Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 72
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Nature ; 517(7535): 501-4, 2015 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-25363774

RESUMEN

Immunoglobulins protect against disease to a considerable extent by activating complement and stimulatory immunoglobulin crystallizable fragment receptors (Ig FcRs), and aggregating microbial pathogens. Yet IgG1, the predominant murine serum Ig isotype, cannot activate complement by the classical pathway, binds more avidly to an inhibitory than to stimulatory FcRs, and has limited ability to aggregate pathogens. In these regards, it resembles human IgG4 (ref. 4). We hypothesized that limited ability to activate effector mechanisms might protect against immune complex immunopathology. Here we show that IgG1-deficient (γ1(-)) mice, immunized with a potent antigen, develop lethal renal disease soon after they begin to produce antigen-specific antibody, whereas similarly immunized wild-type mice remain healthy. Surprisingly, renal disease in this model is complement and FcR independent and results from immune complex precipitation in glomerular capillaries, as in some cryoglobulinaemic humans. IgG3, which self-associates to form large immune complexes, accounts for more than 97% of the mouse Ig in this cryoglobulin; furthermore, glomerular disease develops when mice are injected with IgG3 anti-trinitrophenyl (TNP) monoclonal antibody followed by a TNP-labelled protein. Renal disease is prevented in both active and passive immunization models by antigen-specific IgG1; other isotypes are less potent at preventing disease. These observations demonstrate the adaptive significance of Ig isotypes that poorly activate effector mechanisms, reveal an immune-complex-dependent, complement- and FcR-independent nephrotoxic mechanism, and suggest that isotypes that poorly activate effector mechanisms may be useful for inhibiting immune complex immunopathology.


Asunto(s)
Crioglobulinemia/complicaciones , Glomerulonefritis/etiología , Glomerulonefritis/prevención & control , Inmunoglobulina G/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Complejo Antígeno-Anticuerpo/química , Complejo Antígeno-Anticuerpo/inmunología , Antígenos/inmunología , Unión Competitiva , Proteínas del Sistema Complemento , Crioglobulinemia/inmunología , Crioglobulinemia/patología , Modelos Animales de Enfermedad , Femenino , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Cabras , Masculino , Ratones , Receptores de IgG , Solubilidad , Trinitrobencenos/inmunología
2.
Hum Mol Genet ; 27(21): 3813-3824, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30085094

RESUMEN

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.


Asunto(s)
Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Complejo Mayor de Histocompatibilidad/genética , Polimorfismo de Nucleótido Simple , Negro o Afroamericano/genética , Femenino , Estudios de Asociación Genética , Haplotipos , Humanos , Masculino , Modelos Genéticos , Población Blanca/genética
3.
Hum Mol Genet ; 27(13): 2392-2404, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29912393

RESUMEN

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.


Asunto(s)
Alelos , Lupus Eritematoso Sistémico/genética , Polimorfismo Genético , Sitios de Carácter Cuantitativo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT4/genética , Femenino , Humanos , Lupus Eritematoso Sistémico/epidemiología , Masculino , Factores de Riesgo
4.
J Immunol ; 201(2): 393-405, 2018 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-29884703

RESUMEN

Systemic lupus erythematosus is an autoimmune disease characterized by increased type I IFNs, autoantibodies, and inflammatory-mediated multiorgan damage. TLR7 activation is an important contributor to systemic lupus erythematosus pathogenesis, but the mechanisms by which type I IFNs participate in TLR7-driven pathologic conditions remain uncertain. In this study, we examined the requirement for type I IFNs in TLR7-stimulated lupus nephritis. Lupus-prone NZM2328, INZM (which lack a functional type I IFN receptor), and NZM2328 IL-1ß-/- mice were treated at 10 wk of age on the right ear with R848 (TLR7 agonist) or control (DMSO). Autoantibody production and proteinuria were assessed throughout treatment. Multiorgan inflammation was assessed at the time of decline in health. Renal infiltrates and mRNA expression were also examined after 14 d of treatment. Both NZM2328 and INZM mice exhibited a decline in survival after 3-4 wk of R848 but not vehicle treatment. Development of splenomegaly and liver inflammation were dependent on type I IFN. Interestingly, autoantibody production, early renal infiltration of dendritic cells, upregulation of IL-1ß, and lupus nephritis occurred independent of type I IFN signaling. Development of TLR7-driven lupus nephritis was not abolished by the deletion of IL-1ß. Thus, although IFN-α is sufficient to induce nephritis acceleration, our data emphasize a critical role for IFN-independent signaling in TLR7-mediated lupus nephritis. Further, despite upregulation of IL-1ß after TLR7 stimulation, deletion of IL-1ß is not sufficient to reduce lupus nephritis development in this model.


Asunto(s)
Interferón Tipo I/inmunología , Nefritis Lúpica/inmunología , Glicoproteínas de Membrana/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 7/inmunología , Animales , Autoanticuerpos/inmunología , Células Dendríticas/inmunología , Femenino , Inflamación/metabolismo , Interleucina-1beta/inmunología , Lupus Eritematoso Sistémico/inmunología , Ratones , ARN Mensajero/inmunología
5.
J Autoimmun ; 103: 102291, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31248690

RESUMEN

Ultraviolet (UV) light is a known trigger of skin and possibly systemic inflammation in systemic lupus erythematosus (SLE) patients. Although type I interferons (IFN) are upregulated in SLE skin after UV exposure, the mechanisms to explain increased UVB-induced inflammation remain unclear. This paper compares the role of type I IFNs in regulating immune cell activation between wild-type and lupus-prone mice following UVB exposure. 10-week old female lupus-prone (NZM2328), wild-type (BALB/c) and iNZM mice (lack a functional type I IFN receptor on NZM2328 background) were treated on their dorsal skin with 100 mJ/cm2 of UVB for 5 consecutive days. Following UVB treatment, draining lymph node cell populations were characterized via flow cytometry and suppression assays; treated skin was examined for changes in expression of type I IFN genes. Only NZM2328 mice showed an increase in T cell numbers and activation 2 weeks post UVB exposure. This was preceded by a significant increase in UVB-induced type I IFN expression in NZM2328 mice compared to BALB/c mice. Following UVB exposure, both BALB/c and iNZM mice demonstrated an increase in functional T regulatory (TReg) cells; however, this was not seen in NZM2328 mice. These data suggest a skewed UVB-mediated T cell response in lupus-prone mice where activation of T cells is enhanced secondary to a type I IFN-dependent suppression of TReg cells. Thus, we propose type I IFNs are important for UVB-induced inflammation in lupus-prone mice and may be an effective target for prevention of UVB-mediated flares.


Asunto(s)
Inflamación/inmunología , Interferón Tipo I/metabolismo , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Piel/patología , Linfocitos T Reguladores/inmunología , Rayos Ultravioleta/efectos adversos , Animales , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Humanos , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Mutantes , Exposición a la Radiación , Piel/efectos de la radiación
6.
Am J Hum Genet ; 96(5): 731-9, 2015 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-25865496

RESUMEN

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.


Asunto(s)
Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Proteína Proto-Oncogénica c-ets-1/genética , Factor de Transcripción STAT1/genética , Alelos , Animales , Pueblo Asiatico , Teorema de Bayes , Genotipo , Haplotipos , Humanos , Ratones , Unión Proteica , Proteína Proto-Oncogénica c-ets-1/metabolismo , Factor de Transcripción STAT1/metabolismo
7.
Am J Hum Genet ; 94(4): 586-98, 2014 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-24702955

RESUMEN

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.


Asunto(s)
Lupus Eritematoso Sistémico/genética , Regiones Promotoras Genéticas , Transcripción Genética , Familia-src Quinasas/genética , Alelos , Cromosomas Humanos Par 8 , Ensayo de Cambio de Movilidad Electroforética , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Polimorfismo de Nucleótido Simple
8.
J Immunol ; 194(9): 4055-7, 2015 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-25888699

RESUMEN

Hiromi Kubagawa and John E. Coligan coordinated an online meeting to define an appropriate nomenclature for the cell surface glycoprotein presently designated by different names: Toso, Fas apoptosis inhibitory molecule 3 (FAIM3), and IgM FcR (FcµR). FAIM3 and Faim3 are the currently approved symbols for the human and mouse genes, respectively, in the National Center for Biotechnology Information, Ensembl, and other databases. However, recent functional results reported by several groups of investigators strongly support a recommendation for renaming FAIM3/Faim3 as FCMR/Fcmr, a name better reflecting its physiological function as the FcR for IgM. Participants included 12 investigators involved in studying Toso/FAIM3(Faim3)/FµR, representatives from the Human Genome Nomenclature Committee (Ruth Seal) and the Mouse Genome Nomenclature Committee (Monica McAndrews), and an observer from the IgM research field (Michael Carroll). In this article, we provide a brief background of the key research on the Toso/FAIM3(Faim3)/FcµR proteins, focusing on the ligand specificity and functional activity, followed by a brief summary of discussion about adopting a single name for this molecule and its gene and a resulting recommendation for genome nomenclature committees.


Asunto(s)
Proteínas Reguladoras de la Apoptosis , Proteínas Portadoras , Proteínas de la Membrana , Terminología como Asunto , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Portadoras/genética , Humanos , Inmunoglobulina M , Proteínas de la Membrana/genética , Ratones , Receptores Fc/clasificación
9.
J Biol Chem ; 290(20): 12595-602, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25795782

RESUMEN

In a case-control association study with 3716 North Americans of Hispanic descent and 4867 North Americans of European descent, we show that the associations of rs17849502 (NCF2 His-389 → Gln) and rs13306575 (NCF2 Arg-395 → Trp) with systemic lupus erythematosus are independent. We have shown that His-389 → Gln disrupts the binding of NCF2 to the ZF domain of VAV1, resulting in decreased NADPH oxidase activity. With respect to Arg-395 → Trp, using protein docking and structure analyses, we provide a model for the involvement of this mutation in the structure and function of the NADPH oxidase complex. This model assigns a central role to Arg-395 in the structure and stability of the quaternary NCF2/NCF4/VAV1/RAC1 NADPH oxidase complex. Arg-395 stabilizes the C-terminal tail of NCF4 and the conformation of NCF2 loop 395-402, which in turn stabilize the evolutionarily conserved interactions of NCF2/NCF4 with the DH domain of VAV1 and RAC1 region 120-137. Our findings are consistent with the high levels of conservation of all of the residues involved in these interactions.


Asunto(s)
Lupus Eritematoso Sistémico , Simulación del Acoplamiento Molecular , Mutación Missense , NADPH Oxidasas/química , Sustitución de Aminoácidos , Estabilidad de Enzimas/genética , Femenino , Hispánicos o Latinos , Humanos , Masculino , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-vav/química , Proteínas Proto-Oncogénicas c-vav/genética , Proteínas Proto-Oncogénicas c-vav/metabolismo , Población Blanca , Proteína de Unión al GTP rac1/química , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismo
10.
Ann Rheum Dis ; 75(11): 2007-2013, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26783109

RESUMEN

OBJECTIVES: Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case-control multi-ancestry population and tested functions of identified variants. METHODS: We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. RESULTS: We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10-8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10-3 and 6.8×10-8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=-0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10-5 and 2.0×10-4, respectively). CONCLUSION: We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.


Asunto(s)
Anticuerpos Antinucleares/metabolismo , Proteínas Portadoras/genética , Leucocitos Mononucleares/inmunología , Lupus Eritematoso Sistémico/genética , Nicotinamida-Nucleótido Adenililtransferasa/genética , Alelos , Indio Americano o Nativo de Alaska/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Células HEK293 , Hispánicos o Latinos/genética , Humanos , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico/inmunología , Masculino , Linaje , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Riesgo , Población Blanca/genética
11.
Ann Rheum Dis ; 75(1): 242-52, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25180293

RESUMEN

OBJECTIVES: Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. METHODS: Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. RESULTS: The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10(-4), OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10(-7), OR 0.71; case-only pmeta=1.9×10(-4), OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. CONCLUSIONS: These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.


Asunto(s)
Anticuerpos Antinucleares/sangre , Lupus Eritematoso Sistémico/genética , Receptores de Complemento 3d/genética , Adolescente , Adulto , Subgrupos de Linfocitos B/inmunología , Estudios de Casos y Controles , ADN/inmunología , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Haplotipos , Humanos , Lupus Eritematoso Sistémico/inmunología , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Receptores de Complemento 3b/biosíntesis , Medición de Riesgo/métodos , Factores de Transcripción/metabolismo , Adulto Joven
13.
PLoS Genet ; 9(2): e1003222, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23441136

RESUMEN

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.


Asunto(s)
Negro o Afroamericano/genética , ARN Helicasas DEAD-box/genética , Lupus Eritematoso Sistémico/genética , Alelos , Antígenos Nucleares/genética , Antígenos Nucleares/inmunología , Apoptosis/genética , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Mapeo Cromosómico , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Predisposición Genética a la Enfermedad , Genoma Humano , Haplotipos , Humanos , Inflamación/genética , Helicasa Inducida por Interferón IFIH1 , Autoantígeno Ku , Lupus Eritematoso Sistémico/inmunología , Polimorfismo de Nucleótido Simple , Unión Proteica , Población Blanca/genética
14.
PLoS Genet ; 9(2): e1003336, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23468661

RESUMEN

We previously reported that the G allele of rs3853839 at 3'untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10(-10), odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10(-11), OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3'UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R(2) = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3'UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta  = 2.0×10(-19), OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.


Asunto(s)
Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , MicroARNs/genética , Receptor Toll-Like 7 , Regiones no Traducidas 3' , Negro o Afroamericano/genética , Alelos , Pueblo Asiatico/genética , Regulación de la Expresión Génica/genética , Células HEK293 , Hispánicos o Latinos/genética , Humanos , Lupus Eritematoso Sistémico/metabolismo , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Población Blanca
15.
PLoS Genet ; 9(10): e1003870, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24130510

RESUMEN

Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10⁻8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.


Asunto(s)
Predisposición Genética a la Enfermedad , Interleucina-10/genética , Lupus Eritematoso Sistémico/genética , Proteína Elk-1 con Dominio ets/genética , Alelos , Pueblo Asiatico , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos , Hispánicos o Latinos , Humanos , Interleucina-10/biosíntesis , Intrones , Lupus Eritematoso Sistémico/patología , Polimorfismo de Nucleótido Simple , Unión Proteica , Regulación hacia Arriba , Población Blanca/genética , Proteína Elk-1 con Dominio ets/biosíntesis
16.
PLoS Genet ; 9(7): e1003554, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23874208

RESUMEN

We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P=1.71 × 10(-34) , OR=1.43[1.26-1.60]) and rs1234317-T (P=1.16 × 10(-28) , OR=1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5' region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5' risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.


Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico/genética , Ligando OX40/genética , Negro o Afroamericano/genética , Alelos , Pueblo Asiatico/genética , Mapeo Cromosómico , Femenino , Genotipo , Haplotipos , Hispánicos o Latinos/genética , Humanos , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico/patología , Linfocitos/patología , Masculino , FN-kappa B/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genética
17.
Clin Immunol ; 161(2): 157-62, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26385092

RESUMEN

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Leptina/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple/genética , Estudios de Casos y Controles , Genotipo , Humanos
18.
Am J Hum Genet ; 90(4): 648-60, 2012 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-22464253

RESUMEN

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.


Asunto(s)
Proteínas del Huevo/genética , Predisposición Genética a la Enfermedad , Factor de Transcripción Ikaros/genética , Factores Reguladores del Interferón/genética , Lupus Eritematoso Sistémico/genética , Proteínas de la Membrana/genética , Pueblo Asiatico/genética , Población Negra/genética , Mapeo Cromosómico , Femenino , Haplotipos/genética , Hispánicos o Latinos/genética , Humanos , Indígenas Norteamericanos/genética , Lupus Eritematoso Sistémico/etnología , Masculino , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de ADN , Población Blanca/genética
19.
Proc Natl Acad Sci U S A ; 109(2): E59-67, 2012 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-22203994

RESUMEN

Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Variación Genética , Lupus Eritematoso Sistémico/genética , Modelos Moleculares , Complejos Multiproteicos/genética , NADPH Oxidasas/metabolismo , Secuencia de Aminoácidos , California , Genotipo , Humanos , Datos de Secuencia Molecular , Complejos Multiproteicos/química , Mutación Missense/genética , NADPH Oxidasas/química , NADPH Oxidasas/genética , Plásmidos/genética , Polimorfismo de Nucleótido Simple/genética , Análisis de Componente Principal , Unión Proteica , Proteínas Proto-Oncogénicas c-vav/química , Proteínas Proto-Oncogénicas c-vav/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína de Unión al GTP rac1/química
20.
J Am Soc Nephrol ; 25(12): 2859-70, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24925725

RESUMEN

Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis-predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10(-7)), 16p12 (SLC5A11; P=5.1×10(-7)), 6p22 (ID4; P=7.4×10(-7)), and 8q24.12 (HAS2, SNTB1; P=1.1×10(-6)). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10(-5), respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10(-6)). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci.


Asunto(s)
Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Antígeno HLA-DR2/genética , Antígeno HLA-DR3/genética , Humanos , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/fisiopatología , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , ARN Mensajero/metabolismo , Población Blanca/genética , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA