Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 4 uppsatser.

Inflammatory arthritis (IA) types such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and psoriatic arthritis (PsA) have been shown to exhibit common clinical features. As complex diseases they have a known genetic component, some of which is known to be shared. The aim of this study was to assess the genetic overlap between 3 types of IA (RA, JIA and PsA) using genotype data generated on the Immunochip array and to select a biologically promising overlapping region for further genetic and functional investigation. Overlap analysis was performed using association data generated for a large cohort of inflammatory arthritis cases and shared controls (11,475 RA; 2816 JIA; 929 PsA respectively). 50 genetic regions were identified as being associated with more than 1 type of IA (p < 1x10-3), with several interesting similarities and differences observed between the diseases. As several of the overlapping regions detected represented novel disease associations, they required replication in an independent sample cohort. 12 variants were selected for replication in an independent RA cohort of 3879 cases and 2561 controls. Of these, 2 variants in the CTLA4 and MTMR3 regions were successfully replicated in RA at p<0.05. Bioinformatics analysis was performed for the 50 overlapping regions, with one particularly promising region, RUNX1, selected for further investigation. In this region, the same variant (rs9979383) is associated across the 3 diseases, with similar odds ratios (OR 0.8-0.9) observed in each disease. As this region represented both a novel IA association and had not been densely genotyped on the Immunochip array, fine mapping was performed by genotyping 51 SNPS in 3491 cases and 2359 controls. This resulted in replication of the association at rs9979383 (p=0.02) with no additional significant genetic effects detected, therefore this variant was selected for further functional analysis. As rs9979383 lies ~280kb upstream of the RUNX1 gene, a cis-eQTL analysis was performed to identify if the variant acts by regulation of RUNX1 gene expression. This was performed in whole blood, CD4+ and CD8+ lymphocytes from 75 (and a subset of 23) healthy volunteers respectively. No significant eQTLs were detected between rs9979383 and RUNX1 in whole blood (p =0.9) or RUNX1/LOC100506403 CD4+ and CD8+ lymphocytes (p=0.1). This study has provided insight into the genetic similarities and differences between different types of inflammatory arthritis, which can be applied to further investigations into disease susceptibility. Although no significant cis-eQTL was detected in any of these tissues with either RUNX1 or the nearby lnc-RNA LOC100506403, in cells from healthy volunteers under unstimulated conditions, these findings will direct future functional investigations into the role of this overlapping region in the susceptibility of IA.

Introdução: A psoríase é uma doença sistêmica crônica, inflamatória e imuno- mediada, que afeta a pele, vasos e sistema osteomuscular. A inflamação é um fator de risco importante para a aterosclerose, e a psoríase está associada com risco aumentado de dislipidemia, diabetes, hipertensão, obesidade e esteato-hepatite não alcoólica. No entanto, o impacto da inflamação crônica sistêmica sobre a saúde vascular e aterosclerose permanece mal compreendido. Objetivos: Analisar a associação entre psoríase e aterosclerose subclínica com uma medição não invasiva, avaliada no ramo das artérias carótidas, usando a espessura médio-intimal (IMTc). O objetivo secundário foi comparar a IMTc entre os subgrupos psoríase: leve, moderada à psoríase/grave e artropática, com o grupo controle. Métodos: Neste estudo caso-controle transversal, 221 pacientes com psoríase (31,2% psoríase leve, 41,6% psoríase moderada/grave e 31,2% psoríase artropática) foram comparados com um grupo de 5.061 controles existentes recrutados a partir de um inquérito anterior (ELSA-Brasil HU-USP). Os critérios de inclusão compreendem os seguintes fatores: acima de 40 anos de idade para mulheres e 35 anos para homens; psoríase diagnosticada e clinicamente ativa, pelo menos há dois anos. Os critérios de exclusão foram: gravidez, presença de neoplasia, gota, artrite reumatóide e lúpus eritematoso sistêmico. Todos os participantes foram submetidos a exame médico, exame clínico e dados antropométricos recolhidos, bem como amostras de sangue para análise laboratorial. Em seguida, foram realizados exame de ultrassonografia das artérias carótidas direita e esquerda a fim de determinar IMTc. Ambos os lados analisados com média dos valores; quando aumentados foram utilizadas como um indicador da aterosclerose subclínica. Resultados: No grupo psoríase, o tempo médio de doença foi de 16 (± 13) anos. Em relação ao IMT da carótida (média dos lados direito e esquerdo), não observamos valores aumentados no grupo de psoríase, em comparação com o grupo controle, com os dados crus (P = 0,24 e P = 0,83, IMT esquerda e IMT direita, respectivamente). No entanto, quando o ajuste por sexo e idade (P = 0,038 e P < 0,0001, IMT para a esquerda e direita, respectivamente) e um ajuste multivariado para o risco cardiovascular, uma diferença significativa é encontrada (P = 0,028 e P < 0,0001, IMT esquerda e IMT direita, respectivamente) com valores mais elevados da carótida IMT no grupo de psoríase do que no grupo controle. Em consonância com isso, não foram observadas diferenças na IMT entre ameno, sub-grupos artrite psoriática moderado-grave e grupo controle (P = 0,50 e P = 0,52, respectivamente). Hipertensão, Hs CRP, IMC, HDL e LDL foram maiores nos pacientes com psoríase, em comparação com os controles (ambos p < 0,001). Conclusões: Na coorte brasileira, pacientes com psoríase apresentaram um perfil mais grave de fatores de risco cardiovascular do que os controles, em função do aumento da espessura da parede da artéria carótida encontrada nesses pacientes. O papel preciso da inflamação sistêmica crônica e outros fatores sobre a progressão da doença e comorbidades devem ainda ser elucidados . / Introduction: Psoriasis is a chronic systemic immune-mediated inflammatory disease affecting skin, vessels and osteomuscular system. Inflammation is an important risk-factor for atherosclerosis and psoriasis is associated with increased risk for dislipidemia, diabetes, hypertension, obesity and non-alcoholic steatohepatitis. However, the impact of chronic systemic inflammation on vascular health and atherosclerosis remains poorly understood. Objectives: To examine the association between psoriasis and subclinical atherosclerosis assessed at the carotid artery branch using a non-invasive measurement of the intima-media thickness (IMTc). The secondary objective was to compare the IMTc between psoriasis subgroups: mild, moderate / severe psoriasis and arthropathica with control group. Methods: In this cross-sectional case-control study, 221 psoriasis patients (31.2% mild psoriasis, 41.6% moderate-severe psoriasis and 31.2% arthritic psoriasis) were compared with a group of 5,061 existing controls recruited from a previous investigation (ELSA-Brasil HU-USP). Inclusion criteria were: 40 y of age for women and 35 y of age for men; psoriasis diagnosed and clinically active for at least 2 years. Exclusion criteria were: pregnancy, neoplasia, gout, rheumatic arthritis and systemic lupus erythematosus. All participants were submitted to medical screening, clinical examination and had anthropometric data collected as well as blood samples for laboratorial analysis. Then, they undertook an ultrasound scan of the right and left carotid arteries in order to determine IMTc. Both sides were averaged and increased values were used as an indicator of subclinical atherosclerosis. Results: The psoriasis group the mean disease time was 16±13 years. In relation to the carotid IMT (right and left sides averaged), we did not observe increased values in the psoriasis group as compared to the control group, with crude data (P = 0,24 and P = 0,83, IMT left and IMT right respectively). However, when adjusting by sex, age (P = 0,038 and P < 0,0001, IMT left and IMT right respectively) and a multivariate adjustment for cardiovascular risk, a significant difference is found (P = 0,028 and P < 0.0001, IMT left and IMT right respectively) with higher carotid IMT values in the psoriasis group than in the control group. In line with this, no differences were observed in the IMT between mild, moderate-severe, psoriatic arthritis sub-groups and control group (P = 0.50 e P = 0.52, respectively). Hypertension, Hs CRP, BMI, HDL and LDL were higher in psoriasis patients as compared to controls (both p < 0.001). Conclusions: In the Brazilian cohort, psoriasis patients presented a more severe profile of cardiovascular risk factors than controls, with increased carotid arterial wall thickness being found in these patients. The precise role of chronic systemic inflammation and other factors on disease progression and comorbidities are yet to be elucidated

Introdução: A psoríase é uma doença sistêmica crônica, inflamatória e imuno- mediada, que afeta a pele, vasos e sistema osteomuscular. A inflamação é um fator de risco importante para a aterosclerose, e a psoríase está associada com risco aumentado de dislipidemia, diabetes, hipertensão, obesidade e esteato-hepatite não alcoólica. No entanto, o impacto da inflamação crônica sistêmica sobre a saúde vascular e aterosclerose permanece mal compreendido. Objetivos: Analisar a associação entre psoríase e aterosclerose subclínica com uma medição não invasiva, avaliada no ramo das artérias carótidas, usando a espessura médio-intimal (IMTc). O objetivo secundário foi comparar a IMTc entre os subgrupos psoríase: leve, moderada à psoríase/grave e artropática, com o grupo controle. Métodos: Neste estudo caso-controle transversal, 221 pacientes com psoríase (31,2% psoríase leve, 41,6% psoríase moderada/grave e 31,2% psoríase artropática) foram comparados com um grupo de 5.061 controles existentes recrutados a partir de um inquérito anterior (ELSA-Brasil HU-USP). Os critérios de inclusão compreendem os seguintes fatores: acima de 40 anos de idade para mulheres e 35 anos para homens; psoríase diagnosticada e clinicamente ativa, pelo menos há dois anos. Os critérios de exclusão foram: gravidez, presença de neoplasia, gota, artrite reumatóide e lúpus eritematoso sistêmico. Todos os participantes foram submetidos a exame médico, exame clínico e dados antropométricos recolhidos, bem como amostras de sangue para análise laboratorial. Em seguida, foram realizados exame de ultrassonografia das artérias carótidas direita e esquerda a fim de determinar IMTc. Ambos os lados analisados com média dos valores; quando aumentados foram utilizadas como um indicador da aterosclerose subclínica. Resultados: No grupo psoríase, o tempo médio de doença foi de 16 (± 13) anos. Em relação ao IMT da carótida (média dos lados direito e esquerdo), não observamos valores aumentados no grupo de psoríase, em comparação com o grupo controle, com os dados crus (P = 0,24 e P = 0,83, IMT esquerda e IMT direita, respectivamente). No entanto, quando o ajuste por sexo e idade (P = 0,038 e P < 0,0001, IMT para a esquerda e direita, respectivamente) e um ajuste multivariado para o risco cardiovascular, uma diferença significativa é encontrada (P = 0,028 e P < 0,0001, IMT esquerda e IMT direita, respectivamente) com valores mais elevados da carótida IMT no grupo de psoríase do que no grupo controle. Em consonância com isso, não foram observadas diferenças na IMT entre ameno, sub-grupos artrite psoriática moderado-grave e grupo controle (P = 0,50 e P = 0,52, respectivamente). Hipertensão, Hs CRP, IMC, HDL e LDL foram maiores nos pacientes com psoríase, em comparação com os controles (ambos p < 0,001). Conclusões: Na coorte brasileira, pacientes com psoríase apresentaram um perfil mais grave de fatores de risco cardiovascular do que os controles, em função do aumento da espessura da parede da artéria carótida encontrada nesses pacientes. O papel preciso da inflamação sistêmica crônica e outros fatores sobre a progressão da doença e comorbidades devem ainda ser elucidados . / Introduction: Psoriasis is a chronic systemic immune-mediated inflammatory disease affecting skin, vessels and osteomuscular system. Inflammation is an important risk-factor for atherosclerosis and psoriasis is associated with increased risk for dislipidemia, diabetes, hypertension, obesity and non-alcoholic steatohepatitis. However, the impact of chronic systemic inflammation on vascular health and atherosclerosis remains poorly understood. Objectives: To examine the association between psoriasis and subclinical atherosclerosis assessed at the carotid artery branch using a non-invasive measurement of the intima-media thickness (IMTc). The secondary objective was to compare the IMTc between psoriasis subgroups: mild, moderate / severe psoriasis and arthropathica with control group. Methods: In this cross-sectional case-control study, 221 psoriasis patients (31.2% mild psoriasis, 41.6% moderate-severe psoriasis and 31.2% arthritic psoriasis) were compared with a group of 5,061 existing controls recruited from a previous investigation (ELSA-Brasil HU-USP). Inclusion criteria were: 40 y of age for women and 35 y of age for men; psoriasis diagnosed and clinically active for at least 2 years. Exclusion criteria were: pregnancy, neoplasia, gout, rheumatic arthritis and systemic lupus erythematosus. All participants were submitted to medical screening, clinical examination and had anthropometric data collected as well as blood samples for laboratorial analysis. Then, they undertook an ultrasound scan of the right and left carotid arteries in order to determine IMTc. Both sides were averaged and increased values were used as an indicator of subclinical atherosclerosis. Results: The psoriasis group the mean disease time was 16±13 years. In relation to the carotid IMT (right and left sides averaged), we did not observe increased values in the psoriasis group as compared to the control group, with crude data (P = 0,24 and P = 0,83, IMT left and IMT right respectively). However, when adjusting by sex, age (P = 0,038 and P < 0,0001, IMT left and IMT right respectively) and a multivariate adjustment for cardiovascular risk, a significant difference is found (P = 0,028 and P < 0.0001, IMT left and IMT right respectively) with higher carotid IMT values in the psoriasis group than in the control group. In line with this, no differences were observed in the IMT between mild, moderate-severe, psoriatic arthritis sub-groups and control group (P = 0.50 e P = 0.52, respectively). Hypertension, Hs CRP, BMI, HDL and LDL were higher in psoriasis patients as compared to controls (both p < 0.001). Conclusions: In the Brazilian cohort, psoriasis patients presented a more severe profile of cardiovascular risk factors than controls, with increased carotid arterial wall thickness being found in these patients. The precise role of chronic systemic inflammation and other factors on disease progression and comorbidities are yet to be elucidated