Rosario del Tala, Argentina
Rosario del Tala, Argentina

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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 | Year: 2012

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.

PubMed | National Major San Marcos University, McGill University, Center for Public Health Genomics, Stanford University and 2 more.
Type: Journal Article | Journal: PLoS genetics | Year: 2015

South America has a complex demographic history shaped by multiple migration and admixture events in pre- and post-colonial times. Settled over 14,000 years ago by Native Americans, South America has experienced migrations of European and African individuals, similar to other regions in the Americas. However, the timing and magnitude of these events resulted in markedly different patterns of admixture throughout Latin America. We use genome-wide SNP data for 437 admixed individuals from 5 countries (Colombia, Ecuador, Peru, Chile, and Argentina) to explore the population structure and demographic history of South American Latinos. We combined these data with population reference panels from Africa, Asia, Europe and the Americas to perform global ancestry analysis and infer the subcontinental origin of the European and Native American ancestry components of the admixed individuals. By applying ancestry-specific PCA analyses we find that most of the European ancestry in South American Latinos is from the Iberian Peninsula; however, many individuals trace their ancestry back to Italy, especially within Argentina. We find a strong gradient in the Native American ancestry component of South American Latinos associated with country of origin and the geography of local indigenous populations. For example, Native American genomic segments in Peruvians show greater affinities with Andean indigenous peoples like Quechua and Aymara, whereas Native American haplotypes from Colombians tend to cluster with Amazonian and coastal tribes from northern South America. Using ancestry tract length analysis we modeled post-colonial South American migration history as the youngest in Latin America during European colonization (9-14 generations ago), with an additional strong pulse of European migration occurring between 3 and 9 generations ago. These genetic footprints can impact our understanding of population-level differences in biomedical traits and, thus, inform future medical genetic studies in the region.

PubMed | Karolinska Institutet, Sanatorio Parque, University of Strasbourg, Cedars Sinai Medical Center and 21 more.
Type: | Journal: Clinical immunology (Orlando, Fla.) | Year: 2016

Primary Sjgrens syndrome (pSS) has a strong female bias. We evaluated an X chromosome dose effect by analyzing 47,XXY (Klinefelters syndrome, 1 in 500 live male births) among subjects with pSS. 47,XXY was determined by examination of fluorescence intensity of single nucleotide polymorphisms from the X and Y chromosomes. Among 136 pSS men there were 4 with 47,XXY. This was significantly different from healthy controls (1 of 1254 had 47,XXY, p=0.0012 by Fishers exact test) as well men with rheumatoid arthritis (0 of 363 with 47,XXY), but not different compared to men with systemic lupus erythematosus (SLE) (4 of 136 versus 8 of 306, Fishers exact test p=NS). These results are consistent with the hypothesis that the number of X chromosomes is critical for the female bias of pSS, a property that may be shared with SLE but not RA.

PubMed | University of Pennsylvania, Sanatorio Parque, University of Queensland, Catholic University of Louvain and 7 more.
Type: Journal Article | Journal: Arthritis care & research | Year: 2016

To evaluate the safety and efficacy of golimumab through 5 years in adults with active rheumatoid arthritis (RA) who had not previously received methotrexate (MTX).In the GO-BEFORE study, 637 MTX-naive adult patients with active RA were randomized (1:1:1:1) to placebo+MTX (group 1), golimumab 100 mg+placebo (group 2), golimumab 50 mg+MTX (group 3), or golimumab 100 mg+MTX (group 4). Inadequate responders in groups 1, 2, and 3 entered early escape at week 28 to golimumab 50 mg+MTX, golimumab 100 mg+MTX, or golimumab 100 mg+MTX, respectively; remaining patients in group 1 could cross over to golimumab 50 mg+MTX at week 52. Assessments included the American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) response, the Disease Activity Score in 28 joints (DAS28) using C-reactive protein (CRP) level, and the modified Sharp/van der Heijde score (SHS). Efficacy was analyzed using an intent-to-treat (ITT) analysis. Pharmacokinetics and immunogenicity were evaluated at selected visits.A total of 422 patients completed golimumab treatment through week 256. At week 256, 72.8%, 54.6%, and 38.0% of all patients in the full ITT population (n=637) had an ACR20/50/70 response, respectively; 84.1% had a good or moderate DAS28-CRP response; and 72.7% had a clinically meaningful improvement in physical function. Radiographic progression was minimal in all treatment groups through week 256, and the overall mean change from baseline in SHS was 1.36. Serum trough golimumab concentrations were approximately dose proportional and maintained through week 256. Antibodies to golimumab occurred in 9.6% of patients through week 256. Infections were the most common type of adverse event (AE); 204 of 616 patients (33.1%) had 1 serious AE.Clinical efficacy with golimumab treatment was maintained through week 256 of the GO-BEFORE trial of MTX-naive RA patients. No unexpected AEs occurred; safety results through 5 years are consistent with earlier reports.

PubMed | Hospital General Of Culiacan, University of California at Los Angeles, Stanford University, Hospital Interzonal General Of Agudos General San Martin and 25 more.
Type: Journal Article | Journal: Arthritis & rheumatology (Hoboken, N.J.) | Year: 2016

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage.We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj =1.11 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj =6.46 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj =1.39 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl =8.0 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE.Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.

PubMed | Hospital Universitario San Cecilio, Health Science University, University of Granada, University of Szeged and 13 more.
Type: Journal Article | Journal: Annals of the rheumatic diseases | Year: 2015

To perform fine mapping of the PXK locus associated with systemic lupus erythematosus (SLE) and study functional effects that lead to susceptibility to the disease.Linkage disequilibrium (LD) mapping was conducted by using 1251 SNPs (single nucleotide polymorphism) covering a 862 kb genomic region on 3p14.3 comprising the PXK locus in 1467 SLE patients and 2377 controls of European origin. Tag SNPs and genotypes imputed with IMPUTE2 were tested for association by using SNPTEST and PLINK. The expression QTLs data included three independent datasets for lymphoblastoid cells of European donors: HapMap3, MuTHER and the cross-platform eQTL catalogue. Correlation analysis of eQTLs was performed using Vassarstats. Alternative splicing for the PXK gene was analysed on mRNA from PBMCs.Fine mapping revealed long-range LD (>200 kb) extended over the ABHD6, RPP14, PXK, and PDHB genes on 3p14.3. The highly correlated variants tagged an SLE-associated haplotype that was less frequent in the patients compared with the controls (OR=0.89, p=0.00684). A robust correlation between the association with SLE and enhanced expression of ABHD6 gene was revealed, while neither expression, nor splicing alterations associated with SLE susceptibility were detected for PXK. The SNP allele frequencies as well as eQTL pattern analysed in the CEU and CHB HapMap3 populations indicate that the SLE association and the effect on ABHD6 expression are specific to Europeans.These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants.

Baranchuk A.,Queen's University | Femenia F.,Hospital Espanol | Lopez-Diez J.C.,Hospital Militar | Muratore C.,Hospital Fernandez | And 7 more authors.
Annals of Noninvasive Electrocardiology | Year: 2014

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.

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 | Year: 2011

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.

Delgado-Vega A.M.,Uppsala University | Dozmorov M.G.,Oklahoma Medical Research Foundation | Quiros M.B.,University of Granada | Wu Y.-Y.,Oklahoma Medical Research Foundation | And 21 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objectives: To perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE). Methods: Genotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor κ B (NFkB) binding. Results: Fine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NFκB-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR=2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life. Conclusions: These results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein.

PubMed | Karolinska Institutet, University of South Australia, Sanatorio Parque, University of Strasbourg and 32 more.
Type: Journal Article | Journal: Arthritis & rheumatology (Hoboken, N.J.) | Year: 2016

More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjgrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls.All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction.We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P=0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P=0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients.The estimated prevalence of SLE and SS in women with 47,XXX was 2.5 and 2.9 times higher, respectively, than that in women with 46,XX and 25 and 41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

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