RESUMEN
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies.
Asunto(s)
Autoanticuerpos , Cadenas HLA-DRB1 , Lupus Eritematoso Sistémico/genética , Modelos Genéticos , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Europa (Continente) , Femenino , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Humanos , Lupus Eritematoso Sistémico/inmunología , MasculinoRESUMEN
BACKGROUND: The molecular basis of genetic predisposition to pulmonary tuberculosis (PTB) in adults remains largely elusive. A chronic granulomatous inflammatory reaction is one of the main characteristics of the immune response to TB; however, a similar reaction is observed in other diseases, such as Crohn's disease. OBJECTIVE: To assess the association of genetic polymorphisms previously associated with Crohn's disease and PTB in a Colombian population of PTB patients and controls. DESIGN: A case-control study was performed among 500 newly diagnosed PTB patients and 320 healthy control subjects. Thirty-one single nucleotide polymorphisms (SNPs) identified in a previous meta-analysis of genome-wide association studies of Crohn's disease were used for genotyping using MassARRAY technology. RESULTS: In this study, we identified an association with borderline significance (P = 0.0009433 and P = 0.029 after multiple testing by Bonferroni's correction) of SNP rs10995271 with PTB. SNP rs10995271 is in linkage disequilibrium with SNPs belonging to the zinc finger protein (ZNF365) gene. CONCLUSIONS: Our results suggest that human PTB shares a genetic basis with Crohn's disease, and that SNPs in the ZNF365 gene would have a role in the occurrence of chronic granulomatous inflammatory reaction in TB as well as Crohn's disease.
Asunto(s)
Enfermedad de Crohn/genética , Polimorfismo de Nucleótido Simple , Tuberculosis Pulmonar/genética , Adulto , Estudios de Casos y Controles , Colombia/epidemiología , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/epidemiología , Proteínas de Unión al ADN/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Fenotipo , Factores de Riesgo , Factores de Transcripción/genética , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología , Adulto JovenAsunto(s)
Parasitología/historia , Francia , Historia del Siglo XX , Historia del Siglo XXI , Reino UnidoRESUMEN
Immunological studies have supported the idea that innate immunity is critical for the control of Mycobacterium tuberculosis (Mtb) infection in humans. Despite the overwhelming evidence showing the critical role of Toll-like receptors (TLRs) in the in vitro recognition of Mtb, the in vivo significance of individual TLRs has been more difficult to demonstrate consistently. We were interested in examining the role of genes of TLRs and molecules involved in their signalling cascades, and a case-control study was designed to test the association of polymorphisms of these innate immune genes with pulmonary tuberculosis (TB) in a Colombian population. In this study, we did not find an association with TLR2, TLR4, TLR9, MyD88 or MAL/TIRAP polymorphic variants. These findings suggest that those genes are not involved as risk factors for pulmonary TB in our population.
Asunto(s)
Glicoproteínas de Membrana/genética , Factor 88 de Diferenciación Mieloide/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-1/genética , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genética , Receptor Toll-Like 9/genética , Tuberculosis Pulmonar/genética , Adulto , Alelos , Estudios de Casos y Controles , Colombia , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Multiple genetic and environmental factors contribute to the pathogenesis of this disease. Recent genome-wide association studies have added substantially to the number of genes associated with SLE. To replicate some of these susceptibility loci, single-nucleotide polymorphisms reported to be associated to SLE were evaluated in a cohort of 245 well-phenotyped Canadian SLE trios. Our results replicate previously reported associations to alleles of interferon regulatory factor 5 (IRF5), major histocompatibility complex (MHC), tumor necrosis factor (ligand) superfamily member 4 (TNFSF4), Kell blood group complex subunit-related family member 6 (XKR6), B-cell scaffold protein with ankyrin repeats 1 (BANK1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), ubiquitin-conjugating enzyme E2L 3 (UBE2L3) and islet cell autoantigen 1 (ICA1). We also identify putative associations to cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a gene associated with several autoimmune disorders, and ERBB3, a locus on 12q13 that was previously reported to be associated with type 1 diabetes. This study confirms the existence of multiple genetic risk factors for SLE, and supports the notion that some risk factors for SLE are shared with other inflammatory disorders.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico/genética , Enfermedades Autoinmunes/genética , Femenino , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Anemia secondary to end-stage renal disease (ESRD) is an important but complex syndrome which directly contributes to significant morbidity and mortality in this patient population. The interactions between uremia, bone marrow biology and erythropoietin (EPO) responsiveness are of significant interest to improve our basic understanding of anemia management in ESRD. Nocturnal home hemodialysis is an intensive mode of renal replacement therapy, which has been associated with an improvement in EPO responsiveness. The aims of the present review are (1) to update the recent advances in uremia associated perturbations in bone marrow-derived hematopoietic stem cells and (2) to discuss the potential mechanistic explanations by which augmented uremia clearance may directly affect EPO responsiveness.
Asunto(s)
Anemia/prevención & control , Eritropoyetina/farmacología , Hemodiálisis en el Domicilio/métodos , Fallo Renal Crónico/terapia , Anemia/etiología , Citocinas/sangre , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicacionesRESUMEN
Nocturnal home hemodialysis (NHHD) has been associated with several clinical benefits compared to conventional thrice-weekly in-center hemodialysis. However, the prevalence of NHHD remains low. To date, few studies have focused on the importance of training and education of a complex medical procedure such as NHHD. In the present review, we will describe guidelines for implementation of a NHHD program by focusing on 1) patients' selection, assessment and training; 2) challenges of adult education; 3) prescription and 4) barriers to adoption of home hemodialysis. Future challenges in research, the importance of quality assurance and innovations in clinical care delivery in NHHD will also be discussed.
Asunto(s)
Ritmo Circadiano , Hemodiálisis en el Domicilio , Fallo Renal Crónico/terapia , Catéteres de Permanencia/economía , Conocimientos, Actitudes y Práctica en Salud , Hemodiálisis en el Domicilio/economía , Hemodiálisis en el Domicilio/métodos , Humanos , Fallo Renal Crónico/economía , Educación del Paciente como Asunto , Selección de Paciente , Guías de Práctica Clínica como Asunto , Garantía de la Calidad de Atención de Salud/economía , Calidad de Vida , Medición de RiesgoRESUMEN
OBJECTIVES: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that interleukin 2 (IL2) and IL21 play in the immune response also make them attractive candidates for IBD. The objective of this study was to test for association between the IL2/IL21 locus and the IBDs. METHODS: The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated with coeliac disease were genotyped in 1590 subjects with IBD and 929 controls from The Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran-Mantel-Haenszel test were performed. RESULTS: All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p = 1.35 x 10(-10), rs13119723 p = 8.60 x 10(-8), rs6840978 p = 3.0 7x 10(-8), rs6822844 p = 2.77 x 10(-9)). A moderate association with CD was also found in the pooled analysis (p value range 0.0016-9.86 x 10(-5)). CONCLUSIONS: A strong association for the IL2/IL21 locus with UC was found, which also confirms it as a general susceptibility locus for inflammatory disease.
Asunto(s)
Colitis Ulcerosa/genética , Interleucina-2/genética , Interleucinas/genética , Polimorfismo de Nucleótido Simple , Distribución de Chi-Cuadrado , Enfermedad de Crohn/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Italia , Países Bajos , Oportunidad Relativa , Estados UnidosRESUMEN
Association mapping and candidate gene studies within inflammatory bowel diseases (IBD) linkage regions, as well as genome-wide association studies in Crohn's disease (CD) have led to the discovery of multiple risk genes, but these explain only a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21-22 showing linkage to CD and ulcerative colitis (UC) using a gene-centric association mapping approach. We identified 12 functional candidate genes by searching for literature cocitations with relevant keywords and for gene expression patterns consistent with immune/intestinal function. We then performed an association study composed of a screening phase, where tagging single nucleotide polymorphisms (SNPs) were evaluated in 1,020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association with IBD for four SNPs within a 1.2 Mb linkage disequilibrium region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage-stimulating 1 (MST1) gene (P-value 3.62 x 10(-6)) that accounts for the association signal, and shows association with both CD and UC. MST1 encodes macrophage-stimulating protein (MSP), a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.
Asunto(s)
Cromosomas Humanos Par 3/genética , Enfermedad de Crohn/genética , Predisposición Genética a la Enfermedad , Genoma Humano/inmunología , Factor de Crecimiento de Hepatocito/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas/genética , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 3/inmunología , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Femenino , Factor de Crecimiento de Hepatocito/inmunología , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Desequilibrio de Ligamiento/inmunología , Masculino , Unión Proteica/genética , Unión Proteica/inmunología , Proteínas Proto-Oncogénicas/inmunología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/inmunología , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
Climate driven and other changes in landscape structure and texture, plus more general factors, may create favourable ecological niches for emerging diseases. Abiotic factors impact on vectors, reservoirs and pathogen bionomics and their ability to establish in new ecosystems. Changes in climatic patterns and in seasonal conditions may affect disease behaviour in terms of spread pattern, diffusion range, amplification and persistence in novel habitats. Pathogen invasion may result in the emergence of novel disease complexes, presenting major challenges for the sustainability of future animal agriculture at the global level. In this paper, some of the ecological mechanisms underlying the impact of climatic change on disease transmission and disease spread are further described. Potential effects of different climatic variables on pathogens and host population dynamics and distribution are complex to assess, and different approaches are used to describe the underlying epidemiological processes and the availability of ecological niches for pathogens and vectors. The invasion process can disrupt the long-term co-evolution of species. Pathogens adhering to an r-type strategy (e.g. RNA viruses) may be more inclined to encroach on a novel niche resulting from climate change. However, even when linkage between disease dynamics and climate change are relatively strong, there are other factors changing disease behaviour, and these should be accounted for as well. Overall vulnerability of a given ecosystem is a key variable in this regard. The impact of climate-driven changes varies in different parts of the world and in the different agro-climatic zones. Perhaps priority should go to those geographical areas where the integrity of the ecosystem is most severely affected and the adaptability, in terms of robustness and sustainability of response, relatively low.
Asunto(s)
Enfermedades de los Animales/epidemiología , Enfermedades de los Animales/prevención & control , Enfermedades Transmisibles Emergentes/veterinaria , Transmisión de Enfermedad Infecciosa/veterinaria , Ecosistema , Enfermedades de los Animales/transmisión , Animales , Biodiversidad , Clima , Enfermedades Transmisibles Emergentes/epidemiología , Enfermedades Transmisibles Emergentes/prevención & control , Enfermedades Transmisibles Emergentes/transmisión , Reservorios de Enfermedades/veterinaria , Vectores de Enfermedades , Efecto Invernadero , Dinámica Poblacional , Vigilancia de la Población , Estaciones del Año , Vigilancia de Guardia/veterinariaRESUMEN
Potential climate driven changes in the epidemiology of human and animal disease are widely discussed and complex to assess. Recent spreads of exotic pathogens or vectors feed speculations; although most of these introductions are mainly linked to the increased worldwide traffic, trade of goods and transportation of animal and human, abiotic factors are known to impact on vectors and pathogens bionomics and their ability to establish in new ecosystems; altogether changes in climatic patterns and in seasonal conditions may affect disease behaviour in term of spread pattern, diffusion range, amplification and persistence in novel habitats. Invasion may result in the emergence of novel disease processes, presenting major challenges for the epidemiologists. In this paper, some of the ecological mechanisms underlying the impact of climatic change on disease transmission and disease spread are further described. Potential effects of different climatic variables on pathogens and hosts population dynamics and distributions are complex to assess and different approaches are used to describe the dynamics in ecological range and the availability of ecological niches for pathogens and vectors. However even when linkage between disease dynamics and climate change are relatively strong, there are always other factors also changing disease behaviour and these should be accounted for as well.
Asunto(s)
Clima , Enfermedades Transmisibles/epidemiología , Enfermedades Transmisibles/transmisión , África/epidemiología , Animales , Vectores de Enfermedades , Ecosistema , Humanos , Leishmaniasis/epidemiología , Leishmaniasis/transmisión , Estaciones del AñoRESUMEN
Inflammatory bowel disease (IBD) is a chronic disorder caused by multiple factors in a genetically susceptible host. Significant advances in the study of genetic susceptibility have highlighted the importance of the innate immune system in this disease. We previously completed a genome-wide linkage study and found a significant locus (IBD6) on chromosome 19p. We were interested in identifying the causal variant in IBD6. We performed a two-stage association mapping study. In stage 1, 1530 single-nucleotide polymorphisms (SNPs) were selected from the HapMap database and genotyped in 761 patients with IBD. Among the SNPs that passed the threshold for replication, 26 were successfully genotyped in 754 additional patients (stage 2). One intronic variant, rs273506, located in the microtubule-associated serine/threonine-protein kinase gene-3 (MAST3), was found to be associated in both stages (pooled P=1.8 x 10(-4)). We identified four MAST3 coding variants, including a non-synonymous SNP rs8108738, correlated to rs273506 and associated with IBD. To test whether MAST3 was expressed in cells of interest, we performed expression assays, which showed abundant expression of MAST3 in antigen-presenting cells and in lymphocytes. The knockdown of MAST3 specifically decreased Toll-like receptor-4-dependent NF-kappaB activity. Our findings are additional proofs of the pivotal role played by modulators of NF-kappaB activity in IBD pathogenesis.
Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Proteínas Asociadas a Microtúbulos/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal/genética , Transducción de Señal/inmunología , Receptor Toll-Like 4/fisiología , Animales , Antígenos CD19/biosíntesis , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Regulación Enzimológica de la Expresión Génica/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Intrones/genética , Desequilibrio de Ligamiento/inmunología , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/biosíntesis , Proteínas Asociadas a Microtúbulos/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Factores de Riesgo , Receptor Toll-Like 4/metabolismoRESUMEN
The diagnosis of occupational asthma can be made by exposing workers to the relevant agent either in a hospital laboratory through specific inhalation challenges (SICs) or in the workplace. As suggested by several authors, workers with negative laboratory SIC can be monitored at the workplace under supervision. The present study aims to assess the frequency of, and identify factors associated with, a positive workplace reaction in workers with negative SIC in the laboratory. The results of workplace challenges were examined in 99 workers who underwent negative SIC between 1994 and 2004. A positive reaction either in the SIC or in the workplace was defined as a sustained fall in forced expiratory volume in one second of > or =20%. In total, 22 (22.2%) workers showed positive responses at the workplace. These subjects more often had increased baseline methacholine responsiveness (90.5 versus 67.6%). They also underwent more days of SIC testing (4.9 versus 3.3 days) and were exposed more often to two or more agents (56 versus 28.4%) and for a longer period of time (363.3 versus 220.4 min) in the laboratory. The present study illustrates the usefulness of workplace monitoring of airway function in the investigation of occupational asthma and identifies factors that are more often associated with a positive reaction.
Asunto(s)
Asma/diagnóstico , Enfermedades Profesionales/diagnóstico , Adulto , Asma/terapia , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Cloruro de Metacolina/farmacología , Persona de Mediana Edad , Enfermedades Profesionales/terapia , Exposición Profesional , Estudios Retrospectivos , Espirometría/métodos , Factores de Tiempo , Resultado del Tratamiento , Lugar de TrabajoRESUMEN
BACKGROUND: Individuals with high levels of antibodies to the Epstein-Barr virus nuclear antigen 1 (EBNA-1) have an increased risk of developing multiple sclerosis (MS), but this association could be confounded by genetic susceptibility. METHODS: We conducted a nested case-control study including 148 women with MS (18 with blood collected before disease onset) and 296 age-matched healthy women to determine whether the human leukocyte antigen (HLA) DRB1*1501 allele (DR15) and anti-Epstein-Barr virus (anti-EBV) antibody titers are independent risk factors for MS. RESULTS: The association between anti-EBNA-1 antibody titers and MS risk was not affected by adjustment for DR15 and was similar in DR15-positive and DR15-negative women. The relative risk of MS among DR15-positive women with elevated (>1:320) anti-EBNA-1 titers was ninefold higher than that of DR15-negative women with low (<1:80) anti-EBNA-1 titers. CONCLUSIONS: Anti-Epstein-Barr virus nuclear antigen 1 (anti-EBNA-1) antibody titers are a risk factor for multiple sclerosis (MS), independently from the DR15 allele. Carriers of the DR15 allele with elevated anti-EBNA-1 antibody titers may have a markedly increased risk of MS.
Asunto(s)
Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Virus de Epstein-Barr/inmunología , Antígenos HLA-DR/sangre , Antígenos HLA-DR/inmunología , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/inmunología , Adulto , Anticuerpos/análisis , Anticuerpos/sangre , Anticuerpos/inmunología , Biomarcadores/análisis , Biomarcadores/sangre , Estudios de Casos y Controles , Comorbilidad , Infecciones por Virus de Epstein-Barr/genética , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Femenino , Frecuencia de los Genes/genética , Frecuencia de los Genes/inmunología , Predisposición Genética a la Enfermedad/epidemiología , Genotipo , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Herpesvirus Humano 4/inmunología , Heterocigoto , Humanos , Persona de Mediana Edad , Esclerosis Múltiple/genética , Factores de RiesgoRESUMEN
Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.
Asunto(s)
Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 3/genética , Enfermedad de Crohn/genética , Judíos/genética , Polimorfismo de Nucleótido Simple/genética , Colitis Ulcerosa/epidemiología , Colitis Ulcerosa/genética , Enfermedad de Crohn/epidemiología , Femenino , Ligamiento Genético/genética , Marcadores Genéticos/genética , Humanos , Escala de Lod , Masculino , Linaje , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Systemic lupus erythematosus (SLE) is a complex disease trait of unknown aetiology. Genome-wide linkage studies in human SLE identified several linkage regions, including one at 1q23, which contains multiple susceptibility genes, including the members of the signalling lymphocyte activation molecule (SLAM) locus. In mice there is a syntenic linkage region, Sle1. The SLAM genes are functionally related cell-surface receptors, which regulate signal transduction of cells in the immune system. Family-based association study in UK and Canadian SLE families identified variants in the promoter and coding region of SLAMF7 and LY9 contributing to SLE disease susceptibility. The strongest association was from rs509749, in exon 8 of LY9 (P=0.00209). rs509749 encodes a Val/Met nonsynonymous change in amino acid 602 in the cytoplasmic domain of LY9. In the parents and affected individuals from the Canadian SLE families, the risk allele of rs509049 skews the T-cell population by increasing the number of CD8+ memory T cells, while decreasing the proportion of CD4+ naïve T cells and activated T cells. Since rs509749 lies within the consensus binding site for SAP/SH2D1a, which influences downstream signalling events from LY9, the mechanism for increased CD8+ memory T cells may include differential binding SAP/SH2D1a to the cytoplasmic domain of LY9.
Asunto(s)
Alelos , Antígenos CD/genética , Ligamiento Genético/genética , Lupus Eritematoso Sistémico/genética , Glicoproteínas de Membrana/genética , Canadá/epidemiología , Predisposición Genética a la Enfermedad , Humanos , Lupus Eritematoso Sistémico/epidemiología , Linaje , Polimorfismo de Nucleótido Simple/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Reino Unido/epidemiologíaRESUMEN
The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.
Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedades Inflamatorias del Intestino/genética , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-1/genética , Receptor Toll-Like 4/genética , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Estudios Longitudinales , Masculino , Glicoproteínas de Membrana/metabolismo , Receptores de Interleucina-1/metabolismo , Transducción de Señal , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMEN
This study reports isoenzyme polymorphism of Leishmania strains isolated in different regions of Portugal between 1982 and 2005. A total of 213 strains were obtained from cases of visceral and cutaneous leishmaniasis isolated from immunocompetent patients (adults and children) and immunocompromised adults, as well as from dogs and sandflies. Four zymodemes were identified: MON-1, MON-24, MON-29 and MON-80. Zymodeme MON-1 was identified in 96.7% of the strains, predominating in both immunocompetent and immunocompromised human patients, and it was the only zymodeme isolated from dogs. Isoenzyme diversity in HIV-infected patients was higher than in the immunocompetent group, in which all the strains from visceral leishmaniasis were MON-1. The domestic dog was confirmed as the reservoir host of zoonotic leishmaniasis in Portugal and Phlebotomus perniciosus and Phlebotomus ariasi as vectors. The overall low enzyme polymorphism observed in the Portuguese foci contrasts with the neighbouring foci in Spain.
Asunto(s)
Leishmania infantum/genética , Leishmaniasis/genética , Polimorfismo Genético/genética , Adulto , Animales , Niño , Enfermedades de los Perros/enzimología , Enfermedades de los Perros/genética , Perros , Infecciones por VIH/enzimología , Humanos , Insectos Vectores/parasitología , Isoenzimas/genética , Leishmania infantum/enzimología , Leishmaniasis/enzimología , Leishmaniasis/veterinaria , Leishmaniasis Cutánea/enzimología , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/veterinaria , Leishmaniasis Visceral/enzimología , Leishmaniasis Visceral/genética , Leishmaniasis Visceral/veterinaria , Phlebotomus , Portugal , ZoonosisRESUMEN
To date, three loci have been validated to confer susceptibility to inflammatory bowel disease (IBD): the CARD15/NOD2 gene, the discs large homolog 5 gene (DLG5), and the IBD5 locus on 5q31 (IBD5). We have explored the possibility that these loci may also be associated with susceptibility to two other chronic inflammatory diseases, multiple sclerosis (MS) and systemic lupus erythematosus (SLE). As the CARD15 risk alleles had previously been assessed in our collection of 496 MS trios, we focused our efforts on the DLG5 risk allele and the IBD5(risk) haplotype (IBD5(risk)) for MS. While there is no evidence of association within our MS sample with either of these polymorphisms, screening of 1027 subjects with SLE suggests that IBD5(risk) may have a modest contribution to disease risk in the subset of SLE subjects without lupus nephritis. In addition, a pooled analysis of existing published and unpublished data in 1305 cases of SLE genotyped for the CARD15 risk alleles suggests that only the CARD15(908R) IBD risk allele may have a strong effect on risk of SLE. Our data, therefore, suggest that both the CARD15 gene and the IBD5 locus may have a role as general susceptibility loci for certain common, genetically complex inflammatory diseases.