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1.
Front Immunol ; 10: 1459, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312201

RESUMO

Background: Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints. Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response. The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA. Methods: We performed a sequential multi-omic analysis integrating different sources of molecular information. First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium. Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy. The clinical response was determined at week 14 using the EULAR criteria. Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level. For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain. The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients. Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses. Results: A total of 149 GCMs were identified in the RA synovium. From these, 13 GCMs were found to be significantly associated with anti-TNF response (P < 0.05). At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab (P = 0.0015) and infliximab (P = 0.021) in the Spain cohort. Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab (P = 0.0019). The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism (P = 2.41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells (P = 0.041). Conclusions: These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA.

2.
Pharmacogenomics J ; 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31043678

RESUMO

The production of antibodies to anti-tumor necrosis factor alpha (TNF) agents is one of the main causes of treatment failure in Crohn's disease (CD). To date, however, the contribution of genetics to anti-TNF immunogenicity in CD is still unknown. The objective of the present study was to identify genetic variation associated with anti-TNF immunogenicity in CD. We performed a two-stage genome-wide association study in a cohort of 96 and 123 adalimumab-treated patients, respectively. In the discovery stage, we identified a genome-wide significant association between the CD96 locus and the production of antibodies to anti-TNF treatment (P = 1.88e-09). This association was validated in the replication stage (P < 0.05). The risk allele for anti-TNF immunogenicity was found to be also associated with a lack of response to anti-TNF therapy (P = 0.019). These findings represent an important step toward the understanding of the immunogenicity-based mechanisms that underlie anti-TNF response in CD.

3.
Arthritis Res Ther ; 20(1): 100, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29848360

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci for SLE. METHODS: We genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959 controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software. RESULTS: We identified five new loci associated with SLE at the genome-wide level of significance (p < 5 × 10- 8): GRB2, SMYD3, ST8SIA4, LAT2 and ARHGAP27. Pathway analysis revealed several biological processes significantly associated with SLE risk: B cell receptor signaling (p = 5.28 × 10- 6), CTLA4 co-stimulation during T cell activation (p = 3.06 × 10- 5), interleukin-4 signaling (p = 3.97 × 10- 5) and cell surface interactions at the vascular wall (p = 4.63 × 10- 5). CONCLUSIONS: Our results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci.

4.
Arthritis Res Ther ; 19(1): 138, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28619073

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. METHODS: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. RESULTS: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. CONCLUSIONS: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Úlceras Orais/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Feminino , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/complicações , Masculino , Fenótipo
5.
Hum Mol Genet ; 26(14): 2803-2811, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28475762

RESUMO

Epigenetic regulation of immune cell types could be critical for the development and maintenance of autoimmune diseases like rheumatoid arthritis (RA). B cells are highly relevant in RA, since patients express autoantibodies and depleting this cell type is a successful therapeutic approach. Epigenetic variation, such as DNA methylation, may mediate the pathogenic activity of B cells. In this study, we performed an epigenome-wide association study (EWAS) for RA with three different replication cohorts, to identify disease-specific alterations in DNA methylation in B cells. CpG methylation in isolated B lymphocytes was assayed on the Illumina HumanMethylation450 BeadChip in a discovery cohort of RA patients (N = 50) and controls (N = 75). Differential methylation was observed in 64 CpG sites (q < 0.05). Six biological pathways were also differentially methylated in RA B cells. Analysis in an independent cohort of patients (N = 15) and controls (N = 15) validated the association of 10 CpG sites located on 8 genes CD1C, TNFSF10, PARVG, NID1, DHRS12, ITPK1, ACSF3 and TNFRSF13C, and 2 intergenic regions. Differential methylation at the CBL signaling pathway was replicated. Using an additional case-control cohort (N = 24), the association between RA risk and CpGs cg18972751 at CD1C (P = 2.26 × 10-9) and cg03055671 at TNFSF10 (P = 1.67 × 10-8) genes was further validated. Differential methylation at genes CD1C, TNFSF10, PARVG, NID1, DHRS12, ITPK1, ACSF3, TNFRSF13C and intergenic region chr10p12.31 was replicated in a cohort of systemic lupus erythematosus (SLE) patients (N = 47) and controls (N = 56). Our results highlight genes that may drive the pathogenic activity of B cells in RA and suggest shared methylation patterns with SLE.


Assuntos
Artrite Reumatoide/genética , Linfócitos B/metabolismo , Idoso , Artrite Reumatoide/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Transdução de Sinais
6.
Rheumatology (Oxford) ; 55(6): 1106-11, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26983453

RESUMO

OBJECTIVE: RA patients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach. METHODS: A total of 924 ACPA-positive RA patients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry. RESULTS: In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P < 5×10(-4) and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P < 0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19×10(-8)]. CONCLUSIONS: SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RA patients to identify new genetic risk variants.

7.
J Invest Dermatol ; 136(3): 593-602, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26743605

RESUMO

Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility.


Assuntos
Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Psoríase/epidemiologia , Psoríase/genética , Adulto , Estudos de Casos e Controles , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Psoríase/fisiopatologia , Valores de Referência , Medição de Risco , Espanha/epidemiologia
8.
Arthritis Rheumatol ; 68(6): 1384-91, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26815016

RESUMO

OBJECTIVE: Rheumatoid factor (RF) is a well-established diagnostic and prognostic biomarker in rheumatoid arthritis (RA). However, ∼20% of RA patients are negative for this anti-IgG antibody. To date, only variation at the HLA-DRB1 gene has been associated with the presence of RF. This study was undertaken to identify additional genetic variants associated with RF positivity. METHODS: A genome-wide association study (GWAS) for RF positivity was performed using an Illumina Quad610 genotyping platform. A total of 937 RF-positive and 323 RF-negative RA patients were genotyped for >550,000 single-nucleotide polymorphisms (SNPs). Association testing was performed using an allelic chi-square test implemented in Plink software. An independent cohort of 472 RF-positive and 190 RF-negative RA patients was used to validate the most significant findings. RESULTS: In the discovery stage, a SNP in the IRX1 locus on chromosome 5p15.3 (SNP rs1502644) showed a genome-wide significant association with RF positivity (P = 4.13 × 10(-8) , odds ratio [OR] 0.37 [95% confidence interval (95% CI) 0.26-0.53]). In the validation stage, the association of IRX1 with RF was replicated in an independent group of RA patients (P = 0.034, OR 0.58 [95% CI 0.35-0.97] and combined P = 1.14 × 10(-8) , OR 0.43 [95% CI 0.32-0.58]). CONCLUSION: To our knowledge, this is the first GWAS of RF positivity in RA. Variation at the IRX1 locus on chromosome 5p15.3 is associated with the presence of RF. Our findings indicate that IRX1 and HLA-DRB1 are the strongest genetic factors for RF production in RA.


Assuntos
Artrite Reumatoide/genética , Loci Gênicos , Proteínas de Homeodomínio/genética , Fator Reumatoide/genética , Fatores de Transcrição/genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Risco
9.
Arthritis Res Ther ; 17: 242, 2015 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-26336855

RESUMO

INTRODUCTION: Interleukin-6 (IL-6) cytokine signaling is key in Rheumatoid Arthritis (RA) pathophysiology. Blocking IL-6 receptor (IL6R) has proven to be a highly effective treatment to prevent joint damage. This study was performed to investigate the association between the genetic variation at IL6R gene and the severity of joint damage in RA. METHODS: IL6R gene tagging SNPs (n = 5) were genotyped in a discovery group of 527 RA patients from 5 different university hospitals from Spain. For each marker, a linear regression analysis was performed using an additive model and adjusting for the years of evolution of the disease, autoantibody status, gender and age. Haplotypes combining the SNPs were also estimated and tested for association with the level of joint destruction. Using an independent cohort of 705 RA patients from 6 university hospitals we performed a validation study of the SNPs associated in the discovery phase. RESULTS: In the discovery group we found a highly significant association between IL6R SNP rs4845618 and the level of joint destruction in RA (P = 0.0058, P corrected = 0.026), and a moderate association with SNP rs4453032 (P = 0.02, P corrected = 0.05). The resulting haplotype from both SNPs was more significantly associated with joint damage (P = 0.0037, P corrected = 0.011). Using the validation cohort, we replicated the association between the two IL-6R SNPs with the degree of joint destruction in RA (P = 0.007 and P = 0.04, meta-analysis P = 0.00011 and P = 0.0021, respectively), and the haplotype association (P = 0.0058, meta-analysis P = 6.64 e-5). CONCLUSIONS: Genetic variation at IL6R gene is associated with joint damage in RA.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Articulações/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética , Alelos , Estudos de Coortes , Frequência do Gene , Genótipo , Haplótipos , Humanos , Articulações/patologia , Modelos Lineares , Desequilíbrio de Ligação , Metanálise como Assunto , Espanha
10.
Ann Rheum Dis ; 74(10): 1875-81, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25990289

RESUMO

OBJECTIVE: Copy number variants (CNVs) have been associated with the risk to develop multiple autoimmune diseases. Our objective was to identify CNVs associated with the risk to develop psoriatic arthritis (PsA) using a genome-wide analysis approach. METHODS: A total of 835 patients with PsA and 1498 healthy controls were genotyped for CNVs using the Illumina HumanHap610 BeadChip genotyping platform. Genomic CNVs were characterised using CNstream analysis software and analysed for association using the χ(2) test. The most significant genomic CNV associations with PsA risk were independently tested in a validation sample of 1133 patients with PsA and 1831 healthy controls. In order to test for the specificity of the variants with PsA aetiology, we also analysed the association to a cohort of 822 patients with purely cutaneous psoriasis (PsC). RESULTS: A total of 165 common CNVs were identified in the genome-wide analysis. We found a highly significant association of an intergenic deletion between ADAMTS9 and MAGI1 genes on chromosome 3p14.1 (p=0.00014). Using the independent patient and control cohort, we validated the association between ADAMTS9-MAGI1 deletion and PsA risk (p=0.032). Using next-generation sequencing, we characterised the 26 kb associated deletion. Finally, analysing the PsC cohort we found a lower frequency of the deletion compared with the PsA cohort (p=0.0088) and a similar frequency to that of healthy controls (p>0.3). CONCLUSIONS: The present genome-wide scan for CNVs associated with PsA risk has identified a new deletion associated with disease risk and which is also differential from PsC risk.


Assuntos
Proteínas ADAM/genética , Artrite Psoriásica/genética , Moléculas de Adesão Celular Neuronais/genética , Deleção de Genes , Proteína ADAMTS9 , Adulto , Idoso , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/genética , Fatores de Risco
11.
PLoS One ; 10(4): e0122088, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25848939

RESUMO

OBJECTIVE: Anti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25-30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response. METHODS: A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy. RESULTS: We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042). CONCLUSIONS: In the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/imunologia , Resultado do Tratamento
12.
Gastroenterology ; 148(4): 794-805, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25557950

RESUMO

BACKGROUND & AIMS: Crohn's disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn's disease. METHODS: We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn's disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn's disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn's disease phenotypes (P < 2 × 10(-4)) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry. RESULTS: We replicated the association of 4 loci with different Crohn's disease phenotypes. Variants in MAGI1, CLCA2, 2q24.1, and LY75 loci were associated with a complicated stricturing disease course (Pcombined = 2.01 × 10(-8)), disease location (Pcombined = 1.3 × 10(-6)), mild disease course (Pcombined = 5.94 × 10(-7)), and erythema nodosum (Pcombined = 2.27 × 10(-6)), respectively. CONCLUSIONS: In a GWAS, we associated 4 loci with clinical phenotypes of Crohn's disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease.


Assuntos
Antígenos CD/genética , Moléculas de Adesão Celular Neuronais/genética , Canais de Cloreto/genética , Cromossomos Humanos Par 2/genética , Doença de Crohn/genética , Lectinas Tipo C/genética , Receptores de Superfície Celular/genética , Adulto , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor , Fenótipo , Polimorfismo de Nucleotídeo Único
13.
Pharmacogenomics ; 15(14): 1763-1769, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25493569

RESUMO

Aim: Variation at PDE3A-SLCO1C1 locus has been recently associated with the response to anti-TNF therapy in rheumatoid arthritis. We undertook the present study to determine whether PDE3A-SLCO1C1 is also associated with the response to anti-TNF therapy in psoriatic arthritis. Patients & methods: Genomic DNA was obtained from 81 psoriatic arthritis patients that had been treated with anti-TNF therapy. PDE3A-SLCO1C1 SNP rs3794271 was genotyped using Taqman realt-time PCR. The clinical response to anti-TNF therapy was measured as the change from baseline in the level of disease activity according to the DAS28 score. Results: A significant association between rs3794271 and anti-TNF response in psoriatic arthritis was found (beta = -0.71; p = 0.0036). Conclusion: PDE3A-SLCO1C1 locus is also associated with response to anti-TNF therapy in psoriatic arthritis. Original submitted 12 May 2014; Revision submitted 18 August 2014.

14.
Hum Mol Genet ; 23(25): 6927-34, 2014 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-25082827

RESUMO

The genetic analysis of ulcerative colitis (UC) has provided new insights into the etiology of this prevalent inflammatory bowel disease. However, most of the heritability of UC (>70%) has still not been characterized. To identify new risk loci for UC we have performed the first genome-wide association study (GWAS) in a Southern European population and undertaken a meta-analysis study combining the newly genotyped 825 UC patients and 1525 healthy controls from Spain with the six previously published GWAS comprising 6687 cases and 19 718 controls from Northern-European ancestry. We identified a novel locus with genome-wide significance at 6q22.1 [rs2858829, P = 8.97 × 10(-9), odds ratio (OR) (95% confidence interval, CI] = 1.12 (1.08-1.16)] that was validated with genotype data from a replication cohort of the same Southern European ancestry consisting in 1073 cases and 1279 controls [combined P = 7.59 × 10(-10), OR (95% CI) = 1.12 (1.08-1.16)]. Furthermore, we confirmed the association of 33 reported associations with UC and we nominally validated the GWAS results of nine new risk loci (P < 0.05, same direction of effect). SNP rs2858829 lies in an intergenic region and is a strong cis-eQTL for FAM26F gene, a gene that is shown to be selectively upregulated in UC colonic mucosa with active inflammation. Our results provide new insight into the genetic risk background of UC, confirming that there is a genetic risk component that differentiates from Crohn's Disease, the other major form of inflammatory bowel disease.


Assuntos
Cromossomos Humanos Par 6 , Colite Ulcerativa/genética , Loci Gênicos , Predisposição Genética para Doença , Glicoproteínas de Membrana/genética , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/patologia , DNA Intergênico , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único
15.
BMC Genomics ; 14: 825, 2013 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-24267790

RESUMO

BACKGROUND: Psoriasis is a chronic autoimmune disease in which T cells have a predominant role in initiating and perpetuating the chronic inflammation in skin. However, the mechanisms that regulate T cell activation in psoriasis are still incompletely understood. The objective of the present study was to characterize the main genetic pathways associated with T cell activation in psoriasis. RESULTS: Gene expression profiles from in vitro activated T cells were obtained from 17 psoriasis patients and 7 healthy controls using Illumina HT-12 v4 microarrays. From a total of 47,321 analyzed transcripts, 42 genes were found to be differentially expressed between psoriasis and controls (FDR p-value < 0.1, absolute fold-change > 1.2). Using an independent cohort of 8 patients and 8 healthy controls we validated the overexpression of SPATS2L (p-value =0.0009) and KLF6 (p-value =0.0012) genes in activated T cells from psoriasis patients. Using weighted correlation analysis we identified SPATS2L and KLF6 coexpression networks, which were also significantly associated with psoriasis (p-value < 0.05). Gene Ontology analysis allowed the identification of several biological processes associated with each coexpression network. Finally, using Gene Set Enrichment Analysis over the global T cell transcriptome we also found additional genetic pathways strongly associated with psoriasis (p-value < 0.0001). CONCLUSIONS: This study has identified two new genes, SPATS2L and KLF6, strongly associated with T cell activation in psoriasis. Functional analyses of the gene expression profiles also revealed new biological processes and genetic pathways associated with psoriasis. The results of this study provide an important insight into the biology of this common chronic inflammatory disease.


Assuntos
Ativação Linfocitária , Psoríase/imunologia , Linfócitos T/imunologia , Transcriptoma/imunologia , Adulto , Estudos de Casos e Controles , Células Cultivadas , Feminino , Regulação da Expressão Gênica/imunologia , Ontologia Genética , Redes Reguladoras de Genes , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Psoríase/metabolismo , Linfócitos T/metabolismo
16.
Pharmacogenomics ; 14(7): 727-34, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23651021

RESUMO

AIM: The present study was undertaken to replicate the association of candidate genes for anti-TNF response in rheumatoid arthritis. Candidate genes were selected from a recent genome-wide association study on anti-TNF response performed in a population from Denmark. MATERIALS & METHODS: Genomic DNA was obtained from 315 Spanish rheumatoid arthritis patients having received an anti-TNF agent as their first biological therapy. SNPs from NR2FR2, MAP2K6, CBLN2 and PDE3A-SLCO1C1 candidate loci were genotyped. RESULTS: The PDE3A-SLCO1C1 locus rs3794271 SNP showed a highly significant association with anti-TNF treatment response (p = 1.74 × 10⁻5). Combining the statistical evidence from the Spanish and Danish rheumatoid arthritis cohorts, the associated rs3794271 SNP reached a genome-wide significance level of association (p = 3.3 × 10⁻¹°). CONCLUSION: The present findings establish the PDE3A-SLCO1C1 locus as a strong genetic marker of anti-TNF therapy response.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Transportadores de Ânions Orgânicos/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antirreumáticos/uso terapêutico , Dinamarca , Feminino , Loci Gênicos , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Resultado do Tratamento
17.
Reumatol. clín. (Barc.) ; 9(1): 18-23, ene.-feb. 2013. tab
Artigo em Inglês | IBECS | ID: ibc-109048

RESUMO

Objetivo. Determinar si los pacientes con artritis reumatoide (AR) a los que se les prescribe terapia biológica tienen comorbilidad diferente a los pacientes con AR a los que se les prescribe solo fármacos antirreumáticos modificadores de la enfermedad (FAME). Entender la asociación de comorbilidad con otras variables y con multimorbilidad. Métodos. Estudio observacional de casos y controles, incluyó 114 pacientes con AR a los que se les prescribió terapia biológica, y un grupo control de 163 pacientes emparejados por sexo y edad a los que solo se les había prescrito FAME. Se recogieron datos previos y actuales sobre actividad de enfermedad, comorbilidad y tratamientos. Se realizó análisis de regresión bivariante y multivariante. Resultados. Los pacientes a los que se les prescribió terapia biológica tenían: peor control de la enfermedad, recibieron más FAME y glucocorticoides y se habían sometido a más artroplastias en comparación con el grupo control. Sin embargo, los factores de riesgo cardiovascular y la frecuencia de comorbilidad fueron similares entre casos y controles. Las comorbilidades más frecuentes fueron: hipercolesterolemia (33%), hipertensión (27%), obesidad (26%), y trastornos respiratorios (16%), tiroideos(13%) y gastrointestinales (10%). La incidencia de enfermedad cardiovascular es baja (2%). Solo el 29% de los pacientes tenían multimorbilidad. Se observó asociación bivariante entre edad, diagnóstico tardío, reemplazos articulares y HAQ, con comorbilidad. También se observaron correlaciones entre índice de Charlson y edad, la cirugía reconstructiva, actividad de la enfermedad y HAQ. Cuando se aplican los modelos de regresión Log binario, solo la edad se mantuvo asociada significativamente con comorbilidad y multimorbilidad (hazard ratio 1,8; intervalo de confianza al 95% 1,05-1,12; p<0,0005). Conclusión. Los pacientes con AR con terapia biológica tienen comorbilidad equivalente a los tratados solo con FAME. La edad es el principal factor predictivo de comorbilidad en estos pacientes (AU)


Aim: To determine whether rheumatoid arthritis (RA) patients who have been prescribed biological agents exhibit a different comorbidity burden than RA patients who take disease-modifying antirheumatic drugs (DMARDs) alone, and to understand the association between comorbidity and other variables, as well as the association between comorbidity and multimorbidity. Methods: This observational case–control study included 114 RA patients treated with biological agents and a control group comprising 163 sex- and age-matched RA patients treated with DMARDs only. Current and previous data regarding the patients’ disease activity, comorbidities, and treatments were collected. The data were analysed using bivariate and multivariate regression models. Results: The patients who were prescribed biological agents exhibited poorer disease control, received more DMARDs and steroids, and underwent more total joint arthroplasties compared with the patients in the control group. However, the risk factors for cardiovascular disease and the comorbidity frequency were similar between cases and controls. The most prevalent comorbidities were hypertension, obesity, and respiratory, thyroid, and upper gastrointestinal disorders. The incidence of cardiovascular disease was low, and only 29% of the patients exhibited multimorbidities. A bivariate association of age, late diagnosis, joint replacements and a high score on the health assessment questionnaire score (HAQ) with comorbidity was observed. There were also correlations between the Charlson index and age, joint reconstructive surgery, disease activity (DAS28), and HAQ score. However, when binary logarithmic regression models were applied, only patient age remained significantly associated with comorbidity and multimorbidity [hazard ratio, 1.08; 95% confidence interval, 1.05–1.12; p < 0.0005]. Conclusion: RA patients taking biological drugs have a comorbidity burden equivalent to those treated with DMARDs alone. Age is the main predictive factor of comorbidity in these patients (AU)


Assuntos
Humanos , Masculino , Feminino , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/prevenção & controle , Terapia Biológica/instrumentação , Terapia Biológica/métodos , Terapia Biológica/normas , Grupos Controle , Antirreumáticos/metabolismo , Antirreumáticos/uso terapêutico , Artroplastia/métodos , Artroplastia/tendências , Comorbidade , Terapia Biológica/tendências , Terapia Biológica , Modelos Logísticos , Antirreumáticos/farmacologia , Análise Multivariada , Protocolos Clínicos/normas
18.
Gut ; 62(10): 1440-5, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22936669

RESUMO

OBJECTIVE: Genome-wide association studies (GWAS) have identified multiple risk loci for Crohn's disease (CD). However, the cumulative risk exerted by these loci is low, and the likelihood that additional, as-yet undiscovered loci contribute to the risk of CD is very high. We performed a GWAS on a southern European population to identify new CD risk loci. DESIGN: We genotyped 620 901 genome markers on 1341 CD patients and 1518 controls from Spain. The top association signals representing new candidate risk loci were subsequently analysed in an independent replication cohort of 1365 CD patients and 1396 controls. RESULTS: We identified a genome-wide significant association on chromosome 22q13.2 in the intergenic region between the RBX1 and EP300 genes (single nucleotide polymorphism rs4820425, OR 1.27, 95% CI 1.17 to 1.38, p=3.42E-8). We also found suggestive evidence for the association of the IFNGR2 (21q22.11), FOXP2 (7q31), MACROD2 (20p12.1) and AIF1 (6p21.3) loci with CD risk. CONCLUSIONS: In this GWAS performed on a southern European cohort, we have identified a new risk locus for CD between RBX1 and EP300. This study demonstrates that using populations of different ancestry is a useful strategy to identify new risk loci for CD.


Assuntos
Proteínas de Transporte/genética , Doença de Crohn/genética , Proteína p300 Associada a E1A/genética , Adulto , Estudos de Casos e Controles , Cromossomos Humanos Par 22/genética , Doença de Crohn/epidemiologia , DNA Intergênico/genética , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espanha/epidemiologia
19.
Reumatol Clin ; 9(1): 18-23, 2013 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22938792

RESUMO

AIM: To determine whether rheumatoid arthritis (RA) patients who have been prescribed biological agents exhibit a different comorbidity burden than RA patients who take disease-modifying antirheumatic drugs (DMARDs) alone, and to understand the association between comorbidity and other variables, as well as the association between comorbidity and multimorbidity. METHODS: This observational case-control study included 114 RA patients treated with biological agents and a control group comprising 163 sex- and age-matched RA patients treated with DMARDs only. Current and previous data regarding the patients' disease activity, comorbidities, and treatments were collected. The data were analysed using bivariate and multivariate regression models. RESULTS: The patients who were prescribed biological agents exhibited poorer disease control, received more DMARDs and steroids, and underwent more total joint arthroplasties compared with the patients in the control group. However, the risk factors for cardiovascular disease and the comorbidity frequency were similar between cases and controls. The most prevalent comorbidities were hypertension, obesity, and respiratory, thyroid, and upper gastrointestinal disorders. The incidence of cardiovascular disease was low, and only 29% of the patients exhibited multimorbidities. A bivariate association of age, late diagnosis, joint replacements and a high score on the health assessment questionnaire score (HAQ) with comorbidity was observed. There were also correlations between the Charlson index and age, joint reconstructive surgery, disease activity (DAS28), and HAQ score. However, when binary logarithmic regression models were applied, only patient age remained significantly associated with comorbidity and multimorbidity [hazard ratio, 1.08; 95% confidence interval, 1.05-1.12; p<0.0005]. CONCLUSION: RA patients taking biological drugs have a comorbidity burden equivalent to those treated with DMARDs alone. Age is the main predictive factor of comorbidity in these patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/epidemiologia , Adalimumab , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Murinos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Comorbidade , Etanercepte , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Infliximab , Modelos Logísticos , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Análise Multivariada , Receptores do Fator de Necrose Tumoral/uso terapêutico , Estudos Retrospectivos , Rituximab , Espanha , Resultado do Tratamento , Adulto Jovem
20.
Clin Exp Rheumatol ; 30(5): 768-71, 2012 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22935134

RESUMO

OBJECTIVES: To compare the routine use of musculoskeletal ultrasonography (MSUS) with traditional clinical care in daily practice at shoulder and hand level. METHODS: An observational study was performed in four rheumatology departments. Within each department, 2 rheumatologists were selected; one rheumatologist used MSUS, and the other followed traditional rheumatology care. Consecutive patients with nontraumatic pain, hand numbness or disability, or pain and/or limitations in the shoulder were selected. We collected information regarding the clinical and MSUS diagnoses, changes in diagnosis and treatment following MSUS, local injections, the rheumatologist's satisfaction and the use of health care resources. A descriptive analysis was performed. RESULTS: A total of 168 patients were analysed, with 104 and 64 patients in the MSUS and traditional care groups, respectively. MSUS led to a diagnosis and therapeutic change in 53 (52%) and 55 patients (54%), respectively. The rate of local injection was 47% in the MSUS group (73% unexpected, 61% performed using US) compared with 21% in the traditional group (p=0.001). According to the rheumatologists, MSUS was useful in 72 cases (71%) and extremely useful in 20 cases (20%), and the rheumatologists reported a higher satisfaction with their patient evaluations (p<0.001). The MSUS group required fewer additional tests (38% vs. 81%, respectively, p<0.001), fewer medical visits (46% vs. 84%, p<0.001), and lower direct costs (11 vs. 30 euros, p<0.001) than the traditional care group. CONCLUSIONS: Compared with traditional care, the routine use of MSUS in rheumatology practice at hand and shoulder level can lead to important improvements in care, thereby reducing the number of additional tests and medical visits.


Assuntos
Mãos/diagnóstico por imagem , Doenças Musculoesqueléticas/diagnóstico por imagem , Ombro/diagnóstico por imagem , Adulto , Idoso , Atitude do Pessoal de Saúde , Redução de Custos , Análise Custo-Benefício , Feminino , Custos de Cuidados de Saúde , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/tratamento farmacológico , Doenças Musculoesqueléticas/economia , Medição da Dor , Valor Preditivo dos Testes , Prognóstico , Qualidade da Assistência à Saúde , Encaminhamento e Consulta , Índice de Gravidade de Doença , Espanha , Esteroides/administração & dosagem , Ultrassonografia
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