RESUMO
OBJECTIVE: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA. METHODS: We performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case-control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA. RESULTS: We identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (pFDR<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs. CONCLUSION: These findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.
Assuntos
Artrite Psoriásica/genética , Glicosaminoglicanos/genética , N-Acetilglucosaminiltransferases/genética , Psoríase/genética , Transdução de Sinais/genética , Adulto , Artrite Psoriásica/epidemiologia , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , América do Norte/epidemiologia , Polimorfismo de Nucleotídeo Único , Psoríase/epidemiologia , Espanha/epidemiologiaRESUMO
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 , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Estudos de Casos e Controles , Moléculas de Adesão Celular , Variações do Número de Cópias de DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Guanilato Quinases , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/genética , Fatores de RiscoRESUMO
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.