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OBJECTIVES: Previous studies have reported an association between inflammatory cytokines and inflammatory arthritis, including Ankylosing spondylitis (AS), rheumatoid arthritis (RA), and psoriatic arthritis (PsA). This study aims to explore the causal relationship between inflammatory cytokines and AS, RA, and PsA using Mendelian randomization (MR). METHODS: We conducted a bidirectional two-sample MR analysis using genetic summary data from a publicly available genome-wide association study (GWAS) that included 41 genetic variations of inflammatory cytokines, as well as genetic variant data for AS, RA, and PsA from the FinnGen consortium. The main analysis method used was Inverse variance weighted (IVW) to investigate the causal relationship between exposure and outcome. Additionally, other methods such as MR Egger, weighted median (WM), simple mode, and weighted mode were employed to strengthen the final results. Sensitivity analysis was also performed to ensure the reliability of the findings. RESULTS: The results showed that macrophage colony-stimulating factor (MCSF) was associated with an increased risk of AS (OR = 1.163, 95 % CI = 1.016-1.33, p = 0.028). Conversely, high levels of TRAIL and beta nerve growth factor (ß-NGF) were associated with a decreased risk of AS (OR = 0.892, 95 % CI = 0.81-0.982, p = 0.002; OR = 0.829, 95 % CI = 0.696-0.988, p = 0.036). Four inflammatory cytokines were found to be associated with an increased risk of PsA: vascular endothelial growth factor (VEGF) (OR = 1.161, 95 % CI = 1.057-1.275, p = 0.002); Interleukin 12p70 (IL12p70) (OR = 1.189, 95 % CI = 1.049-1.346, p = 0.007); IL10 (OR = 1.216, 95 % CI = 1.024-1.444, p = 0.026); IL13 (OR = 1.159, 95 % CI = 1.05-1.28, p = 0.004). Interleukin 1 receptor antagonist (IL-1rα) was associated with an increased risk of seropositive RA (OR = 1.181, 95 % CI = 1.044-1.336, p = 0.008). Similarly, genetic susceptibility to inflammatory arthritis was found to be causally associated with multiple inflammatory cytokines. Lastly, the sensitivity analysis supported the robustness of these findings. CONCLUSIONS: This study provides additional insights into the relationship between inflammatory cytokines and inflammatory arthritis, and may offer new clues for the etiology, diagnosis, and treatment of inflammatory arthritis.
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Artrite Psoriásica , Artrite Reumatoide , Espondilite Anquilosante , Humanos , Citocinas/genética , Artrite Psoriásica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Reprodutibilidade dos Testes , Fator A de Crescimento do Endotélio Vascular , Artrite Reumatoide/genética , Espondilite Anquilosante/genéticaRESUMO
BACKGROUND: Lipid pathways play a crucial role in psoriatic arthritis development, and some lipid-lowering drugs are believed to have therapeutic benefits due to their anti-inflammatory properties. Traditional observational studies face issues with confounding factors, complicating the interpretation of causality. This study seeks to determine the genetic link between these medications and the risk of psoriatic arthritis. METHODS: This drug target study utilized the Mendelian randomization strategy. We harnessed high-quality data from population-level genome-wide association studies sourced from the UK Biobank and FinnGen databases. The inverse variance-weighted method, complemented by robust pleiotropy methods, was employed. We examined the causal relationships between three lipid-lowering agents and psoriatic arthritis to unveil the underlying mechanisms. RESULTS: A significant association was observed between genetically represented proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and a decreased risk of psoriatic arthritis (odds ratio [OR]: 0.51; 95% CI 0.14-0.88; P < 0.01). This association was further corroborated in an independent dataset (OR 0.60; 95% CI 0.25-0.94; P = 0.03). Sensitivity analyses affirmed the absence of statistical evidence for pleiotropic or genetic confounding biases. However, no substantial associations were identified for either 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or Niemann-Pick C1-like 1 inhibitors. CONCLUSIONS: This Mendelian randomization analysis underscores the pivotal role of PCSK9 in the etiology of psoriatic arthritis. Inhibition of PCSK9 is associated with reduced psoriatic arthritis risk, highlighting the potential therapeutic benefits of existing PCSK9 inhibitors.
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Artrite Psoriásica , Pró-Proteína Convertase 9 , Humanos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Estudo de Associação Genômica Ampla , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/genética , Hipolipemiantes/uso terapêutico , LipídeosRESUMO
INTRODUCTION: tRNA-derived fragments (tRFs) play an important role in immune responses. To clarify the role of tRFs in autoimmunity we studied circulating tRF-levels in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), and in a murine model for arthritis. MATERIAL AND METHODS: Circulating tRF-levels were quantified by miR-Q RT-qPCR. tRNA processing and modification enzyme expression was analysed by RT-qPCR and public transcriptomics data. RESULTS: Significant reduction (up to 3-fold on average) of tRF-levels derived from tRNA-Gly-GCC,CCC, tRNA-Glu-CTC and tRNA-Val-CAC,AAC was observed in RA patients, whereas tRNA-Glu-CTC and tRNA-Val-CAC,AAC tRFs were found at significantly higher levels (up to 3-fold on average) in PsA patients, compared to healthy controls. Also in arthritic IL1Ra-KO mice reduced levels of tRNA-Glu-CTC fragments were seen. The expression of NSUN2, a methyltransferase catalysing tRNA methylation, was increased in RA-peripheral blood mononuclear cells (PBMCs) compared to PsA, but this is not consistently supported by public transcriptomics data. DISCUSSION: The observed changes of specific tRF-levels may be involved in the immune responses in RA and PsA and may be applicable as new biomarkers. CONCLUSION: Circulating tRF-levels are decreased in RA and increased in PsA and this may, at least in part, be mediated by methylation changes.
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Artrite Psoriásica , Artrite Reumatoide , Humanos , Animais , Camundongos , Artrite Psoriásica/genética , Leucócitos Mononucleares/metabolismo , RNA de Transferência/genética , Biomarcadores/metabolismoRESUMO
BACKGROUND: Psoriasis (Ps) is a disorder attributed to the immune system that involves inflammation of the skin and joints. Psoriasis is a multifactorial disorder in which genetic factors represent about 70% of the disease risk. This study aims to establish the correlation between the ERAP2 gene's single nucleotide polymorphisms (SNPs) rs2910686 and rs2248374 with the susceptibility to Ps and/or psoriatic arthritis (PsA) among the Egyptian population. METHODS AND RESULTS: Genotyping of ERAP2 gene SNPs (rs2910686 and rs2248374) in 120 psoriatic patients with and without arthritis and 100 controls was done using real-time PCR. The genotype frequency and distribution of the ERAP2 SNP (rs2910686 and rs2248374) were in Hardy-Weinberg equilibrium (HWE). For rs2910686, the TC and CC genotypes and C allele frequency were significant risk factors for PsA compared to the controls (OR = 5.708, OR = 10.165, and OR = 4.282, respectively). They also were significant risk factors for Ps compared to the controls (OR = 5.165, OR = 5.040, and OR = 3.258, respectively). For rs2248374, the AG genotype significantly increased the risk of PsA (OR = 2.605) and Ps (OR = 3.768) compared to controls. The AG genotype was significantly related to the risk of Ps (OR = 3.369) G allele with PsA (OR = 1.608) and Ps (OR = 1.965) compared to controls. CONCLUSION: In Egyptian individuals, the ERAP2 gene polymorphisms (rs2248374 and rs2910686) may contribute genetically to the pathophysiology of psoriasis and PsA.
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Aminopeptidases , Artrite Psoriásica , Frequência do Gene , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Psoríase , Humanos , Polimorfismo de Nucleotídeo Único/genética , Aminopeptidases/genética , Artrite Psoriásica/genética , Egito , Masculino , Feminino , Psoríase/genética , Frequência do Gene/genética , Adulto , Pessoa de Meia-Idade , Estudos de Casos e Controles , Genótipo , Fatores de Risco , Alelos , Estudos de Associação Genética , População do Norte da ÁfricaRESUMO
OBJECTIVE: This study is designed to explore the potential causal relationship between psoriasis and psoriatic arthritis (PsA) while investigating the genetic basis shared by these inflammatory diseases. METHODS: Significant single nucleotide polymorphisms (SNPs) associated with UC, psoriasis, and PsA were selected as genetic instrumental variables using Genome-Wide Association Study (GWAS) datasets. Additionally, Mendelian randomization (MR) methods, including inverse-variance weighting (IVW), MR-Egger regression, and Weighted Median (WME), were utilized to evaluate the causal relationships between these diseases. Moreover, sensitivity analysis and heterogeneity testing were conducted to validate the stability of the results. RESULTS: A total of 123 significant SNPs associated with psoriasis, PsA, and UC were identified as genetic instrumental variables based on GWAS datasets. The analysis revealed a 36% increased risk of UC with psoriasis (odds ratio [OR] = 1.350, 95% confidence interval [CI] = 1.065-1.729, P = 0.012) and a 32.9% increased risk of UC with PsA (OR = 1.329, 95% CI = 1.176-1.592, P < 0.001). Further analysis showed a 43.5% increased risk of psoriasis with UC (OR = 1.435, 95% CI = 1.274-1.831, P < 0.001) and a 45.8% increased risk of PsA with UC (OR = 1.458, 95% CI = 1.166-1.822, P = 0.0013). In addition, sensitivity analysis and heterogeneity testing demonstrated the high stability of these results. Particularly, neither MR-Egger regression analysis nor leave-one-out analysis revealed significant heterogeneity or pleiotropy bias, indicating the reliability of these causal estimates. Moreover, the use of the MR-PRESSO further confirmed the positive correlation between psoriasis and UC, and the corrected estimates remained consistent with IVW analysis results after excluding potential outlier SNPs, enhancing the credibility of the analysis. CONCLUSIONS: This study strengthens the understanding of the genetic and causal relationships among UC, psoriasis, and PsA through GWAS and MR methods, revealing the genetic basis they may share. These findings not only provide a novel perspective on the comorbidity mechanisms of these diseases but also offer a valuable reference for the development of future treatment strategies and intervention measures.
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Artrite Psoriásica , Colite Ulcerativa , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Psoríase , Humanos , Artrite Psoriásica/genética , Artrite Psoriásica/epidemiologia , Psoríase/genética , Psoríase/epidemiologia , Colite Ulcerativa/genética , Colite Ulcerativa/epidemiologia , Predisposição Genética para Doença/genética , Fatores de RiscoRESUMO
BACKGROUND: Prior observational studies have suggested a potential direct link between psoriasis (PSO) and interstitial lung disease (ILD). Consequently, we applied Mendelian randomization (MR) to further evaluate the bidirectional causal relationships between PSO and its different phenotypes [psoriatic arthritis (PSA)/psoriasis vulgaris (PSV)] and ILD. METHODS: Data regarding PSO/PSA/PSV and ILD were sourced from publicly accessible genome-wide association studies (GWAS) databases, focusing on European populations. We used five algorithms- MR Egger, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode- to evaluate the causal relationships between PSO/PSA/PSV and ILD, with a primary emphasis on the IVW method. RESULTS: The analysis indicated a potential association between PSA and an elevated risk of ILD [IVW odds ratio (OR): 1.035 (95% CI 1.008, 1.064; P = 0.012)], with no evidence of a direct relationship between total PSO and PSV with ILD. Conversely, no substantial evidence emerged from the reverse MR analysis to suggest that ILD significantly affects total PSO or the specific PSA/PSV phenotypes. CONCLUSION: Our findings provide genetic evidence supporting the notion that PSA may be a contributory risk factor for ILD. Further investigations are warranted to explore the underlying mechanisms of this potential causal relationship between PSA and ILD.
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Artrite Psoriásica , Estudo de Associação Genômica Ampla , Doenças Pulmonares Intersticiais , Análise da Randomização Mendeliana , Psoríase , Humanos , Doenças Pulmonares Intersticiais/genética , Psoríase/genética , Artrite Psoriásica/genética , Fenótipo , Fatores de Risco , Polimorfismo de Nucleotídeo Único , Predisposição Genética para DoençaRESUMO
BACKGROUND: Previous observational studies indicated a complex association between frailty and arthritis. AIMS: To investigate the genetic causal relationship between the frailty index and the risk of common arthritis. METHODS: We performed a large-scale Mendelian randomization (MR) analysis to assess frailty index associations with the risk of common arthritis in the UK Biobank (UKB), and the FinnGen Biobank. Summary genome-wide association statistics for frailty, as defined by the frailty index, and common arthritis including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PSA), and ankylosing spondylitis (AS). The inverse-variance weight (IVW) method served as the primary MR analysis. Heterogeneity testing and sensitivity analysis were also conducted. RESULTS: Our results denoted a genetic association between the frailty index with an increased risk of OA, the odds ratio (OR)IVW in the UKB was 1.03 (95% confidence interval [CI]: 1.01-1.05; P = 0.007), and ORIVW was 1.55 (95% CI: 1.16-2.07; P = 0.003) in the FinnGen. For RA, the ORIVW from UKB and FinnGen were 1.03 (1.01-1.05, P = 0.006) and 4.57 (1.35-96.49; P = 0.025) respectively. For PSA, the frailty index was associated with PSA (ORIVW = 4.22 (1.21-14.67), P = 0.023) in FinnGen, not in UKB (P > 0.05). However, no association was found between frailty index and AS (P > 0.05). These results remained consistent across sensitivity assessments. CONCLUSION: This study demonstrated a potential causal relationship that genetic predisposition to frailty index was associated with the risk of arthritis, especially RA, OA, and PSA, not but AS. Our findings enrich the existing body of knowledge on the subject matter.
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Fragilidade , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Fragilidade/genética , Artrite/genética , Artrite/epidemiologia , Osteoartrite/genética , Osteoartrite/epidemiologia , Artrite Reumatoide/genética , Artrite Reumatoide/epidemiologia , Idoso , Masculino , Feminino , Artrite Psoriásica/genética , Artrite Psoriásica/epidemiologia , Predisposição Genética para Doença , Pessoa de Meia-IdadeRESUMO
The Proviral Integration site for the Moloney murine leukemia virus (PIM)-1 kinase and its family members (PIM-2 and PIM-3) regulate several cellular functions including survival, proliferation, and apoptosis. Recent studies showed their involvement in the pathogenesis of rheumatoid arthritis RA, while no studies are available on psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). The main objective of this study is to assess the expression of PIM kinases in inflammatory arthritides, their correlation with proinflammatory cytokines, and their variation after treatment with biologic disease-modifying anti-rheumatic drugs or JAK inhibitors. We evaluated PIM-1, -2, and -3 expression at the gene and protein level, respectively, in the peripheral blood mononuclear cells and serum of patients with RA, PsA, axSpA, and healthy individuals (CTR). All the samples showed expression of PIM-1, -2, and -3 kinases both at the gene and protein level. PIM-1 was the most expressed protein, PIM-3 the least. PIM kinase levels differed between controls and disease groups, with reduced PIM-1 protein and increased PIM-3 protein in all disease samples compared to controls. No difference was found in the expression of these molecules between the three different pathologies. PIM levels were not modified after 6 months of therapy. In conclusion, our preliminary data suggest a deregulation of the PIM pathway in inflammatory arthritides. In-depth studies on the role of PIM kinases in this field are warranted.
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Artrite Psoriásica , Espondiloartrite Axial , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-pim-1 , Humanos , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/genética , Leucócitos Mononucleares , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismoRESUMO
Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis assessing the association between single nucleotide polymorphisms (SNPs) and response to biologics. Odds ratio (OR) with 95% confidence interval (CI) meta-analyses were performed. In total, 185 studies examining 62,774 individuals were included. For the diseases combined, the minor allele of MYD88 (rs7744) was associated with good response to TNFi (OR: 1.24 [1.02-1.51], 6 studies, 3158 patients with psoriasis or RA) and the minor alleles of NLRP3 (rs4612666) (OR: 0.71 [0.58-0.87], 5 studies, 3819 patients with RA or IBD), TNF-308 (rs1800629) (OR: 0.71 [0.55-0.92], 25 studies, 4341 patients with psoriasis, RA, or IBD), FCGR3A (rs396991) (OR: 0.77 [0.65-0.93], 18 studies, 2562 patients with psoriasis, PsA, RA, or IBD), and TNF-238 (rs361525) (OR: 0.57 [0.34-0.96]), 7 studies, 818 patients with psoriasis, RA, or IBD) were associated with poor response to TNFi together or infliximab alone. Genetic variants in TNFα, NLRP3, MYD88, and FcRγ genes are associated with response to TNFi across several inflammatory diseases. Most other genetic variants associated with response were observed in a few studies, and further validation is needed.
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Artrite Psoriásica , Artrite Reumatoide , Produtos Biológicos , Doenças Inflamatórias Intestinais , Polimorfismo de Nucleotídeo Único , Psoríase , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Psoríase/genética , Psoríase/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Artrite Reumatoide/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Psoriásica/genética , Artrite Psoriásica/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fator 88 de Diferenciação Mieloide/genéticaRESUMO
In recent years, research has intensified in exploring the genetic basis of psoriasis (PsO) and psoriatic arthritis (PsA). Genome-wide association studies (GWASs), including tools like ImmunoChip, have significantly deepened our understanding of disease mechanisms by pinpointing risk-associated genetic loci. These efforts have elucidated biological pathways involved in PsO pathogenesis, particularly those related to the innate immune system, antigen presentation, and adaptive immune responses. Specific genetic loci, such as TRAF3IP2, REL, and FBXL19, have been identified as having a significant impact on disease development. Interestingly, different genetic variants at the same locus can predispose individuals to either PsO or PsA (e.g., IL23R and deletion of LCE3B and LCE3C), with some variants being uniquely linked to PsA (like HLA B27 on chromosome 6). This article aims to summarize known and new data on the genetics of PsO and PsA, their associated genes, and the involvement of the HLA system and cytokines.
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Artrite Psoriásica , Citocinas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA , Psoríase , Humanos , Artrite Psoriásica/genética , Artrite Psoriásica/imunologia , Psoríase/genética , Psoríase/imunologia , Antígenos HLA/genéticaRESUMO
OBJECTIVE: The objective is to describe the HLA allelic frequency in PsA and correlate it with demographic and clinical variables. METHODS: Retrospective study of adult patients with a diagnosis of PsA (n=23) and healthy controls (n=46), all with a request for HLA-A, B, C, DR. Typing was performed using HLA-PCR/SSO LifeCodes and analyzed on the LUMINEX IS100/200 xMAP® system. (Ethics/Code HMC2022-014). RESULTS: One hundred thirty-eight alleles were included from 69 individuals, 43,5% women, aged 44,5±16,5 years in patients with PsA, with a mean age of disease onset of 33.4±14 years. Only 9.5% had a high Body Mass Index and dyslipidemia was the most frequent comorbidity (34.8%), followed by high blood pressure (26,1%). 82% debuted with skin manifestation and once the joint disease was established, the predominance was peripheral (74%) due to arthritis/arthralgia in 74%, enthesitis in 30% and dactylitis in 13%. The allele frequencies were for HLA*A 2402 (13%), 3201 (13%) and 2427 (8,7%), for HLA*B 1402 (17,4%), 4002 (17,4%), 3801 (13%) and HLA*DR 0404 (17,4%), 0407 (13%). No HLA*B27 was identified and HLA*C0602 was only 2,2%. HLA A*0201 and DR*1301 were less frequent in controls versus PsA (p=0.024 and 0,029, respectively), while HLA*B1302 was frequent in PsA (p=0,035). CONCLUSIONS: Curiously, there were no positive results for HLAB*27, which may be related to the population mix. HLA Cw6 is traditionally associated with psoriasis. However, its absence has been linked to nail disorders and PsA; consequently, in our study, it had a low frequency (2,2%). On the other hand, HLA*B1302 has been related to the disease and its early onset; in the healthy Colombian population, it has been described in 0,92%; in our group, it is found to be significant in patients without establishing a clinical association. Few previous studies report HLA results in PsA in Colombia.
OBJETIVO: Describir la frecuencia alélica de HLA en APs y asociarlo con variables demográficas y clínicas. MÉTODOS: Estudio retrospectivo de pacientes adultos con diagnóstico de APs (n=23), y controles sanos (n=46), todos con solicitud de HLA-A, B, C y DR. La tipificación se realizó por medio de HLA-PCR/SSO LifeCodes, y se analizó en el sistema LUMINEX IS 100/200 xMAP®. (Ética/Código HMC2022-014). RESULTADOS: Se incluyeron 138 alelos de 69 individuos, 43,5% mujeres, con edad 44,5±16,5 años, en pacientes con APs, con edad media de inicio de la enfermedad de 33,4±14 años. Solo el 9,5% tuvo Índice de Masa Corporal alto y la dislipidemia fue la comorbilidad más frecuente (34,8%), seguida de hipertensión arterial (26,1%). El 82% debutó con manifestación en piel y una vez establecida la enfermedad articular, el predominio fue periférico (74%), por artritis/artralgias en un 74%, entesitis en 30%, y dactilitis 13%. Las frecuencias alélicas fueron para HLA*A 2402 (13%), 3201 (13%) y 2427 (8,7%), para HLA*B 1402 (17,4%), 4002 (17,4%), 3801 (13%) y HLA*DR 0404 (17,4%), 0407 (13%). No se identificó HLA*B27 y HLA*C0602 fue solo del 2,2 %. HLA A*0201 y DR*1301 fueron menos frecuentes en controles versus APs (p=0,024 y 0,029, respectivamente), mientras que HLA*B1302 frecuente en APs (p=0,035). CONCLUSIÓN: Curiosamente no hubo resultados positivos para HLAB*27 y esto puede relacionarse con el mestizaje de la población. HLA Cw6 es tradicionalmente asociado a psoriasis, sin embargo, su ausencia se ha relacionado con mayor reporte de alteraciones ungueales y Aps; como consecuencia, en nuestro estudio tuvo una baja frecuencia (2,2%). Por otro lado, el HLA*B1302 ha tenido relación con la enfermedad y su inicio temprano, en población sana colombiana se ha descrito en 0,92%, en nuestro grupo se encuentra de manera significativa en los pacientes sin establecerse asociación clínica. Pocos estudios previos refieren resultados de HLA en APs en Colombia.
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Alelos , Artrite Psoriásica , Frequência do Gene , Humanos , Feminino , Masculino , Colômbia , Adulto , Artrite Psoriásica/genética , Artrite Psoriásica/diagnóstico , Estudos Retrospectivos , Pessoa de Meia-Idade , Antígenos HLA/genéticaRESUMO
Psoriatic arthritis mutilans (PAM) is the rarest and most severe form of psoriatic arthritis, characterized by erosions of the small joints and osteolysis leading to joint disruption. Despite its severity, the underlying mechanisms are unknown, and no susceptibility genes have hitherto been identified. We aimed to investigate the genetic basis of PAM by performing massive parallel sequencing in sixty-one patients from the PAM Nordic cohort. We found rare variants in the NADPH oxidase 4 (NOX4) in four patients. In silico predictions show that the identified variants are potentially damaging. NOXs are the only enzymes producing reactive oxygen species (ROS). NOX4 is specifically involved in the differentiation of osteoclasts, the cells implicated in bone resorption. Functional follow-up studies using cell culture, zebrafish models, and measurement of ROS in patients uncovered that these NOX4 variants increase ROS levels both in vitro and in vivo. We propose NOX4 as the first candidate susceptibility gene for PAM. Our study links high levels of ROS caused by NOX4 variants to the development of PAM, offering a potential therapeutic target.
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Artrite Psoriásica , Animais , Humanos , NADPH Oxidase 4/genética , Espécies Reativas de Oxigênio , Artrite Psoriásica/genética , Artrite Psoriásica/tratamento farmacológico , Peixe-Zebra , Diferenciação CelularRESUMO
Psoriasis (PsO) is a chronic inflammatory skin condition, often accompanied by psoriatic arthritis (PsA) and linked to various comorbidities and increased mortality rates. This study aimed to explore the relationship between PsO and accelerated biological aging, specifically focusing on epigenetic DNA methylation clocks. Using a matched case-control design, 20 PsO cases were selected along with age, race, and sex-matched 20 controls without PsO from the Skin Disease Biorepository at Brown Dermatology, Inc, Providence, Rhode Island. Blood samples retrieved from both groups were analyzed for DNA methylation, and epigenetic ages were calculated using DNA methylation clocks, including Horvath, Hannum, Pheno, SkinBlood, and Grim ages. Generalized estimation equations were employed to test the differences in epigenetic and chronological ages between PsO cases and controls, as well as within various subgroups in comparison to their respective controls. There were no statistically significant differences in epigenetic ages between PsO cases and controls. However, notably, PsO cases with PsA demonstrated an accelerated PhenoAge, compared to their matched controls. This study represents a pioneering investigation into the potential link between PsO and epigenetic aging, shedding light on the possibility of accelerated epigenetic aging in PsA, possibly associated with heightened inflammatory burden. These findings emphasize the systemic impact of PsA on the aging process, prompting the need for deeper exploration into autoimmune pathways, inflammation, and epigenetic modifications underlying PsO pathogenesis and aging mechanisms. Larger-scale studies with diverse populations are imperative to discern PsO subgroups experiencing accelerated biological aging and decipher the intricate interplay between PsO, inflammation, and aging pathways.
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Metilação de DNA , Epigênese Genética , Psoríase , Humanos , Estudos de Casos e Controles , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Psoríase/genética , Idoso , Envelhecimento/genética , Artrite Psoriásica/genéticaRESUMO
Background: Numerous observational studies have identified associations between both psoriasis (PsO) and psoriatic arthritis (PsA), and autoimmune diseases (AIDs); however, the causality of these associations remains undetermined. Methods: We conducted a bidirectional two-sample Mendelian Randomization study to identify causal associations and directions between both PsO and PsA and AIDs, such as systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), uveitis, bullous pemphigoid (BP), Hashimoto's thyroiditis (HT), rheumatoid arthritis (RA), vitiligo, and ankylosing spondylitis (AS). The causal inferences were drawn by integrating results from four regression models: Inverse Variance Weighting (IVW), MR-Egger, Weighted Median, and Maximum Likelihood. Furthermore, we performed sensitivity analyses to confirm the reliability of our findings. Results: The results showed that CD [IVW odds ratio (ORIVW), 1.11; 95% confidence interval (CI), 1.06-1.17; P = 8.40E-06], vitiligo (ORIVW, 1.16; 95% CI, 1.05-1.28; P = 2.45E-03) were risk factors for PsO, while BP may reduce the incidence of PsO (ORIVW, 0.91; 95% CI, 0.87-0.96; P = 1.26E-04). CD (ORIVW, 1.07; 95% CI, 1.02-1.12; P = 0.01), HT (ORIVW, 1.23; 95% CI, 1.08-1.40; P = 1.43E-03), RA (ORIVW, 1.11; 95% CI, 1.02-1.21, P = 2.05E-02), AS (ORIVW, 2.18; 95% CI, 1.46-3.27; P = 1.55E-04), SLE (ORIVW, 1.04; 95% CI, 1.01-1.08; P = 1.07E-02) and vitiligo (ORIVW, 1.27; 95% CI, 1.14-1.42; P = 2.67E-05) were risk factors for PsA. Sensitivity analyses had validated the reliability of the results. Conclusions: Our study provides evidence for potential causal relationships between certain AIDs and both PsO and PsA. Specifically, CD and vitiligo may increase the risk of developing PsO, while CD, HT, SLE, RA, AS, and vitiligo may elevate the risk for PsA. Additionally, it is crucial to closely monitor the condition of PsO patients with specific AIDs, as they have a higher likelihood of developing PsA than those without AIDs. Moving forward, greater attention should be paid to PsA and further exploration of other PsO subtypes is warranted.
Assuntos
Artrite Psoriásica , Doenças Autoimunes , Análise da Randomização Mendeliana , Psoríase , Humanos , Artrite Psoriásica/genética , Doenças Autoimunes/genética , Doenças Autoimunes/epidemiologia , Psoríase/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Background: Previous epidemiological studies have identified a correlation between serum protein levels and Psoriatic Arthritis (PsA). However, the precise nature of this relationship remains uncertain. Therefore, our objective was to assess whether circulating levels of 2,923 plasma proteins are associated with the risk of PsA, utilizing the Mendelian randomization (MR) approach. Methods: Two-sample MR analysis was performed to assess the causal impact of proteins on PsA risk. Exposure data for plasma proteins were sourced from a genome-wide association study (GWAS) conducted within the UK Biobank Pharma Proteomics Project, which encompassed 2,923 unique plasma proteins. The outcome data for PsA were sourced from the FinnGen study, a large-scale genomics initiative, comprising 3,537 cases and 262,844 controls. Additionally, colocalization analysis, Phenome-wide MR analysis, and candidate drug prediction were employed to identify potential causal circulating proteins and novel drug targets. Results: We thoroughly assessed the association between 1,837 plasma proteins and PsA risk, identifying seven proteins associated with PsA risk. An inverse association of Interleukin-10 (IL-10) with PsA risk was observed [odds ratio (OR)=0.45, 95% confidence interval (CI), 0.28 to 0.70, P FDR=0.072]. Additionally, Apolipoprotein F (APOF) has a positive effect on PsA risk (OR=2.08, 95% CI, 1.51 to 2.86, P FDR=0.005). Subsequently, we found strong evidence indicating that IL-10 and APOF were colocalized with PsA associations (PP.H4 = 0.834 for IL-10 and PP.H4 = 0.900 for APOF). Phenome-wide association analysis suggested that these two proteins may have dual effects on other clinical traits (P FDR<0.1). Conclusion: This study identified 7 plasma proteins associated with PsA risk, particularly IL-10 and APOF, which offer new insights into its etiology. Further studies are needed to assess the utility and effectiveness of these candidate proteins.
Assuntos
Artrite Psoriásica , Proteínas Sanguíneas , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Proteoma , Humanos , Artrite Psoriásica/genética , Artrite Psoriásica/sangue , Proteínas Sanguíneas/genética , Polimorfismo de Nucleotídeo Único , Proteômica/métodos , Interleucina-10/sangue , Interleucina-10/genética , Predisposição Genética para Doença , Masculino , Biomarcadores/sangue , FemininoRESUMO
OBJECTIVE: Inflammatory bowel disease (IBD) is strongly associated with Spondylarthritis (SpA), but the causal relationship remains unclear. This study explores the causal associations between IBD (Crohn's disease [CD] and ulcerative colitis [UC]) and several common subtypes of SpA (Ankylosing Spondylitis [AS], Psoriatic Arthritis [PsA], and Reactive Arthritis [ReA]), using bidirectional two-sample Mendelian randomization (TSMR). METHODS: The causal effects of genetically predicted IBD on AS, PsA, and ReA were firstly investigated in this forward study. The causal effects from AS, PsA, and ReA on IBD were analyzed in the reverse MR. Inverse variance weighted, weighted median, and MR-Egger were applied in the MR analyses. The pleiotropic effects, heterogeneity, and leave-one-out sensitivity analysis were also evaluated. RESULTS: The forward MR analysis demonstrated that IBD increased risk for AS (OR:1.278; P = 1.273 × 10-5), PsA (OR:1.192; P = 1.690 × 10-5), and ReA (OR:1.106; P = 1.524 × 10-3). Among them, CD increased risk of AS (OR:1.196; P = 3.424 × 10-4), PsA (OR:1.101; P = 1.537 × 10-3), ReA (OR:1.079; P = 6.321 × 10-3) whereas UC increased risk of AS (OR:1.166; P = 2.727 × 10-2), PsA (OR:1.110; P = 1.944 × 10-2), and ReA (OR:1.091; P = 1.768 × 10-2). The reverse-direction MR disclosed no notable association; neither was any evidence of pleiotropy detected. CONCLUSION: Our study verifies a causal effect of IBD to AS, PsA as well as ReA, but not vice versa. This might bring new insights for the management of IBD and SpA in clinical practice.
Assuntos
Artrite Psoriásica , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Espondilartrite , Espondilite Anquilosante , Humanos , Análise da Randomização Mendeliana , Artrite Psoriásica/genética , Espondilartrite/genética , Espondilite Anquilosante/genética , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Estudo de Associação Genômica AmplaRESUMO
Joint diseases affect hundreds of millions of people worldwide, and their prevalence is constantly increasing. To date, despite recent advances in the development of therapeutic options for most rheumatic conditions, a significant proportion of patients still lack efficient disease management, considerably impacting their quality of life. Through the spectrum of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA) as quintessential and common rheumatic diseases, this review first provides an overview of their epidemiological and clinical features before exploring how the better definition of clinical phenotypes has helped their clinical management. It then discusses the recent progress in understanding the diversity of endotypes underlying disease phenotypes. Finally, this review highlights the current challenges of implementing molecular endotypes towards the personalized management of RA, PsA and OA patients in the future.
Assuntos
Artrite Psoriásica , Osteoartrite , Fenótipo , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Osteoartrite/terapia , Osteoartrite/genética , Artrite Psoriásica/genética , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/terapia , Artrite Reumatoide/genética , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/classificação , Artrite Reumatoide/imunologia , Artrite Reumatoide/terapia , Doença Crônica , Masculino , Feminino , Artropatias/genética , Artropatias/diagnóstico , Artropatias/terapiaRESUMO
Previous research has demonstrated a robust association between osteoarthritis (OA) and psoriasis. Notably, a significant proportion of psoriasis patients exhibit symptoms of arthritis, particularly psoriatic arthritis. However, a definitive causal relationship between psoriasis, psoriatic arthritis and OA remains to be established. This study aimed to elucidate the causal relationship between psoriasis, psoriatic arthritis, and osteoarthritis using a 2-sample Mendelian randomization approach. The causal relationship between psoriasis, psoriatic arthritis and OA was rigorously investigated using a 2-sample Mendelian Randomization (MR) approach. Instrumental variables pertinent to psoriasis, psoriatic arthritis and 4 distinct types of OA (knee osteoarthritis (KOA), hand osteoarthritis (HOA), total knee replacement (TKR), and total hip replacement (THR)) were sourced from extensive, published genome-wide association studies (GWAS). To estimate the causal effects, methodologies such as inverse variance weighting (IVW), MR-Egger, and weighted median estimation (WM) were employed. Mendelian Randomization analysis suggested a potential causal effect of psoriasis on osteoarthritis (OA). For hand OA (HOA), the P value was .381 (ORâ =â 0.28); for knee OA (KOA), the P value was .725 (ORâ =â 1.46); for TKR, the P value was .488 (ORâ =â 0.274); and for THR, the P value was .454 (ORâ =â 0.216). Furthermore, we explored the causality of psoriatic arthritis on OA. For HOA, the P value was .478 (ORâ =â 0.0095); for KOA, the P value was .835 (ORâ =â 0.345); for THR, the P value was .807 (ORâ =â 0.120); and for TKR, the P value was .860 (ORâ =â 0.190). Our findings indicate that there is no evidence of a causal connection between psoriasis or psoriatic arthritis and OA, suggesting that while psoriasis may contribute to arthritis, it does not influence OA development.
Assuntos
Artrite Psoriásica , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Osteoartrite , Psoríase , Humanos , Psoríase/genética , Psoríase/complicações , Psoríase/epidemiologia , Osteoartrite/genética , Osteoartrite/epidemiologia , Artrite Psoriásica/genética , Artrite Psoriásica/complicações , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/epidemiologia , Causalidade , Artroplastia de Quadril , Artroplastia do JoelhoRESUMO
Despite observational studies suggesting a link between psoriatic disease (including psoriasis and psoriatic arthritis) and migraine, it is unclear whether there is a shared genetic etiology or a causal relationship between the two conditions. We aimed to reveal the genetic overlap and causality using the Mendelian randomization (MR) framework. The genetic analysis utilized summary data from the most extensive European genome-wide association study (GWAS) of migraine. Well-powered psoriatic disease GWAS data were obtained from two independent cohort studies, which served as discovery and validation datasets. Global and regional genetic correlations between psoriatic disease and migraine were assessed, and pleiotropic regions identified by pairwise GWAS analysis were further annotated. We further applied a two-sample MR multivariate MR to investigate the potential causal relationship between them. The global genetic correlation test indicated weak correlations between psoriatic disease and migraine, while regional correlation analyses delineated one significant shared locus between psoriasis and migraine. Pathway enrichment analysis revealed that shared genes were involved biological processes to the major histocompatibility and antigen processing and presentation. In terms of causality estimates, genetically predicted psoriasis (Pmeta = 0.003) and psoriatic arthritis (Pmeta = 0.028) were associated with an increased risk of migraine. Multivariate MR analysis indicated that psoriasis was an independent risk factor for migraine (P < 0.05). No significant associations were found in the reverse direction. Our study supported the causal role of psoriasis on migraine, and the central role for immunomodulatory etiology. These findings have significant implications for the management of migraine and clinical practice in patients with psoriasis.
Assuntos
Artrite Psoriásica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos de Enxaqueca , Polimorfismo de Nucleotídeo Único , Psoríase , Humanos , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/epidemiologia , Psoríase/genética , Psoríase/epidemiologia , Artrite Psoriásica/genética , Artrite Psoriásica/epidemiologia , Fatores de RiscoRESUMO
Previous studies reveal that psoriatic arthritis (PsA) and ankylosing spondylitis (AS) share susceptibility genes, such as HLA-B27, demonstrating a degree of genetic overlap between these diseases. Recent studies have identified a number of novel AS and PsA genetic susceptibility loci, but data on these loci in Chinese PsA patients are limited. To identify candidate genes that confer susceptibility to PsA in Chinese patients with PsA, psoriasis vulgaris (PsV), and healthy controls. Sixteen susceptibility loci, reported in a genome-wide association study of AS, and nine susceptibility loci, reported in candidate gene studies of PsA, were examined. Single-nucleotide polymorphisms (SNPs) were genotyped in 503 patients with PsA, 496 patients with PsV, and 979 healthy controls using the SNPscanTM multiplex SNP genotyping platform. PLINK software and logistic regression analysis were used to estimate the statistical significance of associations. PPP2R3C (rs8006884) was shown to significantly associate with PsA+PsV (p = 1.92×10-3, OR = 1.28) and was suggested to associate with PsV (p = 0.03, OR = 1.19). A suggestive association was also observed between IL-23R (rs12141575) and PsA as well as with axial PsA based on subtype analysis, KIF3A (rs2897442) and PsV, and ERN1 (rs196941) or IFIH1 (rs984971) and axial PsA. Our results suggest that PPP2R3C confers susceptibility to PsA and PsV, and that this gene may be related to the pathogenesis of psoriatic lesions and arthritis. Moreover, our results indicate a possible association between IL-23R, ERN1, or IFIH1 and subtypes of PsA, and between KIF3A and PsV.