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1.
Ann Rheum Dis ; 78(3): 311-319, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30573655

RESUMO

OBJECTIVE: Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. METHODS: We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. RESULTS: Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. CONCLUSIONS: We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.


Assuntos
Artrite Reumatoide/genética , Lúpus Eritematoso Sistêmico/genética , Miosite/genética , Locos de Características Quantitativas/genética , Doenças Reumáticas/genética , Escleroderma Sistêmico/genética , Adulto , Artrite Reumatoide/imunologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Quinases Lim/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana/imunologia , Miosite/imunologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/imunologia , Proteínas Repressoras/imunologia , Doenças Reumáticas/imunologia , Escleroderma Sistêmico/imunologia , alfa Carioferinas/imunologia
2.
Ann Rheum Dis ; 76(12): 2095-2103, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28818832

RESUMO

OBJECTIVES: TNFSF4 (encodes OX40L) is a susceptibility locus for systemic lupus erythematosus (SLE). Risk alleles increase TNFSF4 expression in cell lines, but the mechanism linking this effect to disease is unclear, and the OX40L-expressing cell types mediating the risk are not clearly established. Blockade of OX40L has been demonstrated to reduce disease severity in several models of autoimmunity, but not in SLE. We sought to investigate its potential therapeutic role in lupus. METHODS: We used a conditional knockout mouse system to investigate the function of OX40L on B and T lymphocytes in systemic autoimmunity. RESULTS: Physiologically, OX40L on both B and T cells contributed to the humoral immune response, but B cell OX40L supported the secondary humoral response and antibody affinity maturation. Our data also indicated that loss of B cell OX40L impeded the generation of splenic T follicular helper cells. We further show that in two models of SLE-a spontaneous congenic model and the H2-IAbm12 graft-versus-host-induced model-loss of B cell OX40L ameliorates the autoimmune phenotype. This improvement was, in each case, accompanied by a decline in T follicular helper cell numbers. Importantly, the germline knockout did not exhibit a markedly different phenotype from the B cell knockout in these models. CONCLUSIONS: These findings contribute to a model in which genetically determined increased OX40L expression promotes human SLE by several mechanisms, contingent on its cellular expression. The improvement in pathology in two models of systemic autoimmunity indicates that OX40L is an excellent therapeutic target in SLE.


Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Glicoproteínas de Membrana/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Necrose Tumoral/imunologia , Animais , Autoanticorpos/imunologia , Camundongos , Camundongos Knockout
3.
Ann Rheum Dis ; 72(3): 437-44, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22904263

RESUMO

OBJECTIVES: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE. METHODS: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups. RESULTS: Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p<5×10(-8) with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 1.3×10(-27), OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064). CONCLUSIONS: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.


Assuntos
Cromossomos Humanos X/genética , Grupos de Populações Continentais/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Lúpus Eritematoso Sistêmico/genética , Proteína 2 de Ligação a Metil-CpG/genética , Sequência de Bases , Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
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