Diss. (sammanfattning) Linköping : Univ., 2004. / 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.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Michigan, 1985.

Thesis (M.S.)--University of Michigan, 1985.

Thesis (M.S.)--University of Michigan, 1985.

Orientador: Manoel Barros Bertolo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T03:37:39Z (GMT). No. of bitstreams: 1 Pires_CatarinaFernandes_D.pdf: 2601322 bytes, checksum: 1acb7f604b763cb1fd45c71455e387bf (MD5) Previous issue date: 2014 / Resumo: O presente estudo de caso-controle avaliou 74 crianças piauienses com Artrite Idiopática Juvenil (AIJ) em suas diversas formas: Oligoarticular, Sistêmica, Poliarticular Fator Reumatoide Positivo (FR+), Poliarticular Fator Reumatoide Negativo (FR-), Artrite relacionada a Entesite (ERA), Artrite Psoriásica e Artrite indeterminada, classificadas de acordo com os Critérios da Liga Internacional de Associações de Reumatologia (ILAR) e cento e um controles saudáveis pareados de acordo com idade, sexo, procedência e etnia. Os objetivos foram identificar e determinar os alelos HLA-DR e HLA-DQ em uma amostra da população infanto-juvenil piauiense com AIJ nas formas oligoarticular, sistêmica, poliarticular FR+, poliarticular FR-, artrite psoriásica, artrite relacionada a entesite e artrite indeterminada e compará-las com as frequências observadas no grupo de controle saudáveis; conhecer os alelos HLA-DR e HLA-DQ que estão associados a maior susceptibilidade e os que conferem maior proteção na população de crianças com AIJ em suas diversas formas. As tipagens dos alelos HLA-DR e HLA-DQ foram realizadas por meio da técnica de amplificação pela Reação de Cadeia da Polimerase (PCR), utilizando cadeias específicas de primers DR e DQ. O resultado da análise demostrou que, entre todas as formas de apresentação da AIJ, houve associação estatística significativa para a susceptibilidade da doença com o HLA-DRB1*10 OR 8,8 (IC 1,1 a 74,9) e HLA-DRB1*16 OR 2,8 (IC 1,1 a 7.5). Na forma oligoarticular a associação estatística significativa para a susceptibilidade ocorreu com o alelo HLA-DRB1*08 OR 4,6 (IC 1,4 a 14,6). Na forma sistêmica, essa associação aconteceu com o alelo HLA-DRB1*10 OR 22,2 (IC 1,8 a 269,5).Na forma Poliarticular FR+ a associação estatística significativa para a susceptibilidade ocorreu com os alelos DRB1*09 OR 12,1 (IC 2,2 a 66,9) e DRB1*10 OR 28,5 (IC 2,3 a 355,0). Na forma Poliarticular FR-, a associação estatística significativa para a susceptibilidade foi com o alelo DRB1*16 OR 13,4 (IC 1,6 a 111,2). A Artrite Psoriásica não apresentou nenhuma associação estatística significativa com os HLA pesquisados. O resultado da análise demostrou que, entre todas as formas de apresentação da AIJ, houve associação estatística significativa para a proteção da doença com o HLA-DRB1*03 OR 0,7 (IC 0,5 a 0,9) e, na forma sistêmica, essa associação aconteceu igualmente com DRB1*03 OR 0,7 (IC 0,6 a 0,8). As outras formas de apresentação da doença não demonstraram associação estatística significativa para a proteção com nenhum tipo da HLA pesquisado. A população estudada não apresentou nenhum caso de ERA e de Artrite indeterminada. O estudo encontrou ainda, associação para o risco entre o HLA-DQB1*03 OR = 6,06 (IC 1,3 a 27,2) e uveíte em pacientes com a forma oligoarticular da AIJ. Desta forma, concluímos que os nossos resultados apresentam tanto semelhanças em relação a susceptibilidade, quanto diferenças, principalmente quanto a proteção, nas associações tipicamente encontradas na literatura / Abstract: This case-controle valuated 74 children from Piauí with Juvenile Idiopathic Arthritis (AIJ) in its various forms: Oligoarticular, Systemic, Polyarticular Rheumatoid Factor Positive (FR +), Polyarticular Rheumatoid Factor Negative (FR-), Enthesitis-related Arthritis (ERA), Arthritis Psoriatic and Arthritis indeterminate, classified according to the Criteria of the International League of Associations for Rheumatology(ILAR), and one hundred and one healthy control smatched according to age ,sex, origin and ethnicity. The objectives were to identify and determine the HLA-DR and HLA-DQ in a sample of Piauí juvenile population subtypes JIA in oligoarticular, systemic, polyarticular RF + polyarticular RF -, psoriatic arthritis, enthesitis-related arthritis and arthritis indeterminate and compares them with the observed frequencies in the group of healthy control; know the HLA-DR and HLA-DQ alleles are associated with increased susceptibility and conferring greater protection in the population with JIA in its various forms and identify a possible relationship between the alleles HLA-DR and HLA-DQ and the most frequent and most aggressive form of the disease in the population studied. Polymerase Chain Reaction (PCR) using primers specific chains of DR and DQ performed the typing of HLA-DR and HLA-DQ using the technique of amplification. The result of the analysis demonstrate damong all cases of JIA was statistically significant association for disease susceptibility with HLA-DRB1*10 OR 8.8 (CI 1.1 to 74.9) and HLA-DRB1*16 OR 2.8 (CI 1.1 to 7.5). In oligoarticular JIA significant statistical association to susceptibility occurred with HLA-DRB1*08 allele OR 4.6 (CI 1.4 to 14.6), association systemic form happened to HLA-DRB1*10 OR 22.2 (CI 1.8 to 269.5) allele in polyarticular RF + the statistically significant association to susceptibility occurred with the DRB1*09 alleles OR 12.1(CI 2.2 to 66.9) and DRB1*10 OR 28.5(CI 2.3 to 355.0) in polyarticular RF- significant statistical association to susceptibility was with DRB1*16 allele OR 13.4 (CI 1.6 to 111.2). The Psoriatic Arthritis showed no statistically significant association with HLA surveyed. The result of the analysis demonstrate damong all cases of JIA was statistically significant association for disease protection with HLA-DRB1*03 OR 0.7(CI 0.5 to 0.9) and the systemic form this association also happened DRB1*03 OR with 0.7 (CI 0.6 to 0.8). The other forms of the disease showed no statistically significant association for protection on any type of HLA searched. The study population did not show any cases of ERA and indeterminate Arthritis. The study also found, statistically significant difference between the HLA-DQB1*03 OR 6.0 (CI 1.3 to 27.2), and uveitis in patients with oligoarticular form of JIA. Thus, we conclude that our results show both similarities in terms of susceptibility, and differences, especially regarding the protection, associations typically found in the literature / Doutorado / Medicina Interna / Doutora em Ciências Médicas

A artrite idiopática juvenil (AIJ) constitui um grupo heterogêneo de doenças que se caracteriza por inflamação crônica em uma ou mais articulações, com diagnóstico em menores de 16 anos de idade. A poluição atmosférica tem sido responsabilizada pelo aumento da morbidade e mortalidade em doenças cardiorrespiratórias, mas poucos estudos avaliaram os efeitos da exposição prolongada sobre doenças inflamatórias crônicas. Alguns estudos demonstram associação entre fumo e início da doença reumatológica em adultos e outros mostram associação de mães fumantes durante a gravidez com desenvolvimento de AIJ nos filhos. Entretanto, existem poucos estudos na literatura avaliando a exposição à poluição do ar e AIJ. Objetivo: avaliar a influência de poluentes ambientais inalatórios como fatores de risco no desenvolvimento da AIJ em pacientes residentes na Região Metropolitana de São Paulo, acompanhados em um serviço terciário de Reumatologia Pediátrica. Metodologia: Este foi um estudo retrospectivo, do tipo caso-controle, que incluiu 66 pacientes com AIJ e 124 controles saudáveis, semelhantes em idade e gênero, residentes na Região Metropolitana de São Paulo, desde a gestação até o diagnóstico da doença. Um questionário estruturado e com alto índice de confiabilidade (índice kappa para teste-reteste 0,80) avaliou dados demográficos, fatores relacionados à gestação e ao período perinatal, exposição ocupacional materna durante a gravidez a partículas inaláveis e/ou vapor volátil, exposição ao tabaco e exposição à inalação ambiental durante a gravidez e após o nascimento (presença de atividades industriais, pedreiras ou postos de gasolina perto do domiícilio/ trabalho/ creche/ escola). Foram também analisados poluentes troposféricos nos dois períodos: material particulado (PM10), dióxido de enxofre (SO2), dióxido de nitrogênio (NO2), ozônio (O3) e monóxido de carbono (CO). Resultados: Durante a gravidez, o fumo fetal (OR= 3,43, IC 95%: 1,45-8,12, p=0,005) e a exposição ocupacional materna (OR= 13,69, IC95%: 4,43-42,27, p < 0,001) se mostraram fatores de risco independentes para AIJ. Em contrapartida, o fato de a mãe trabalhar fora de casa (OR= 0,06, IC 95%: 0,02- 0,16, p < 0,001) e o ganho de peso ideal da mãe (OR = 0,36, IC 95%: 0,16-0,83, p= 0,017) apresentaram associação negativa. Para o período após o nascimento até o diagnóstico de AIJ, fumo passivo (OR= 3,6, IC 95%: 1,76- 7,31, p < 0,0001) e exposição ao ozônio durante o segundo ano de idade (OR= 2,76, IC 95%: 1,20-6,37, p= 0,017) foram fatores de risco independentes e significativos para o diagnóstico da AIJ. Conclusão: O fumo passivo, a exposição ao ozônio no segundo ano de vida e a exposição ocupacional materna são destacados como importantes fatores de risco para a AIJ / Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases characterized by chronic inflammation in one or more joints with onset in children under 16 years of age. Air pollution has been blamed for increased morbidity and mortality in cardiorespiratory diseases, but few studies have evaluated the effects of prolonged exposure on chronic inflammatory diseases. Some studies show an association between smoking and onset of rheumatologic illness in adults, and others show an association of smoking mothers during pregnancy with the development of JIA in children. However, there are few studies in the literature to date evaluating exposure to air pollution and JIA. Objective: To evaluate the influence of exposure to inhalable environmental factors during pregnancy and after birth until JIA diagnosis in residents of the São Paulo metropolitan area. Methods: Case-control study comprising 66 JIA patients and 124 healthy controls matched by age and gender, living in the Sao Paulo metropolitan area until JIA diagnosis, and whose mothers had resided in this region during pregnancy. A structured and reliable questionnaire (kappa index for test-retest was 0.80) assessed demographic data, gestational and perinatal-related factors, mothers\' work-related exposure during pregnancy to inhalable particles and / or volatile vapor, exposure to inhalable elements during pregnancy and after birth (work-related exposure to inhalable particles and/or volatile vapor, exposure to tobacco and the presence of industrial activities, quarries or gas stations near the home/ work/ daycare/ school). Tropospheric pollutants included: particulate matter (PM10), sulphur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3) and carbon monoxide (CO). Results: During pregnancy, fetal smoking (OR=3.43, 95%CI: 1.45-8.12, p=0.005) and mothers\' work-related exposure (OR=13.69, 95%CI: 4.43-42.27, p < 0.001) were independent significant risk factors for JIA diagnosis. In contrast, working mother (OR=0.06, 95% IC: 0.02-0.16, p < 0.001) and ideal mother weight gain (OR=0.36, 95% IC:0.16-0.83, p=0.017) presented a negative association. After birth until JIA diagnosis, secondhand smoking (OR=3.6, 95% IC: 1.76-7.31, p < 0.0001) and exposure to O3 during the second year of age (OR=2.76, 95% IC: 1.20-6.37, p=0.017) were independent and significant risk factors for JIA diagnosis. Conclusion: Secondhand smoking, exposure to O3 during the second year of age and mothers\' work-related exposure are highlighted as important risk factors to JIA