RESUMO
The modification of proteins by ubiquitin has a major role in cells of the immune system and is counteracted by various deubiquitinating enzymes (DUBs) with poorly defined functions. Here we identified the ubiquitin-specific protease USP8 as a regulatory component of the T cell antigen receptor (TCR) signalosome that interacted with the adaptor Gads and the regulatory molecule 14-3-3ß. Caspase-dependent processing of USP8 occurred after stimulation of the TCR. T cell-specific deletion of USP8 in mice revealed that USP8 was essential for thymocyte maturation and upregulation of the gene encoding the cytokine receptor IL-7Rα mediated by the transcription factor Foxo1. Mice with T cell-specific USP8 deficiency developed colitis that was promoted by disturbed T cell homeostasis, a predominance of CD8(+) γδ T cells in the intestine and impaired regulatory T cell function. Collectively, our data reveal an unexpected role for USP8 as an immunomodulatory DUB in T cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Endopeptidases/imunologia , Complexos Endossomais de Distribuição Requeridos para Transporte/imunologia , Timócitos/imunologia , Ubiquitina Tiolesterase/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Colite/genética , Colite/imunologia , Endopeptidases/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Homeostase , Humanos , Células Jurkat , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Interleucina-7/imunologia , Receptores de Interleucina-7/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timócitos/metabolismo , Ubiquitina Tiolesterase/genéticaRESUMO
Here we present the draft genome of Leucobacter chromiiresistens. This is the first genome sequence of an organism belonging to the genus Leucobacter. L. chromiiresistens was sequenced due to its capability to tolerate up to 300 mM Cr(VI) in the medium, which is so far a unique feature for microorganisms.
Assuntos
Actinomycetales/efeitos dos fármacos , Actinomycetales/genética , Cromo/toxicidade , Genoma Bacteriano , Actinomycetales/metabolismo , Dados de Sequência Molecular , Microbiologia do Solo , Poluentes do Solo/toxicidadeRESUMO
Retrograde signaling is a pathway of communication from mitochondria and plastids to the nucleus in the context of cell differentiation, development, and stress response. In Chlamydomonas reinhardtii, the tetrapyrroles magnesium-protoporphyrin IX and heme are only synthesized within the chloroplast, and they have been implicated in the retrograde control of nuclear gene expression in this unicellular green alga. Feeding the two tetrapyrroles to Chlamydomonas cultures was previously shown to transiently induce five nuclear genes, three of which encode the heat shock proteins HSP70A, HSP70B, and HSP70E. In contrast, controversial results exist on the possible role of magnesium-protoporphyrin IX in the repression of genes for light-harvesting proteins in higher plants, raising the question of how important this mode of regulation is. Here, we used genome-wide transcriptional profiling to measure the global impact of these tetrapyrroles on gene regulation and the scope of the response. We identified almost 1,000 genes whose expression level changed transiently but significantly. Among them were only a few genes for photosynthetic proteins but several encoding enzymes of the tricarboxylic acid cycle, heme-binding proteins, stress-response proteins, as well as proteins involved in protein folding and degradation. More than 50% of the latter class of genes was also regulated by heat shock. The observed drastic fold changes at the RNA level did not correlate with similar changes in protein concentrations under the tested experimental conditions. Phylogenetic profiling revealed that genes of putative endosymbiontic origin are not overrepresented among the responding genes. This and the transient nature of changes in gene expression suggest a signaling role of both tetrapyrroles as secondary messengers for adaptive responses affecting the entire cell and not only organellar proteins.
Assuntos
Chlamydomonas reinhardtii/genética , Regulação da Expressão Gênica de Plantas , Hemina/farmacologia , Protoporfirinas/farmacologia , Chlamydomonas reinhardtii/efeitos dos fármacos , Análise por Conglomerados , Perfilação da Expressão Gênica , Genes de Plantas , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , RNA de Plantas/genéticaRESUMO
Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-ß2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-ß, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.
Assuntos
Proteínas de Membrana/genética , Mutação , Proteínas de Neoplasias/genética , Fenótipo , Adulto , Vesícula/genética , Criança , Citocinas/genética , Citocinas/metabolismo , Epidermólise Bolhosa/genética , Feminino , Fibrose/metabolismo , Fibrose/patologia , Humanos , Queratinócitos/metabolismo , Masculino , Doenças Periodontais/genética , Transtornos de Fotossensibilidade/genética , Pele/metabolismo , Pele/patologiaRESUMO
BACKGROUND: Identification of prognostic gene expression markers from clinical cohorts might help to better understand disease etiology. A set of potentially important markers can be automatically selected when linking gene expression covariates to a clinical endpoint by multivariable regression models and regularized parameter estimation. However, this is hampered by instability due to selection from many measurements. Stability can be assessed by resampling techniques, which might guide modeling decisions, such as choice of the model class or the specific endpoint definition. METHODS: We specifically propose a strategy for judging the impact of different endpoint definitions, endpoint updates, different approaches for marker selection, and exclusion of outliers. This strategy is illustrated for a study with end-stage renal disease patients, who experience a yearly mortality of more than 20 %, with almost 50 % sudden cardiac death or myocardial infarction. The underlying etiology is poorly understood, and we specifically point out how our strategy can help to identify novel prognostic markers and targets for therapeutic interventions. RESULTS: For markers such as the potentially prognostic platelet glycoprotein IIb, the endpoint definition, in combination with the signature building approach is seen to have the largest impact. Removal of outliers, as identified by the proposed strategy, is also seen to considerably improve stability. CONCLUSIONS: As the proposed strategy allowed us to precisely quantify the impact of modeling choices on the stability of marker identification, we suggest routine use also in other applications to prevent analysis-specific results, which are unstable, i.e. not reproducible.
Assuntos
Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Idoso , Doenças Cardiovasculares/complicações , Feminino , Humanos , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Evolutionarily conserved sequences likely have biological function. METHODS: To determine whether variation in conserved sequences in non-coding DNA contributes to risk for human disease, we studied six conserved non-coding elements in the Th2 cytokine cluster on human chromosome 5q31 in a large Hutterite pedigree and in samples of outbred European American and African American asthma cases and controls. RESULTS: Among six conserved non-coding elements (> 100 bp, > 70% identity; human-mouse comparison), we identified one single nucleotide polymorphism (SNP) in each of two conserved elements and six SNPs in the flanking regions of three conserved elements. We genotyped our samples for four of these SNPs and an additional three SNPs each in the IL13 and IL4 genes. While there was only modest evidence for association with single SNPs in the Hutterite and European American samples (P < 0.05), there were highly significant associations in European Americans between asthma and haplotypes comprised of SNPs in the IL4 gene (P < 0.001), including a SNP in a conserved non-coding element. Furthermore, variation in the IL13 gene was strongly associated with total IgE (P = 0.00022) and allergic sensitization to mold allergens (P = 0.00076) in the Hutterites, and more modestly associated with sensitization to molds in the European Americans and African Americans (P < 0.01). CONCLUSION: These results indicate that there is overall little variation in the conserved non-coding elements on 5q31, but variation in IL4 and IL13, including possibly one SNP in a conserved element, influence asthma and atopic phenotypes in diverse populations.
Assuntos
Asma/genética , Cromossomos Humanos Par 5/genética , Interleucina-13/genética , Interleucina-4/genética , Hipersensibilidade Respiratória/genética , Sequência Conservada/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Variação Genética/genética , Heterozigoto , Humanos , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNARESUMO
PURPOSE OF REVIEW: The increase in asthma prevalence over the past 50 years suggests that exposures to environmental risk factors have also increased during this time. Environmental tobacco smoke is one of the most common indoor air pollutants and has been associated in epidemiologic studies with airway and allergic phenotypes in exposed individuals. However, symptoms occur in only some individuals, suggesting that individual genotypes determine sensitivity to environmental tobacco smoke exposure. In this review, we summarize studies evaluating the relationship between genotype, environmental tobacco smoke exposure and risk for asthma and related phenotypes. RECENT FINDINGS: Using either candidate gene or genome-wide approaches, a number of studies have examined interactions between genotypes at specific loci or genome regions and environmental tobacco smoke exposure and risk for asthma or asthma-associated phenotypes. These studies implicate variation in the genes encoding the alpha(2)-adrenergic receptor, interleukin-10, glutathione S-transferase M1, interleukin-1 beta and interleukin-1 receptor antagonist, matrix metalloproteinases 1 and 12, interleukin-4 receptor alpha-chain, alpha(1)-antitrypsin, and microsomal epoxide hydrolase, as well as unknown genes on chromosomes 1p, 5q and 17p as contributing toward susceptibility in smoking exposed individuals. SUMMARY: Considering environmental tobacco smoke exposure in genetic studies may help to identify more homogeneous subsets of patients that share a common disease etiology. By stratifying samples by environmental tobacco smoke exposure, associations or linkages with specific polymorphisms or chromosomal region may be revealed, as illustrated in the studies discussed in this review.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Asma/etiologia , Exposição Ambiental/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Asma/genética , Predisposição Genética para Doença/genética , HumanosRESUMO
Inflammation as a systemic process plays a central role in atherosclerotic plaque progression (PP). Here we investigated other systemic correlates of PP by global gene expression profiling (GEP) in peripheral blood. From a database of 45,727 coronary angiograms, we identified two patient groups with good risk factor control, but different clinical evolution: First, 16 patients had significant PP leading to repeated coronary interventions, and second, 16 patients had angiographically documented stable courses. GEP revealed 93 differentially expressed genes, of which 23 have unknown function. Among the remaining 70 genes, 10 were associated with progenitor and pluripotent cells, but only three genes with atherosclerosis. We developed a risk prediction gene signature by a multivariable statistical model integrating comprehensive laboratory and clinical patient data. This signature identified PP with high sensitivity and specificity for new patients, as estimated by resampling techniques. GEP results were validated by qPCR for ANK2 and GSTT1.
Assuntos
Doença da Artéria Coronariana/genética , Perfilação da Expressão Gênica , Idoso , Anquirinas/genética , Análise por Conglomerados , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Progressão da Doença , Feminino , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Predisposição Genética para Doença , Glutationa Transferase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Placa Aterosclerótica , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
Chlorophyll d is a photosynthetic pigment that, based on chemical analyses, has only recently been recognized to be widespread in oceanic and lacustrine environments. However, the diversity of organisms harbouring this pigment is not known. Until now, the unicellular cyanobacterium Acaryochloris marina is the only characterized organism that uses chlorophyll d as a major photopigment. In this study we describe a new cyanobacterium possessing a high amount of chlorophyll d, which was isolated from waters around Heron Island, Great Barrier Reef (23° 26' 31.2â³ S, 151° 54' 50.4â³ E). The 16S ribosomal RNA is 2% divergent from the two previously described isolates of A. marina, which were isolated from waters around the Palau islands (Pacific Ocean) and the Salton Sea lake (California), suggesting that it belongs to a different clade within the genus Acaryochloris. An overview sequence analysis of its genome based on Illumina technology yielded 871 contigs with an accumulated length of 8 371 965 nt. Their analysis revealed typical features associated with Acaryochloris, such as an extended gene family for chlorophyll-binding proteins. However, compared with A. marina MBIC11017, distinct genetic, morphological and physiological differences were observed. Light saturation is reached at lower light intensities, Chl d/a ratios are less variable with light intensity and the phycobiliprotein phycocyanin is lacking, suggesting that cyanobacteria of the genus Acaryochloris occur in distinct ecotypes. These data characterize Acaryochloris as a niche-adapted cyanobacterium and show that more rigorous attempts are worthwhile to isolate, cultivate and analyse chlorophyll d-containing cyanobacteria for understanding the ecophysiology of these organisms.
Assuntos
Clorofila/análise , Cianobactérias/química , Cianobactérias/isolamento & purificação , Austrália , Cromatografia Líquida de Alta Pressão , Análise por Conglomerados , Cianobactérias/citologia , Cianobactérias/genética , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Luz , Microscopia Eletrônica de Transmissão , Dados de Sequência Molecular , Oceano Pacífico , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Análise EspectralRESUMO
BACKGROUND: Genome-wide linkage scans to identify asthma susceptibility loci have revealed many linked regions, including a broad region on chromosome 5p. OBJECTIVE: To identify a 5p-linked asthma or bronchial hyperresponsiveness (BHR) locus. METHODS: We performed fine mapping and positional candidate studies of this region in the Hutterites and an outbred case-control sample from Germany by genotyping 89 single nucleotide polymorphisms (SNPs) in 22 genes. SNP and haplotype analyses were performed. RESULTS: Three genes in a distal region (zinc finger RNA binding protein [ZFR], natriuretic peptide receptor C, and a disintegrin and metalloproteinase domain with thrombospondin type 1 motif [ADAMTS12]) were associated with BHR, whereas 4 genes in a proximal region (prolactin receptor, IL-7 receptor [IL7R], leukemia inhibitory factor receptor [LIFR], and prostaglandin E4 receptor [PTGER4]) were associated with asthma symptoms in the Hutterites. Furthermore, nearly the entire original linkage signal in the Hutterites was generated by individuals who had the risk-associated alleles in ZFR3, natriuretic peptide receptor C, ADAMTS12, LIFR, and PTGER4. Variation in ADAMTS12, IL7R, and PTGER4 were also associated with asthma in the outbred Germans, and the frequencies of long-range haplotypes composed of SNPs at ZFR, ADAMTS12, IL7R, LIFR, and PTGER4 were significantly different between both the German and Hutterite cases and controls. There is little linkage disequilbrium between alleles in these 2 regions in either population. CONCLUSION: These results suggest that a broad region on 5p, separated by >9 Mb, harbors at least 2 and possibly 5 asthma or BHR susceptibility loci. These findings are consistent with the hypothesis that regions providing evidence for linkage in multiple populations may, in fact, house more than 1 susceptibility locus, as appears to be the case for the linked region on 5p. CLINICAL IMPLICATIONS: Identifying asthma or BHR genes could lead to novel therapeutic approaches.
Assuntos
Asma/genética , Cromossomos Humanos Par 5 , Predisposição Genética para Doença , Asma/epidemiologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Alemanha/epidemiologia , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The chromosomal region 19q13 has been found in linkage to allergic diseases in several genome-wide linkage screens. One candidate gene within this region is the gene coding for TGF-beta1. Transforming growth factor (TGF)-beta acts as an anti-inflammatory cytokine suppressing allergic inflammation and hyper-reactivity. However, in ongoing inflammation of the lungs it can induce fibrosis and airway remodelling as seen in chronic asthma. Several polymorphisms within TGF-beta1 have been identified and one, -C509T, has been shown to be in association with elevated immunoglobulin E levels and severe bronchial asthma in different populations. However, other studies failed to confirm the association. The present study investigated two polymorphisms within the gene coding for TGF-beta1, -C509T and G915C, and for their potential association with bronchial asthma in Caucasian children. Genotyping of these polymorphisms was performed by means of restriction fragment length polymorphisms in a population of 231 asthmatic children and a control population of 269 individuals. Statistical analyses made use of the Armitage's trend test. In addition haplotypes were calculated by arlequin. None of the two polymorphisms showed association with bronchial asthma. They were found to be in linkage disequilibrium. We conclude from our data that TGF-beta1 is unlikely to represent a major gene in the development of bronchial asthma in the Caucasian population.
Assuntos
Asma/etnologia , Asma/genética , Fator de Crescimento Transformador beta/genética , Adolescente , Criança , Pré-Escolar , Alemanha , Humanos , Polimorfismo Genético/genética , População BrancaRESUMO
BACKGROUND: IL-8 is a strong inductor of inflammation. Accordingly, it plays a pivotal role in acute inflammatory responses during respiratory syncytial virus (RSV) infections and in chronic inflammatory diseases such as bronchial asthma and juvenile idiopathic arthritis. Recently, 2 studies have found association of the polymorphism -251A of IL8 with RSV bronchiolitis. Furthermore, epidemiologic studies have demonstrated an increased risk for the development of asthma after RSV bronchiolitis, and a common genetic background for the 2 diseases is currently being discussed. OBJECTIVE: This study investigated whether IL-8 is in association with asthma and/or arthritis and whether the results can confirm a common genetic background of RSV bronchiolitis and asthma. METHODS: The polymorphisms -A251T, C781T, C1633T, and A2767T within IL8 were genotyped in the following 4 populations: children with asthma, atopic children, children with juvenile idiopathic arthritis, and control subjects. Statistical analysis made use of the Armitage trend test and the software program Arlequine. RESULTS: Association of all polymorphisms was found with asthma ( P =.008 to P =.03). Surprisingly -251T was associated with asthma, which is the opposite allele as described in association with RSV bronchiolitis. Furthermore, all polymorphisms were significantly more common in children with arthritis than in asthmatic children ( P =.006 to P =.02). No association was seen with the diagnosis of arthritis per se or with atopy. CONCLUSION: This is the first study to describe association of IL-8 with asthma and a significant inverse distribution of the polymorphisms in juvenile idiopathic arthritis. In addition, the results of this study might suggest that RSV bronchiolitis and bronchial asthma have at least some different genetic factors.
Assuntos
Asma/genética , Bronquiolite Viral/genética , Predisposição Genética para Doença , Interleucina-8/genética , Polimorfismo Genético , Infecções por Vírus Respiratório Sincicial/genética , Adolescente , Adulto , Artrite Juvenil/genética , Criança , Pré-Escolar , Genótipo , Haplótipos , Humanos , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/patogenicidadeRESUMO
BACKGROUND: IL-15 is a T(H)1-related cytokine that is involved in the inflammatory response in various infectious and autoimmune diseases. IL-15 has recently been shown to be upregulated in T-cell-mediated inflammatory disorders. The observations suggest a potential role for this cytokine in a variety of pathologic conditions, including T(H)1-mediated and T(H)2-mediated inflammatory diseases. OBJECTIVE: In this study, we searched for single nucleotide polymorphisms in the whole IL-15 gene and investigated their association with inflammatory and/or atopic phenotypes. METHODS: The screening for single nucleotide polymorphisms was performed by single-strand conformation polymorphism analysis. Genotyping of the identified polymorphisms was performed by restriction fragment length polymorphism. Genotypic association analysis used the Armitage trend test. Haplotype frequency estimation and subsequent testing for differences between cases and controls were performed by using the programs FASTEHPLUS and FAMHAP. RESULTS: We identified 5 novel noncoding nucleotide sequence variants, all of which were typed in our asthmatic, our atopic, and our control population. According to the Armitage trend test, none of the 5 polymorphisms is associated with the phenotype bronchial asthma or atopy. However, multilocus haplotype analysis based on simulations to find out whether the haplotype frequencies differed between cases and controls by using the program FAMHAP yielded a P value of 6.1 x 10(-5) in the asthmatic versus the control population, which is highly significant. Furthermore, we obtained a nominally significant result of P=.0232 for the atopic versus the control population by using FAMHAP. CONCLUSION: These results strongly underscore previous findings that suggest a potential role of this cytokine in allergic diseases.
Assuntos
Asma/genética , Asma/imunologia , Interleucina-15/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/imunologia , Masculino , FenótipoRESUMO
BACKGROUND: Atopy has been linked to chromosome 11q22, a region that harbors the IL18 gene. IL-18 enhances IL-4/IL-13 production and induces IgE production that is directly associated with the pathogenesis of atopic disorders. OBJECTIVE: We sought to investigate whether genetic abnormalities in the regulatory regions of the IL18 gene predispose, in part, to susceptibility to atopy. METHODS: Among a white population of 105 families, the oldest child was examined with regard to atopic phenotypes and single-nucleotide polymorphisms (SNPs) within the IL18 gene. RESULTS: We have identified 5 novel SNPs in the IL18 gene (-920[t/c], -133[c/g], and -132[a/g] in promoter 2 [upstream of exon 2]; +179[c/a; Ser35Ser] in exon 4; and +486[c/t; Phe137Phe] in exon 6). Three SNPs are located in promoter 2, and one (-133[c/g]; nuclear factor 1 site) was significantly associated with high serum IgE levels (P =.001; odds ratio, 3.96) and specific sensitization to common allergens (P =.005; OR, 4.12). In addition, previously identified SNPs in exon 1 (+113[t/g] and +127[c/t]) and in promoter 1 (-137[g/c], GATA3 site) of the IL18 gene were significantly associated with high IgE levels (P < or =.005; OR, 3.27-3.90) and specific sensitization (P =.02 to.008; OR, 3.27-3.83). The SNP +127(g/t) in exon 1 was also a susceptibility locus for seasonal allergic rhinitis (P =.008; OR, 3.22). CONCLUSION: IL18 might be responsible for the linkage effects seen in the chromosomal region 11q22, which has been found previously with the phenotype "sensitization to mite allergen." Thus a suspected direct role of IL18 in the pathogenesis of atopy has been strengthened by the presence of 8 common SNPs in the promoter regions of IL18.
Assuntos
Alérgenos/imunologia , Interleucina-18/genética , Rinite Alérgica Perene/imunologia , Alelos , Éxons , Humanos , Imunização , Mutação , Polimorfismo Genético , Regiões Promotoras Genéticas , Rinite Alérgica Perene/genéticaRESUMO
BACKGROUND: It has previously been shown that various inflammatory diseases, such as diabetes mellitus, bronchial asthma, chronic inflammatory bowel diseases, and rheumatoid arthritis, are in some circumstances genetically linked to the same chromosomal regions. Consequently, common genes underlying the pathogenetics of these diseases have been proposed. Chronic inflammatory disorders can be subdivided by their predominant immune response, either TH1 or TH2. For example, juvenile idiopathic arthritis (JIA) is a TH1 disease, and bronchial asthma is a TH2 disease. OBJECTIVES: The present study investigated the polymorphism Arg110Gln within the IL13 gene, a strong TH2 cytokine. We attempted to determine whether it is associated with these 2 diseases and whether this would reflect the TH1/TH2 paradigm. METHODS: Arg110Gln was typed in 4 different populations: asthmatic children, atopic children, children with JIA, and a control population. Statistical analysis was performed by using logistic and linear regression analysis of serum IgE levels and the Armitage trend test. RESULTS: The variant Gln110 was shown to be associated with increased total serum IgE levels in our atopic population (P =.006) and was weakly associated with bronchial asthma (P =.04). There was no association of the variant with JIA when compared with the control population. However, the variant Gln110 was significantly less frequent in children with JIA compared with its presence in children with bronchial asthma (P =.007). CONCLUSION: This is the first study to compare the same gene variant in TH1 and TH2 chronic inflammatory diseases. The results suggest that the same gene variant might protect from one disease and make an individual susceptible to the other.