Sreih A.,Yale University |
Sreih A.,Rush University Medical Center |
Ezzeddine R.,Bristol Myers Squibb |
Leng L.,Yale University |
And 19 more authors.
Arthritis and Rheumatism
Objective To study the effect of the innate cytokine macrophage migration inhibitory factor (MIF) on the susceptibility and severity of systemic lupus erythematosus (SLE) in a multinational population of 1,369 Caucasian and African American patients. Methods Two functional polymorphisms in the MIF gene, a -794 CATT 5-8 microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were assessed for association with SLE in 3,195 patients and healthy controls. We also measured MIF plasma levels in relation to genotypes and clinical phenotypes, and assessed Toll-like receptor 7 (TLR-7)-stimulated MIF production in vitro. Results Both Caucasians and African Americans with the high-expression MIF haplotype -794 CATT 7/-173*C had a lower incidence of SLE (in Caucasians, odds ratio [OR] 0.63, 95% confidence interval [95% CI] 0.53-0.89, P = 0.001; in African Americans, OR 0.46, 95% CI 0.23-0.95, P = 0.012). In contrast, among patients with established SLE, reduced frequencies of low-expression MIF genotypes (-794 CATT 5) were observed in those with nephritis, those with serositis, and those with central nervous system (CNS) involvement when compared to patients without end-organ involvement (P = 0.023, P = 0.005, and P = 0.04, respectively). Plasma MIF levels and TLR-7-stimulated MIF production in vitro reflected the underlying MIF genotype of the studied groups. Conclusion These findings suggest that MIF, which has both proinflammatory properties and macrophage and B cell survival functions, exerts a dual influence on the immunopathogenesis of SLE. High-expression MIF genotypes are associated with a reduced susceptibility to SLE and may contribute to an enhanced clearance of infectious pathogens. Once SLE develops, however, low-expression MIF genotypes may protect from ensuing inflammatory end-organ damage. © 2011 by the American College of Rheumatology. Source
Baranchuk A.,Queens University |
Femenia F.,Hospital Espanol |
Lopez-Diez J.C.,Hospital Militar |
Muratore C.,Hospital Fernandez |
And 7 more authors.
Annals of Noninvasive Electrocardiology
Background: Main causes of death in chronic Chagas' cardiomyopathy (CChC) are progressive congestive heart failure and sudden cardiac death. Implantable cardioverter defibrillators (ICD) have been proved an effective therapy to prevent sudden death in patients with CChC. Identification of predictors of sudden death remains a challenge. Objective: To determine whether surface fragmented ECG (fQRS) helps identifying patients with CChC and ICDs at higher risk of presenting appropriate ICD therapies. Methods: Multicenter retrospective study. All patients with CChC and ICDs were analyzed. Clinical demographics, surface ECG, and ICD therapies were collected. Results: A total of 98 patients were analyzed. Another four cases were excluded due to pacing dependency. Mean age was 55.5 ± 10.4 years, male gender 65%, heart failure New York Heart Association class I 47% and II 38%. Mean left ventricular ejection fraction (LVEF) 39.6 ± 11.8%. The indication for ICD was secondary prevention in 70% of patients. fQRS was found in 56 patients (59.6%). Location of fragmentation was inferior (57.1%), lateral (35.7%), and anterior (44.6%). Rsr pattern was the more prevalent (57.1%). Predictors of appropriate therapy in the multivariate model were: increased age (P = 0.01), secondary prevention indication (P = 0.01), ventricular pacing >50% of the time (P = 0.004), and LVEF <30% (P = 0.01). The presence of fQRS did not identify patients at higher risk of presenting appropriate therapies delivered by the ICD (P = 0.87); regardless of QRS interval duration. Conclusions: fQRS is highly prevalent among patients with CChC. It has been found a poor predictor of appropriate therapies delivered by the ICD in this population. ©2013 Wiley Periodicals, Inc. Source
Lofgren S.E.,Uppsala University |
Frostegard J.,Karolinska University Hospital |
Truedsson L.,Lund University |
Pons-Estel B.A.,Sanatorio Parque |
And 10 more authors.
Genes and Immunity
A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology. © 2012 Macmillan Publishers Limited All rights reserved. Source
Lofgren S.E.,Uppsala University |
Delgado-Vega A.M.,Uppsala University |
Gallant C.J.,Uppsala University |
Sanchez E.,CSIC |
And 19 more authors.
Arthritis and Rheumatism
Objective Costimulatory receptor CD226 plays an important role in T cell activation, differentiation, and cytotoxicity. This study was undertaken to investigate the genetic association of CD226 with susceptibility to systemic lupus erythematosus (SLE) and to assess the functional implications of this association. Methods Twelve tag single-nucleotide polymorphisms (SNPs) in CD226 were typed in 1,163 SLE patients and 1,482 healthy control subjects from Europe or of European ancestry. Analyses of association were performed by single-marker Cochran-Mantel-Haenszel meta-analysis, followed by haplotype analysis. Gene expression was analyzed by quantitative real-time polymerase chain reaction analyses of RNA from peripheral blood mononuclear cells, and by fluorescence-activated cell sorter analysis. To study the functional impact of the associated variants, luciferase reporter constructs containing different portions of the 3-untranslated region (3-UTR) of the gene were prepared and used in transfection experiments. Results A 3-variant haplotype, rs763361;rs34794968;rs727088 (ATC), in the last exon of CD226 was associated with SLE (P = 1.3 - 10-4, odds ratio 1.24, 95% confidence interval 1.11-1.38). This risk haplotype correlated with low CD226 transcript expression and low CD226 protein levels on the surface of CD4+ and CD8+ T cells and natural killer T (NKT) cells. NK cells expressed high levels of CD226, but this expression was independent of the haplotype. Reporter assays with deletion constructs indicated that only the presence of rs727088 could account for the differences in the levels of luciferase transcripts. Conclusion This study identified an association of CD226 with SLE in individuals of European ancestry. These data support the importance of the 3-UTR SNP rs727088 in the regulation of CD226 transcription both in T cells and in NKT cells. © 2010 by the American College of Rheumatology. Source
Vuckovic F.,Genos Ltd |
Kristic J.,Genos Ltd |
Gudelj I.,Genos Ltd |
Teruel M.,University of Granada |
And 28 more authors.
Arthritis and Rheumatology
Objective Glycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1, HLA-DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case-control study to determine whether SLE is associated with altered IgG glycosylation. Methods Using ultra-performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China). Results Multiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N-acetylglucosamine (which affect antibody-dependent cell-mediated cytotoxicity). Conclusion The IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE. © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology. Source