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J Clin Med ; 8(6)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185701


During the last decade, important advances have occurred regarding understanding of the pathogenesis and treatment of rheumatoid arthritis (RA). Nevertheless, response to treatment is not universal, and choosing among different therapies is currently based on a trial and error approach. The specific patient's genetic background influences the response to therapy for many drugs: In this sense, genomic studies on RA have produced promising insights that could help us find an effective therapy for each patient. On the other hand, despite the great knowledge generated regarding the genetics of RA, most of the investigations performed to date have focused on identifying common variants associated with RA, which cannot explain the complete heritability of the disease. In this regard, rare variants could also contribute to this missing heritability as well as act as biomarkers that help in choosing the right therapy. In the present article, different aspects of genetics in the pathogenesis and treatment of RA are reviewed, from large-scale genomic studies to specific rare variant analyses. We also discuss the shared genetic architecture existing among autoimmune diseases and its implications for RA therapy, such as drug repositioning.

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


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.

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
Rheumatology (Oxford) ; 58(2): 289-298, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30247649


Objectives: SSc is an autoimmune disease characterized by alteration of the immune response, vasculopathy and fibrosis. Most genetic studies on SSc have been performed in European-ancestry populations. The aim of this study was to analyse the genetic component of SSc in Middle Eastern patients from Iran and Turkey through a genome-wide association study. Methods: This study analysed data from a total of 834 patients diagnosed with SSc and 1455 healthy controls from Iran and Turkey. DNA was genotyped using high-throughput genotyping platforms. The data generated were imputed using the Michigan Imputation Server, and the Haplotype Reference Consortium as a reference panel. A meta-analysis combining both case-control sets was conducted by the inverse variance method. Results: The highest peak of association belonged to the HLA region in both the Iranian and Turkish populations. Strong and independent associations between the classical alleles HLA-DRB1*11: 04 [P = 2.10 × 10-24, odds ratio (OR) = 3.14] and DPB1*13: 01 (P = 5.37 × 10-14, OR = 5.75) and SSc were observed in the Iranian population. HLA-DRB1*11: 04 (P = 4.90 × 10-11, OR = 2.93) was the only independent signal associated in the Turkish cohort. An omnibus test yielded HLA-DRB1 58 and HLA-DPB1 76 as relevant amino acid positions for this disease. Concerning the meta-analysis, we also identified two associations close to the genome-wide significance level outside the HLA region, corresponding to IRF5-TNPO3 rs17424921-C (P = 1.34 × 10-7, OR = 1.68) and NFKB1 rs4648133-C (P = 3.11 × 10-7, OR = 1.47). Conclusion: We identified significant associations in the HLA region and suggestive associations in IRF5-TNPO3 and NFKB1 loci in Iranian and Turkish patients affected by SSc through a genome-wide association study and an extensive HLA analysis.

Escleroderma Sistêmico/genética , Alelos , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Cadeias beta de HLA-DP/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade/métodos , Humanos , Fatores Reguladores de Interferon/genética , Irã (Geográfico)/epidemiologia , Polimorfismo Genético , Escleroderma Sistêmico/etnologia , Turquia/epidemiologia
PLoS One ; 13(12): e0209343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586461


BACKGROUND: The TNFSF13B (TNF superfamily member 13b) gene encodes BAFF, a cytokine with a crucial role in the differentiation and activation of B cells. An insertion-deletion variant (GCTGT→A) of this gene, leading to increased levels of BAFF, has been recently implicated in the genetic predisposition to several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Based on the elevated levels of this cytokine found in patients with giant cell arteritis (GCA) and systemic sclerosis (SSc), we aimed to assess whether this functional variant also represents a novel genetic risk factor for these two disorders. METHODS: A total of 1,728 biopsy-proven GCA patients from 4 European cohorts, 4,584 SSc patients from 3 European cohorts and 5,160 ethnically-matched healthy controls were included in the study. The single nucleotide polymorphism (SNP) rs374039502, which colocalizes with the genetic variant previously implicated in autoimmunity, was genotyped using a custom TaqMan assay. First, association analysis was conducted in each independent cohort using χ2 test in Plink (v1.9). Subsequently, different case/control sets were meta-analyzed by the inverse variance method. RESULTS: No statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts. Similarly, combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with GCA (P = 0.421; OR (95% CI) = 0.92 (0.75-1.13)) and SSc (P = 0.500; OR (95% CI) = 1.05 (0.91-1.22)). The stratified analysis considering the main clinical subphenotypes of these diseases yielded similar negative results. CONCLUSION: Our data suggest that the TNFSF13B functional variant does not contribute to the genetic network underlying GCA and SSc.

Fator Ativador de Células B/genética , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Redes Reguladoras de Genes/genética , Técnicas de Genotipagem , Arterite de Células Gigantes/patologia , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/patologia
Sci Rep ; 8(1): 8195, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844438


A rare variant (BAFF-var) of the tumor necrosis factor superfamily 13b (TNFSF13B) gene has been recently associated with multiple sclerosis (MS) and systemic lupus erythematosus (SLE). The aim of this study was to investigate the association between TNFSF13B BAFF-var and susceptibility to rheumatoid arthritis (RA) and replicate that association in SLE. 6,218 RA patients, 2,575 SLE patients and 4,403 healthy controls from three different countries were included in the study. TNFSF13B BAFF-var was genotyped using TaqMan allelic discrimination assay. PLINK software was used for statistical analyses. TNFSF13B BAFF-var was significantly associated with RA (p = 0.015, OR = 1.21, 95% CI = 1.03-1.41) in the Spanish cohort. A trend of association was observed in the Dutch (p = 0.115) and German (p = 0.228) RA cohorts. A meta-analysis of the three RA cohorts included in this study revealed a statistically significant association (p = 0.002, OR = 1.24, 95% CI = 1.10-1.38). In addition, TNFSF13B BAFF-var was significantly associated with SLE in the Spanish (p = 0.001, OR = 1.41, 95% CI = 1.14-1.74) and the German cohorts (p = 0.030, OR = 1.86, 95% CI = 1.05-3.28), with a statistically significant p-value obtained in the meta-analysis (p = 0.0002, OR = 1.46, 95% CI = 1.09-2.32). The results obtained confirm the known association of TNFSF13B BAFF-var with SLE and, for the first time, demonstrate that this variant contributes to susceptibility to RA.

Artrite Reumatoide/genética , Fator Ativador de Células B/genética , Mutação INDEL , Lúpus Eritematoso Sistêmico/genética , Artrite Reumatoide/epidemiologia , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Países Baixos/epidemiologia , Polimorfismo Genético , Espanha/epidemiologia