RESUMO
Carotid Intima-media thickness (CIMT) and plaque are well established markers of subclinical atherosclerosis and are widely used for identifying subclinical atherosclerotic disease. We performed association analyses using Metabochip array to identify genetic variants that influence variation in CIMT and plaque, measured using B-mode ultrasonography, in rheumatoid arthritis (RA) patients. Data on genetic associations of common variants associated with both CIMT and plaque in RA subjects involving Mexican Americans (MA) and European Americans (EA) populations are presented in this article. Strong associations were observed after adjusting for covariate effects including baseline clinical characteristics and statin use. Susceptibility loci and genes and/or nearest genes associated with CIMT in MAs and EAs with RA are presented. In addition, common susceptibility loci influencing CIMT and plaque in both MAs and EAs have been presented. Polygenic Risk Score (PRS) plots showing complementary evidence for the observed CIMT and plaque association signals are also shown in this article. For further interpretation and details, please see the research article titled "A Genetic Association Study of Carotid Intima-Media Thickness (CIMT) and Plaque in Mexican Americans and European Americans with Rheumatoid Arthritis" which is being published in Atherosclerosis (Arya et al., 2018) [1].(Arya et al., in press) Thus, common variants in several genes exhibited significant associations with CIMT and plaque in both MAs and EAs as presented in this article. These findings may help understand the genetic architecture of subclinical atherosclerosis in RA populations.
RESUMO
BACKGROUND AND AIMS: Little is known about specific genetic determinants of carotid-intima-media thickness (CIMT) and carotid plaque in subjects with rheumatoid arthritis (RA). We have used the Metabochip array to fine map and replicate loci that influence variation in these phenotypes in Mexican Americans (MAs) and European Americans (EAs). METHODS: CIMT and plaque were measured using ultrasound from 700 MA and 415 EA patients with RA and we conducted association analyses with the Metabochip single nucleotide polymorphism (SNP) data using PLINK. RESULTS: In MAs, 12 SNPs from 11 chromosomes and 6 SNPs from 6 chromosomes showed suggestive associations (p < 1 × 10-4) with CIMT and plaque, respectively. The strongest association was observed between CIMT and rs17526722 (SLC17A2 gene) (ß ± SE = -0.84 ± 0.18, p = 3.80 × 10-6). In EAs, 9 SNPs from 7 chromosomes and 7 SNPs from 7 chromosomes showed suggestive associations with CIMT and plaque, respectively. The top association for CIMT was observed with rs1867148 (PPCDC gene, ß ± SE = -0.28 ± 0.06, p = 5.11 × 10-6). We also observed strong association between plaque and two novel loci: rs496916 from COL4A1 gene (OR = 0.51, p = 3.15 × 10-6) in MAs and rs515291 from SLCA13 gene (OR = 0.50, p = 3.09 × 10-5) in EAs. CONCLUSIONS: We identified novel associations between CIMT and variants in SLC17A2 and PPCDC genes, and between plaque and variants from COL4A1 and SLCA13 that may pinpoint new candidate risk loci for subclinical atherosclerosis associated with RA.
Assuntos
Artrite Reumatoide/etnologia , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/etnologia , Doenças das Artérias Carótidas/genética , Espessura Intima-Media Carotídea , Americanos Mexicanos/genética , Placa Aterosclerótica , Polimorfismo de Nucleotídeo Único , População Branca/genética , Idoso , Artrite Reumatoide/diagnóstico , Carboxiliases/genética , Doenças das Artérias Carótidas/diagnóstico por imagem , Feminino , Perfilação da Expressão Gênica/métodos , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I/genética , Texas/epidemiologiaRESUMO
Joint destruction in rheumatoid arthritis (RA) is heritable, but knowledge on specific genetic determinants of joint damage in RA is limited. We have used the Immunochip array to examine whether genetic variants influence variation in joint damage in a cohort of Mexican Americans (MA) and European Americans (EA) with RA. We studied 720 MA and 424 EA patients with RA. Joint damage was quantified using a radiograph of both hands and wrists, scored using Sharp's technique. We conducted association analyses with the transformed Sharp score and the Immunochip single nucleotide polymorphism (SNP) data using PLINK. In MAs, 15 SNPs from chromosomes 1, 5, 9, 17 and 22 associated with joint damage yielded strong p-values (p < 1 × 10(-4) ). The strongest association with joint damage was observed with rs7216796, an intronic SNP located in the MAP3K14 gene, on chromosome 17 (ß ± SE = -0.25 ± 0.05, p = 6.23 × 10(-6) ). In EAs, 28 SNPs from chromosomes 1, 4, 6, 9, and 21 showed associations with joint damage (p-value < 1 × 10(-4) ). The best association was observed on chromosome 9 with rs59902911 (ß ± SE = 0.86 ± 0.17, p = 1.01 × 10(-6) ), a synonymous SNP within the CARD9 gene. We also observed suggestive evidence for some loci influencing joint damage in MAs and EAs. We identified two novel independent loci (MAP3K14 and CARD9) strongly associated with joint damage in MAs and EAs and a few shared loci showing suggestive evidence for association.
Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Proteínas Adaptadoras de Sinalização CARD/genética , Articulações/patologia , Proteínas Serina-Treonina Quinases/genética , Artrite Reumatoide/etnologia , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Americanos Mexicanos/genética , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos , População Branca/genética , Quinase Induzida por NF-kappaBRESUMO
OBJECTIVES: C1858T single nucleotide polymorphism in PTPN22 encoding the R620W allele variant of Lyp-PTPN22 (a protein phosphatase negatively regulating T-cell activation) has been associated with autoimmunity. This work has investigated the possible association between PTPN22 C1858T (rs2476601) polymorphism and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) in a Colombian population. METHODS: A case-control study included 1,042 samples from 413 RA, 94 SLE and 101 SSc patients and 434 healthy controls. The TaqMan allele discrimination assay was used for genotyping. RESULTS: The case-control study provided robust evidence of association between allele 1858T and RA (p=5E-05), as well as between 1858T and SLE (p=0.004). These observations were confirmed for both diseases by meta-analysis (p=2E-04, pooled OR 1.9; 1.3-2.7 95% CI for RA; p<0.0001, pooled OR 2.8, 1.8-4.5 95% CI for SLE). No significant association was observed between 1858T and SSc (p=0.98, OR 1.11, 0.46-2.65 95% CI). CONCLUSIONS: The study suggested that the PTPN22 1858T variant influences RA and SLE genetic background but not that of SSc in the Colombian population.
Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Escleroderma Sistêmico/genética , Adulto , Artrite Reumatoide/epidemiologia , Estudos de Casos e Controles , Colômbia/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Variação Genética/genética , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Escleroderma Sistêmico/epidemiologiaRESUMO
Gouty panniculitis is an unusual clinical manifestation of gout, characterized by the deposition of monosodium urate crystals in the lobular hypodermis. Its pathogenesis is poorly understood but is associated with hyperuricemia, and the clinical presence of indurate subcutaneous plaques, which may precede or appear subsequently to the articular clinical expression of tophaceous gout. The aim of this report is to describe the clinical characteristics and potential risk factors for the development of lobular panniculitis secondary to chronic tophaceous gout. This is a retrospective clinical review of 6 patients with gouty panniculitis seen at the rheumatology service at the National University of Colombia. All cases fulfill diagnostic criteria for gout. The presenting clinical characteristics of each case were analyzed. All 6 patients were men, with an average age of 26 years. Two patients initially presented with cutaneous manifestations, and in the remainder 4 joint involvements preceded the cutaneous manifestations. Articular involvement first developed in lower extremities, of intermittent nature, and subsequent occurrence of polyarthritis of upper and lower extremities. A positive family history of gout was observed in half of the patients. Smoking and high alcohol intake were relevant risk factors. On physical examination, all exhibited the presence of erythematous, irregular surface, deep indurate subcutaneous plaques. Biopsy of skin and deep dermis including panniculus revealed the presence of granulomatous inflammatory changes with deposition of amorphous eosinophilic material surrounded by palisading histocytes and lymphocytes. Characteristic negative birefringent monosodium urate crystals were observed in the synovial fluid of patients with arthritis. All patients exhibited high levels of serum uric acid and were non-complaint to treatment with allopurinol, NSAIDs, and colchicine. Gouty panniculitis should be considered in the differential diagnosis of panniculitis, especially in the presence of high levels of uric acid. It is usually observed in the third decade of life and may appear prior to the inflammatory articular manifestations of tophaceous gout.
Assuntos
Gota/diagnóstico , Hiperuricemia/diagnóstico , Paniculite/diagnóstico , Adulto , Alopurinol/uso terapêutico , Colchicina/uso terapêutico , Cristalização , Gota/complicações , Gota/tratamento farmacológico , Gota/metabolismo , Supressores da Gota/uso terapêutico , Humanos , Hiperuricemia/complicações , Masculino , Microscopia de Polarização , Pessoa de Meia-Idade , Paniculite/etiologia , Paniculite/metabolismo , Estudos Retrospectivos , Líquido Sinovial/química , Ácido Úrico/análise , Ácido Úrico/metabolismoRESUMO
OBJECTIVE: Considering the significant morbidity and mortality of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc) and the lack of precise information on disease in Latin America, we investigated the clinical and laboratory characteristics associated with PAH in Colombian patients with SSc and review the literature. METHODS: This multicenter study included patients followed at 5 rheumatology units that were systematically assessed using a pretested questionnaire on clinical and immunological variables, focusing on PAH. Conditional logistic regression was employed to assess association between PAH and specific clinical characteristics. A systematic review of the literature was performed through electronic databases. RESULTS: Of a total of 349 patients with SSc, 61 (17%) met the criteria for PAH. Pulmonary fibrosis [adjusted odds ratio (AOR) 7.37, 95% CI 3.67-14.81, p < 0.0001], microstomia (AOR 3.3, 95% CI 1.70-6.28, p < 0.0001), gastroesophageal reflux (AOR 2.41, 95% CI 1.31-4.43, p = 0.005), dysphagia (AOR 2.7, 95% CI 1.49-4.77, p = 0.001), hyperpigmentation (AOR 2.15, 95% CI 1.11-4.16, p = 0.02), and hypopigmentation (AOR 2.4, 95% CI 1.26-4.64, p = 0.008) were the most prevalent clinical characteristics associated with PAH, while anemia (AOR 5.4, 95% CI 1.98-14.93, p = 0.001) was observed as the unique laboratory risk factor. Association between subtypes of SSc and PAH was not observed. Significant differences in both clinical and laboratory data were observed among different series. CONCLUSION: PAH may be a frequent complication of SSc in the Colombian population regardless of disease subtype. The identified clinical and laboratory risk factors might assist earlier diagnosis and guide decisions on therapeutic interventions on this critical complication of SSc. The reasons underlying the reported divergences among patients from different ethnicities are not fully understood, but it is most likely that both genetic and environmental factors are responsible for them.
Assuntos
Hipertensão Pulmonar/complicações , Escleroderma Sistêmico/complicações , Adulto , Idoso , Colômbia/epidemiologia , Feminino , Refluxo Gastroesofágico/complicações , Humanos , Hipertensão Pulmonar/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fibrose Pulmonar/complicações , Fatores de Risco , Escleroderma Sistêmico/epidemiologiaRESUMO
Durante la práctica médica en reumatología y en otras áreas de la medicina con frecuencia se busca identificar anticuerpos dirigidos contra algunos componentes antigénicos nucleares. Estos anticuerpos se han relacionado con algunas enfermedades y con el tipo de alteraciones que ellas presentan. Las técnicas empleadas para identificar estos anticuerpos han ido variando y mejorando a medida que se amplía el conocimiento en ellos. Presentamos los aspectos históricos más importantes que se dieron en el desarrollo de las técnicas para identificar estos anticuerpos
Assuntos
Anticorpos Antinucleares , Doenças AutoimunesRESUMO
Presentamos el caso de una paciente de 53 años con un cuadro de aparición de placas eritematovioláceas severamente induradas en tronco y extremidades. La correlación clínico-patológica sugirió el diagnóstico de una morfea generalizada pero también se encontraron algunas características de fascitis eosinofílica. La respuesta adecuada a los corticosteroides orales favoreció este último diagnóstico. Se presenta además una revisión de la literatura con respecto a la escleroderma localizada y sus variantes anotando las principales características de cada una de ellas y las diferentes hipótesis sobre su etiopatogenia. Podemos concluir que la escleroderma comprende un espectro de enfermedades cuya característica común es la fíbrosis dérmica y que en ocasiones la completa diferenciación entre éstas no es posible
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Fasciite , Esclerodermia LocalizadaRESUMO
La artritis reumatoide es una enfermedad crónica e incapacitante que afecta grandes y pequeñas articulaciones. La característica más importante de la enfermedad es la poliartritis o sinovitis simétrica que típicamente afecta las manos, muñecas y pies inicialmente y posteriormente puede afectar cualquier articulación sinovial como rodillas, tobillos, codos y hombros. La prevalencia en la mayoría de cohortes es de aproximadamente 1 por ciento. En este artículo resaltamos la importancia de reconocer tempranamente la enfermedad con el fin de lograr una mejor respuesta terapéutica, menos invalidez, menos pérdida de días de trabajo y disminución de los costos directos e indirectos del tratamiento