RESUMEN
Resumen: La artritis reumatoide es una enfermedad inflamatoria sistémica que se caracteriza por sinovitis crónica y producción de autoanticuerpos. Los factores de riesgo incluyen genes HLA-DRῘβ1 con epítope compartido, periodontitis y tabaquismo. Al menos cinco diferentes sistemas de anticuerpos contra autoantígenos están implicados en la patogénesis de la enfermedad: 1) el factor reumatoide; 2) los anticuerpos a péptidos/proteínas citrulinadas (ACPAs); 3) los anticuerpos a proteínas carbamiladas (anti-Pcar); 4) los anticuerpos contra enzimas peptidilarginina desaminasas (anti-PAD2/4) y 5) los anticuerpos contra fibrinógeno citrulinado. La existencia de ACPA ha dividido a los sujetos con artritis reumatoide en dos subclases: artritis reumatoide positiva a ACPA y negativa a ACPA. Solamente los pacientes con artritis reumatoide positiva a ACPA están estrechamente relacionados con alelos HLA-DRβ1 con epítope compartido y son reconocidos por antígenos específicos de células T y células B.
Abstract: Rheumatoid arthritis is a systemic, inflammatory disease characterized by chronic synovitis and presence of autoantibodies. Risk factors include HLA-DRβ1 genes, periodontal disease and smoking. At least 5 different autoantibodies to autoantigens are implicated in the pathogenesis of this disorder: 1) rheumatoid factor; 2) autoantibodies directed against citrullinated peptides/proteins (ACPA); 3) anti-carbamilated protein antibody (anti-carP); 4) anti-peptidylarginine deiminase antibody (anti-PAD2/4), and 5) anti-citrullinated fibrinogen antibody. Patients with rheumatoid arthritis have been divided into two disease subsets: ACPA-positive rheumatoid arthritis and ACPA- negative rheumatoid arthritis. ACPA-positive rheumatoid arthritis is associated with HLA-DRβ1 shared epitope alleles and is recognized by antigen-specific T cells and B cells.
RESUMEN
The objective of our study was to evaluate the association between peptidylarginine deiminase 4 (PAD4) concentration and its polymorphisms with mortality in patients with septic shock. We prospectively evaluated 175 patients aged over 18 years with septic shock upon intensive care unit (ICU) admission. However, 48 patients were excluded. Thus, 127 patients were enrolled in the study. At the time of the patients' enrollment, demographic information was recorded. Blood samples were taken within the first 24 hours of the patient's admission to determine serum PAD4 concentrations and its polymorphism PADI4_89 [rs11203366], PADI4_94 [rs2240340] and PADI4_104 [rs1748033]. The mean age was 63.3 ± 15.2 years, 56.7% were male, PAD4 concentration was 4.62 (2.48-6.20) ng/mL and the ICU mortality rate was 67.7%. The patients who died in the ICU had higher APACHE II and Sequential Organ Failure Assessment (SOFA) scores. In addition, PAD4 concentration was higher in patients who died during ICU stay. However, there were no differences regarding PADI4 polymorphisms and ICU mortality. In the logistic regression models, PAD4 concentrations were associated with ICU mortality when adjusted for APACHE II score and lactate (OR: 1.477; CI 95%: 1.186-1.839; P < .001), and when adjusted for age, gender and APACHE II score (OR: 1.392; CI 95%: 1.145-1.692; P < .001). In conclusion, PAD4 concentration, but not PADI4_89, PADI4_94 and PADI4_104 polymorphisms, is associated with ICU mortality in septic shock patients.
Asunto(s)
Polimorfismo de Nucleótido Simple , Desiminasas de la Arginina Proteica/genética , Choque Séptico/genética , Choque Séptico/mortalidad , APACHE , Anciano , Femenino , Expresión Génica , Mortalidad Hospitalaria/tendencias , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Arginina Deiminasa Proteína-Tipo 4 , Desiminasas de la Arginina Proteica/sangre , Choque Séptico/sangre , Choque Séptico/patología , Análisis de SupervivenciaRESUMEN
Many studies have evaluated the correlation between peptidylarginine deiminase 4 (PADI4) -92C/G polymorphism and rheumatoid arthritis (RA), but the results remain inconclusive. Therefore, we performed a meta-analysis in the Chinese population to provide comprehensive data on the association between PADI4 -92C/G polymorphism and RA. Eligible studies published before May 2016 were identified in PubMed and Chinese databases. The strengths of these associations were assessed by pooled odds ratios (OR) and 95% confidence interval (CI). Eight studies documenting a total of 1351 RA cases and 1585 controls were included in this meta-analysis. In the overall analysis, a significant association between the PADI4 -92C/G polymorphism and RA was found in the Chinese population (G vs C: OR=1.32, 95%CI=1.02-1.71; GG+CG vs CC: OR=1.75, 95%CI=1.20-2.53). The subgroup analyses stratified by geographic area(s) and source of controls revealed significant results in South China, in hospital-based studies and population-based studies. In summary, this meta-analysis suggested that PADI4 -92C/G polymorphism may be associated with the RA incidence in the Chinese population, especially for South China. Further studies conducted on other ethnic groups are required for definite conclusions.
Asunto(s)
Humanos , Artritis Reumatoide/enzimología , Artritis Reumatoide/genética , Polimorfismo de Nucleótido Simple , Desiminasas de la Arginina Proteica/genética , China , Intervalos de Confianza , Predisposición Genética a la Enfermedad , Oportunidad Relativa , Factores de RiesgoRESUMEN
Peptidyl arginine deiminase IV (PADI4) enzyme catalyzes the citrullination of proteins, which are recognized by anti-cyclic citrullinated peptide antibodies (anti-CCP) in rheumatoid arthritis (RA) patients. Here, we determined the association between PADI4 gene polymorphisms and haplotypes with RA susceptibility and clinical characteristics in a western Mexican population. The relationship of PADI4 polymorphisms with anti-CCP and PADI4 mRNA expression was also evaluated. PADI4_89, PADI4_90 and PADI4_92 polymorphisms were individually associated with RA susceptibility. The GTG haplotype was significantly associated with: RA susceptibility; disease onset at ≤ 40 years and anti-CCP antibodies. PADI4 expression was three fold higher in RA patients carrying the susceptibility haplotype (GTG) than in non-susceptibility haplotype carriers (ACC). In conclusion, polymorphisms and functional haplotype (GTG) in PADI4 are associated with RA susceptibility as well as anti-CCP antibodies in a Mexican population. This supports the role of PADI4 early in RA pathogenesis by promoting the generation of citrullinated autoantigens.