933 86

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Recently, single nucleotide polymorphisms (SNPs) in BANK1 and TNFSF4 have been shown to be associated with SLE in Caucasian populations, but it is not known whether they are also involved in the disease in other ethnic groups. Recent data from our genome-wide association study (GWAS) for 314 SLE cases and 920 controls collected in Hong Kong identified SNPs in and around BANK1 and TNFSF4 to be associated with SLE risk. On the basis of the results of the reported studies and our GWAS, SNPs were selected for further genotyping in 949 SLE patients (overlapping with the 314 cases in our GWAS) and non-overlapping 1042 healthy controls. We confirmed the associations of BANK1 and TNFSF4 with SLE in Chinese (BANK1, rs3733197, odds ratio (OR)=0.84, P=0.021; BANK1, rs17266594, OR=0.61, P=4.67 x 10(-9); TNFSF4, rs844648, OR=1.22, P=2.47 x 10(-3); TNFSF4, rs2205960, OR=1.30, P=2.41 x 10(-4)). Another SNP located in intron 1 of BANK1, rs4522865, was separately replicated by Sequenom in 360 cases and 360 controls and was also confirmed to be associated with SLE (OR=0.725, P=2.93 x 10(-3)). Logistic regression analysis showed that rs3733197 (A383T in ankyrin domain) and rs17266594 (a branch point-site SNP) from BANK1 had independent contributions towards the disease association (P=0.037 and 6.63 x 10(-8), respectively). In TNFSF4, rs2205960 was associated with SLE independently from the effect of rs844648 (P=6.26 x 10(-3)), but not vice versa (P=0.55). These findings suggest that multiple independent genetic variants may be present within the gene locus, which exert their effects on SLE pathogenesis through different mechanisms.
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PMID:Association of BANK1 and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese. 1935 97

Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcgamma receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.
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PMID:Recent insights into the genetic basis of systemic lupus erythematosus. 1944 Jan 99

SSc is a complex multiorgan disease. The key steps in its pathogenesis include early endothelial damage, dysregulation of the immune system with abnormal autoantibody production and fibroblast activation resulting in hyperproduction of extracellular matrix. The disease is caused by an interaction between susceptibility genes and environmental triggers since epidemiological data, including family and twin studies, reveal a genetic component in the pathogenesis of SSc. The candidate gene approach has mainly been employed to identify SSc susceptibility genes. We will focus on data obtained through large samples of well-phenotyped patients and replicated in independent cohorts. These case-control association studies have enabled the identification of several genes that are shared with other connective tissue disorders, and for some of these, putative autoimmune susceptibility genes have been identified. Indeed, we will mainly focus on IRF5 (rs2004640), STAT4 (rs7574865), PTPN22 (rs2476601) and BANK1 (rs3733197 and rs10516487) data. Some of these genes/loci are common to several autoimmune diseases, indicating a shared genetic background also contributing to SSc. Among connective tissue disorders, similarities for genetic markers with SLE are noteworthy. Most likely, these immune-modifying genes could interact and influence both disease phenotype and severity. Less evidence is available yet with regard to genetic markers relating to the vascular and fibrotic aspects of the disease.
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PMID:Genetic background of systemic sclerosis: autoimmune genes take centre stage. 1992 4

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.
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PMID:Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. 2016 77

The genetic components in systemic lupus erythematosus (SLE) have long been established, however, it has been unclear for many years whether the same genetic risk factors for SLE are shared across different ethnic groups. Over the past few years, a number of genetic and genomic studies have been conducted in Asian populations to address this question. These studies have demonstrated that genetic heterogeneity does exist in SLE across different ethnic groups. With these studies, it has been established that a number of genes associated with SLE in Caucasians are also risk factors in Asians: HLA class II genes, STAT4, BANK1, BLK, IRF5, TNFSF4, ITGAM, etc., while there are also novel genetic risk factors identified by these studies in Asians, for instance, the ETS1 and WDFY4 in Chinese. For the genomic studies, the interferon signature has been confirmed as a major lupus molecular phenotype in Asians the same as in Caucasians; microRNA expression profiling and its novel role in regulating the interferon pathway has been first revealed in Asians. Further understanding of the function of lupus disease genes and delineating the key molecular pathway(s) will enhance the development of novel therapeutic targets and biomarkers for individualized clinical management for lupus patients.
Lupus 2010 Oct
PMID:Current advances in lupus genetic and genomic studies in Asia. 2094 45

Recent progress in genetics has expanded the number of the genes associated with SLE to more than 20 in the past 2 years. One might assign these candidate genetic factors into several pre-existing biological pathways: (i) innate immune response including TLR/interferon signaling pathways (IRF5, STAT4, TNFAIP3, and TREX1); (ii) adaptive immune response (HLA-DR, PTPN22, PDCD1, STAT4, LYN, BLK, and BANK1) including B, T cells, and antigen-presenting cells; and (iii) immune complex clearance mechanism (FCGRs, CRP, and ITGAM). In addition, there are also several genes and loci that could not be assigned into previous known pathways (KIAA1542, PXK, XKR6, ATG5, etc), providing possible novel mechanisms in SLE. It has also been evident that there are similarities and differences in SLE susceptibility loci across ethnic groups. Here we categorize the susceptible genes into four groups. The first group is the consistently associated genes with similar risk allele frequency between multiple ethnic populations such as STAT4, TNFAIP3, BANK1, and IRAK1/MECP2. The second group is the genes that are consistently associated but show marked difference in risk allele frequency (BLK, IRF5). The third group is the genes in which different risk variants exist within a gene or genetic loci (allelic heterogeneity) such as HLA-DR, FCGRs, and IRF5. The fourth group is the genes that show consistently discrepancy between populations such as PTPN22 and possibly ITGAM, PXK, and LYN (genetic heterogeneity). The possible explanations for differences of susceptible genetic factors between populations could be different genetic backgrounds, contribution of gene-gene or gene-environment interaction, and the relation between marker and causal variants. Therefore, efforts to identify ethnic-specific genetic factors or disease causing variants should be necessary for individualized therapy for SLE in future.
Lupus 2010 Oct
PMID:What can we learn from genetic studies of systemic lupus erythematosus? Implications of genetic heterogeneity among populations in SLE. 2094 57

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Multiple genetic and environmental factors contribute to the pathogenesis of this disease. Recent genome-wide association studies have added substantially to the number of genes associated with SLE. To replicate some of these susceptibility loci, single-nucleotide polymorphisms reported to be associated to SLE were evaluated in a cohort of 245 well-phenotyped Canadian SLE trios. Our results replicate previously reported associations to alleles of interferon regulatory factor 5 (IRF5), major histocompatibility complex (MHC), tumor necrosis factor (ligand) superfamily member 4 (TNFSF4), Kell blood group complex subunit-related family member 6 (XKR6), B-cell scaffold protein with ankyrin repeats 1 (BANK1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), ubiquitin-conjugating enzyme E2L 3 (UBE2L3) and islet cell autoantigen 1 (ICA1). We also identify putative associations to cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a gene associated with several autoimmune disorders, and ERBB3, a locus on 12q13 that was previously reported to be associated with type 1 diabetes. This study confirms the existence of multiple genetic risk factors for SLE, and supports the notion that some risk factors for SLE are shared with other inflammatory disorders.
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PMID:A targeted association study in systemic lupus erythematosus identifies multiple susceptibility alleles. 2096 50


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