In God we trust... all others, must show data

El frecuente reclamo de datos que pretendemos y a veces exigimos los que creemos que hacemos ciencia, nos enfrenta a menudo a realidades numéricas difíciles de entender o justificar. Pero los datos, son datos, y lo único útil es tratar de analizarlos, y nunca enojarse con ellos. La doctora Scolnik y colaboradores, en el artículo titulado “Manejo de arteritis de células gigantes en Argentina”, publicado en este número de la Revista Argentina de Reumatología, nos comparten los datos de una encuesta online de 10 preguntas enviada a los socios de la Sociedad Argentina de Reumatología (SAR)

Lrrk2 p.Q1111H substitution and Parkinson's disease in Latin America

Fil: Mata, Ignacio F. Veterans Affairs Puget Sound Health Care System, Seattle, Washington; Estados Unidos.Fil: Wilhoite, Greggory J. Mayo Clinic College of Medicine. Department of Neuroscience, Jacksonville, Florida; Estados Unidos.Fil: Yearout, Dora. Veterans Affairs Puget Sound Health Care System, Seattle, Washington; Estados Unidos. Mayo Clinic College of Medicine. Department of Neuroscience, Jacksonville, Florida; Estados Unidos.Fil: Bacon, Justin A. Mayo Clinic College of Medicine. Department of Neuroscience, Jacksonville, Florida; Estados Unidos.Fil: Cornejo-Olivas, Mario. Mayo Clinic College of Medicine. Department of Neuroscience, Jacksonville, Florida; Estados Unidos.Fil: Mazzetti, Pilar. Mayo Clinic College of Medicine. Department of Neuroscience, Jacksonville, Florida; Estados Unidos.Fil: Marca, Victoria. Mayo Clinic College of Medicine. Department of Neuroscience, Jacksonville, Florida; Estados Unidos.Fil: Ortega, Olimpio. Universidad Nacional Mayor de San Marcos. School of Medicine, Lima; Perú.Fil: Acosta, Oscar. Instituto Nacional de Ciencias Neurológicas. Movement disorders, Lima; Perú.Fil: Cosentino, Carlos. Instituto Nacional de Ciencias Neurológicas. Movement disorders, Lima; Perú.Fil: Torres, Luis. Universidad Nacional del Altiplano, Puno; Perú.Fil: Medina, Angel C. University of Chile. Faculty of Medicine. ICBM. Molecular and Clinical Pharmacology, Santiago; Chile.Fil: Perez-Pastene, Carolina. University of Chile. Faculty of Medicine. ICBM. Molecular and Clinical Pharmacology, Santiago; Chile.Fil: Díaz-Grez, Fernando. Mayo Clinic College of Medicine. Department of Neuroscience, Jacksonville, Florida; Estados Unidos.Fil: Vilariño-Güell, Carles. Liga del Parkinson de Chile; Chile.Fil: Venegas, Pablo. Liga del Parkinson de Chile; Chile.Fil: Miranda, Marcelo. Liga del Parkinson de Chile; Chile.Fil: Trujillo-Godoy, Osvaldo. Hospital Barros Luco Trudeau; Chile.Fil: Layson, Luis. Hospital Barros Luco Trudeau; Chile.Fil: Avello, Rodrigo. Hospital Regional de Concepción; Chile.Fil: Dieguez, Elena. Universidad de la República. Facultad de Medicina. Departamento de Neurología, Montevideo; Uruguay.Fil: Raggio, Victor. Universidad de la República. Facultad de Medicina. Departamento de Genética, Montevideo; Uruguay.Fil: Micheli, Federico E. ANLIS Dr.C.G.Malbrán; Argentina.Fil: Perandones, Claudia. ANLIS Dr.C.G.Malbrán. Dirección Científico Técnica; Argentina.Fil: Alvarez, Victoria. Hospital Universitario Central de Asturias. Instituto de Investigación Nefrológica (IRSINFRIAT). Laboratorio de Genética Molecular, Oviedo; España.Fil: Segura-Aguilar, Juan. Instituto Nacional de Ciencias Neurológicas. Unidad de Neurogenética, Lima; Perú.Fil: Farrer, Matthew J. Mayo Clinic College of Medicine. Department of Neuroscience, Jacksonville, Florida; Estados Unidos.Fil: Zabetian, Cyrus P. Veterans Affairs Puget Sound Health Care System, Seattle, Washington; Estados Unidos.Fil: Ross, Owen A. Mayo Clinic College of Medicine. Department of Neuroscience, Jacksonville, Florida; Estados Unidos.Mutations in the LRRK2 gene are the most common genetic cause of Parkinson's disease, with frequencies displaying a high degree of population-specificity. Although more than 100 coding substitutions have been identified, only seven have been proven to be highly penetrant pathogenic mutations. Studies however are lacking in non-white populations. Recently, Lrrk2 p.Q1111H (rs78365431) was identified in two affected Hispanic brothers and absent in 386 non-Hispanic white healthy controls. We therefore screened this variant in 1460 individuals (1150 PD patients and 310 healthy controls) from 4 Latin American countries (Peru, Chile, Uruguay and Argentina). In our case-control series from Peru and Chile we observed an increased frequency of Lrrk2 p.Q1111H in patients (7.9%) compared to controls (5.4%) although the difference did not reach significance (OR 1.38; p = 0.10). In addition, the frequency of Lrrk2 p.Q1111H varied greatly between populations and further screening in a set of pure Amerindian and pure Spanish controls suggested that this variant likely originated in an Amerindian population. Further studies in other Latin American populations are warranted to assess its role as a risk factor for Parkinson's disease. Screening in Parkinson's disease patients from under-represented populations will increase our understanding of the role of LRRK2 variants in disease risk worldwide

Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus

Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in chronic inflammation and autoimmune disorders. In this study, we aimed to determine the potential role of the IL18 gene in SLE. To define the genetic association of the IL18 and SLE, we have genotyped nine SNPs in an independent set of Spanish cases and controls. The IL18 polymorphisms were genotyped by PCR, using a predeveloped TaqMan allele discrimination assay. Two SNPs were still significant after fine mapping of the IL18 gene. The SNP (rs360719) surviving correction for multiple tests was genotyped in two replication cohorts from Italy and Argentina. After the analysis, a significance with rs360719 C-allele remained across the sets and after the meta-analysis (Pooled OR 5 1.37, 95% CI 1.21-1.54, combined P 5 3.8E-07, Pc 5 1.16E-06). Quantitative real-time PCR was performed to assess IL18 mRNA expression in PBMC from subjects with different IL18 rs360719 genotypes. We tested the effect of the IL18 rs360719 polymorphism on the transcription of IL18 by electrophoretic mobility shift assay and western blot. We found a significant increase in the relative expression of IL18 mRNA in individuals carrying the rs360719 C-risk allele; in addition we show that the polymorphism creates a binding site for the transcriptional factor OCT-1. These findings suggest that the novel IL18 rs360719 variant may play an important role in determining the susceptibility to SLE and it could be a key factor in the expression of the IL18 gene. © The Author 2009. Published by Oxford University Press. All rights reserved

Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations

Objective American Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients. Methods A total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). Results The average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P less than 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P less than 0.0001). American Indian ancestry protected against photosensitivity (P less than 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P less than 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P less than 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement. Conclusion In general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age. Copyright © 2012 by the American College of Rheumatology

Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations

Objective American Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients. Methods A total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). Results The average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P less than 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P less than 0.0001). American Indian ancestry protected against photosensitivity (P less than 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P less than 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P less than 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement. Conclusion In general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age. Copyright © 2012 by the American College of Rheumatology

Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations

Artículo de publicación ISIObjective American Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients. Methods A total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). Results The average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P < 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P < 0.0001). American Indian ancestry protected against photosensitivity (P < 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P < 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P < 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement. Conclusion In general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age.NIH P01-AR-49084 P60-AR-053308 R01-AR-052300 R21-AI-070304 K24-AR-002138 P60 2-AR-30692 UL1-RR-025741 P30-AR-053483 P30-RR-031152 P01-AI-083194 AR-43727 American Recovery and Reinvestment Act grant AR-058621 Centers of Biomedical Research Excellence (COBRE) grant 8 P20-GM-103456-09 National Center for Research Resources UL1-RR-025005 Alliance for Lupus Research Kirkland Scholar Award Federico Wilhelm Agricola Foundatio

Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA

Objectives Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. Methods Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. Results The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10-4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10-7, OR 0.71; case-only pmeta=1.9×10-4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. Conclusions These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications

Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE