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1.
Clin Nutr ; 2018 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-30497694

RESUMO

Depression is a highly prevalent disorder which exerts a major economic impact in all European countries. The brain-gut-microbiota axis has been described as a new paradigm for advancing understanding and treatment of the disorder. There is now over-whelming evidence to support the fact that gut microbes have a major impact on central neurochemistry and behaviour, especially stress related disorders such as depression. Recent studies indicate that patients with depression have a gut dysbiosis. The reason for this dysbiosis is uncertain. Over recent decades, dietary patterns in Europe and elsewhere have undergone major compositional changes, with increased intakes of red meat, high fat foods, and refined sugars. Individuals who consume a Mediterranean diet have lower rates of depression and a recent study suggests that a Mediterranean diet may have antidepressant properties. Assuming this to be the case, which components of the Mediterranean diet mediate the effects? Highly levels of polyphenols or polyunsaturated fatty acids are obvious candidates. We in the MyNewGut consortium recommend that patients with depression or vulnerability to depression should be encouraged to enhance a plant-based diet with a high content of grains/fibres and fish.

2.
World J Gastroenterol ; 23(30): 5486-5498, 2017 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-28852308

RESUMO

The last decade has witnessed a growing appreciation of the fundamental role played by an early assembly of a diverse and balanced gut microbiota and its subsequent maintenance for future health of the host. Gut microbiota is currently viewed as a key regulator of a fluent bidirectional dialogue between the gut and the brain (gut-brain axis). A number of preclinical studies have suggested that the microbiota and its genome (microbiome) may play a key role in neurodevelopmental and neurodegenerative disorders. Furthermore, alterations in the gut microbiota composition in humans have also been linked to a variety of neuropsychiatric conditions, including depression, autism and Parkinson's disease. However, it is not yet clear whether these changes in the microbiome are causally related to such diseases or are secondary effects thereof. In this respect, recent studies in animals have indicated that gut microbiota transplantation can transfer a behavioral phenotype, suggesting that the gut microbiota may be a modifiable factor modulating the development or pathogenesis of neuropsychiatric conditions. Further studies are warranted to establish whether or not the findings of preclinical animal experiments can be generalized to humans. Moreover, although different communication routes between the microbiota and brain have been identified, further studies must elucidate all the underlying mechanisms involved. Such research is expected to contribute to the design of strategies to modulate the gut microbiota and its functions with a view to improving mental health, and thus provide opportunities to improve the management of psychiatric diseases. Here, we review the evidence supporting a role of the gut microbiota in neuropsychiatric disorders and the state of the art regarding the mechanisms underlying its contribution to mental illness and health. We also consider the stages of life where the gut microbiota is more susceptible to the effects of environmental stressors, and the possible microbiota-targeted intervention strategies that could improve health status and prevent psychiatric disorders in the near future.


Assuntos
Encéfalo/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Doenças Neurodegenerativas/etiologia , Transtornos do Neurodesenvolvimento/etiologia , Estresse Psicológico/complicações , Animais , Encéfalo/crescimento & desenvolvimento , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Transplante de Microbiota Fecal , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Doenças Neurodegenerativas/prevenção & controle , Transtornos do Neurodesenvolvimento/prevenção & controle , Sistema Hipófise-Suprarrenal/fisiopatologia , Estresse Psicológico/fisiopatologia
3.
Eur Child Adolesc Psychiatry ; 26(9): 1081-1092, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28289903

RESUMO

A bidirectional communication between the gut and the brain (gut-brain axis) is well recognized with the gut microbiota viewed as a key regulator of this cross-talk. Currently, a body of preclinical and to a lesser extent epidemiological evidence supports the notion that host-microbe interactions play a key role in brain development and function and in the etiology of neurodevelopmental disorders. Early life events and shifts away from traditional lifestyles are known to impact gut microbiota composition and function and, thereby, may increase the risk of developing neurodevelopmental disorders. Attention deficit hyperactivity disorder (ADHD) is nowadays the most prevalent neurodevelopmental disorder. Despite many years of research its etiology is unclear and its diagnosis and treatment are still challenging. Different factors reported to be associated with the risk of developing ADHD and/or linked to different ADHD manifestations have also been linked to shifts in gut microbiota composition, suggesting a link between the microbiota and the disorder. Evidence from preliminary human studies also suggests that dietary components that modulate gut microbiota may also influence ADHD development or symptoms, although further studies are warranted to confirm this hypothesis. Here, we firstly review the potential mechanisms by which the gut microbiota may regulate the brain-gut axis and influence behavior and neurodevelopmental disorders. Secondly, we discuss the current knowledge about the different factors and dietary components reported to be associated with the risk of developing ADHD or its manifestations and with shifts in gut microbiota composition. Finally, we briefly highlight the need to progress our understanding regarding the role of the gut microbiota in ADHD, since this could open new avenues for early intervention and improved management of the disease.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Encéfalo/microbiologia , Microbioma Gastrointestinal/imunologia , Encéfalo/fisiopatologia , Humanos
4.
Nat Genet ; 48(11): 1407-1412, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27694959

RESUMO

The gut microbiome is affected by multiple factors, including genetics. In this study, we assessed the influence of host genetics on microbial species, pathways and gene ontology categories, on the basis of metagenomic sequencing in 1,514 subjects. In a genome-wide analysis, we identified associations of 9 loci with microbial taxonomies and 33 loci with microbial pathways and gene ontology terms at P < 5 × 10-8. Additionally, in a targeted analysis of regions involved in complex diseases, innate and adaptive immunity, or food preferences, 32 loci were identified at the suggestive level of P < 5 × 10-6. Most of our reported associations are new, including genome-wide significance for the C-type lectin molecules CLEC4F-CD207 at 2p13.3 and CLEC4A-FAM90A1 at 12p13. We also identified association of a functional LCT SNP with the Bifidobacterium genus (P = 3.45 × 10-8) and provide evidence of a gene-diet interaction in the regulation of Bifidobacterium abundance. Our results demonstrate the importance of understanding host-microbe interactions to gain better insight into human health.


Assuntos
Microbioma Gastrointestinal , Genoma Humano , Adolescente , Adulto , Idoso , Animais , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imunidade/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
5.
Science ; 352(6285): 565-9, 2016 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-27126040

RESUMO

Deep sequencing of the gut microbiomes of 1135 participants from a Dutch population-based cohort shows relations between the microbiome and 126 exogenous and intrinsic host factors, including 31 intrinsic factors, 12 diseases, 19 drug groups, 4 smoking categories, and 60 dietary factors. These factors collectively explain 18.7% of the variation seen in the interindividual distance of microbial composition. We could associate 110 factors to 125 species and observed that fecal chromogranin A (CgA), a protein secreted by enteroendocrine cells, was exclusively associated with 61 microbial species whose abundance collectively accounted for 53% of microbial composition. Low CgA concentrations were seen in individuals with a more diverse microbiome. These results are an important step toward a better understanding of environment-diet-microbe-host interactions.


Assuntos
Bactérias/classificação , Microbioma Gastrointestinal/genética , Trato Gastrointestinal/microbiologia , Bactérias/genética , Bactérias/isolamento & purificação , Cromogranina A/análise , Cromogranina A/metabolismo , Dieta , Células Enteroendócrinas/metabolismo , Fezes/química , Fezes/microbiologia , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metagenômica , Países Baixos , Filogenia , RNA Ribossômico 16S/genética
6.
Gut ; 65(5): 740-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26657899

RESUMO

BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome. METHODS: The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis. RESULTS: 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10(-38)). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli. CONCLUSIONS: The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores da Bomba de Prótons/farmacologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Circ Res ; 117(9): 817-24, 2015 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-26358192

RESUMO

RATIONALE: Evidence suggests that the gut microbiome is involved in the development of cardiovascular disease, with the host-microbe interaction regulating immune and metabolic pathways. However, there was no firm evidence for associations between microbiota and metabolic risk factors for cardiovascular disease from large-scale studies in humans. In particular, there was no strong evidence for association between cardiovascular disease and aberrant blood lipid levels. OBJECTIVES: To identify intestinal bacteria taxa, whose proportions correlate with body mass index and lipid levels, and to determine whether lipid variance can be explained by microbiota relative to age, sex, and host genetics. METHODS AND RESULTS: We studied 893 subjects from the Life-Lines-DEEP population cohort. After correcting for age and sex, we identified 34 bacterial taxa associated with body mass index and blood lipids; most are novel associations. Cross-validation analysis revealed that microbiota explain 4.5% of the variance in body mass index, 6% in triglycerides, and 4% in high-density lipoproteins, independent of age, sex, and genetic risk factors. A novel risk model, including the gut microbiome explained ≤ 25.9% of high-density lipoprotein variance, significantly outperforming the risk model without microbiome. Strikingly, the microbiome had little effect on low-density lipoproteins or total cholesterol. CONCLUSIONS: Our studies suggest that the gut microbiome may play an important role in the variation in body mass index and blood lipid levels, independent of age, sex, and host genetics. Our findings support the potential of therapies altering the gut microbiome to control body mass, triglycerides, and high-density lipoproteins.


Assuntos
Índice de Massa Corporal , Microbioma Gastrointestinal/fisiologia , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Bactérias/classificação , Bactérias/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/microbiologia , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos de Coortes , Feminino , Microbioma Gastrointestinal/genética , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Triglicerídeos/sangue , Adulto Jovem
8.
Nutrients ; 7(8): 6900-23, 2015 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-26287240

RESUMO

It is widely recognized that the intestinal microbiota plays a role in the initiation and perpetuation of intestinal inflammation in numerous chronic conditions. Most studies report intestinal dysbiosis in celiac disease (CD) patients, untreated and treated with a gluten-free diet (GFD), compared to healthy controls. CD patients with gastrointestinal symptoms are also known to have a different microbiota compared to patients with dermatitis herpetiformis and controls, suggesting that the microbiota is involved in disease manifestation. Furthermore, a dysbiotic microbiota seems to be associated with persistent gastrointestinal symptoms in treated CD patients, suggesting its pathogenic implication in these particular cases. GFD per se influences gut microbiota composition, and thus constitutes an inevitable confounding factor in studies conducted in CD patients. To improve our understanding of whether intestinal dysbiosis is the cause or consequence of disease, prospective studies in healthy infants at family risk of CD are underway. These studies have revealed that the CD host genotype selects for the early colonizers of the infant's gut, which together with environmental factors (e.g., breast-feeding, antibiotics, etc.) could influence the development of oral tolerance to gluten. Indeed, some CD genes and/or their altered expression play a role in bacterial colonization and sensing. In turn, intestinal dysbiosis could promote an abnormal response to gluten or other environmental CD-promoting factors (e.g., infections) in predisposed individuals. Here, we review the current knowledge of host-microbe interactions and how host genetics/epigenetics and environmental factors shape gut microbiota and may influence disease risk. We also summarize the current knowledge about the potential mechanisms of action of the intestinal microbiota and specific components that affect CD pathogenesis.


Assuntos
Doença Celíaca/microbiologia , Microbioma Gastrointestinal , Intestinos/microbiologia , Evolução Biológica , Doença Celíaca/genética , Dieta Livre de Glúten , Disbiose/genética , Disbiose/microbiologia , Epigênese Genética , Glutens/administração & dosagem , Interações Hospedeiro-Patógeno , Humanos , Intestinos/fisiopatologia , Probióticos , Fatores de Risco
9.
PLoS One ; 9(11): e113090, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25402503

RESUMO

OBJECTIVE: CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis. METHODS: The CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed. RESULTS: T-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis. CONCLUSION: The ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.


Assuntos
Antígenos CD5/genética , Haplótipos/genética , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/etiologia , Ativação Linfocitária/imunologia , Polimorfismo Genético/genética , Linfócitos T/imunologia , Alelos , Autoimunidade/imunologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/diagnóstico
10.
PLoS One ; 8(11): e72892, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24312163

RESUMO

OBJECTIVE: STAT4 and IL23R loci represent common susceptibility genetic factors in autoimmunity. We decided to investigate for the first time the possible role of different STAT4/IL23R autoimmune disease-associated polymorphisms on the susceptibility to develop non-anterior uveitis and its main clinical phenotypes. METHODS: Four functional polymorphisms (rs3821236, rs7574865, rs7574070, and rs897200) located within STAT4 gene as well as three independent polymorphisms (rs7517847, rs11209026, and rs1495965) located within IL23R were genotyped using TaqMan® allelic discrimination in a total of 206 patients with non-anterior uveitis and 1553 healthy controls from Spain. RESULTS: No statistically significant differences were found when allele and genotype distributions were compared between non-anterior uveitis patients and controls for any STAT4 (rs3821236: P=0.39, OR=1.12, CI 95%=0.87-1.43; rs7574865: P=0.59 OR=1.07, CI 95%=0.84-1.37; rs7574070: P=0.26, OR=0.89, CI 95%=0.72-1.10; rs897200: P=0.22, OR=0.88, CI 95%=0.71-1.08;) or IL23R polymorphisms (rs7517847: P=0.49, OR=1.08, CI 95%=0.87-1.33; rs11209026: P=0.26, OR=0.78, CI 95%=0.51-1.21; rs1495965: P=0.51, OR=0.93, CI 95%=0.76-1.15). CONCLUSION: Our results do not support a relevant role, similar to that described for other autoimmune diseases, of IL23R and STAT4 polymorphisms in the non-anterior uveitis genetic predisposition. Further studies are needed to discard a possible weak effect of the studied variant.


Assuntos
Autoimunidade/genética , Polimorfismo Genético , Receptores de Interleucina/genética , Fator de Transcrição STAT4/genética , Uveíte/genética , Uveíte/imunologia , Adulto , Alelos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Uveíte/diagnóstico
11.
PLoS One ; 8(10): e76777, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24116155

RESUMO

OBJECTIVE: Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated IRF5 genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes. METHODS: Three IRF5 polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin. RESULTS: A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (P FDR =5.07E-03, OR=1.48, CI 95%=1.14-1.92 and P FDR =3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: P=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: P=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both IRF5 genetic variants are specifically associated with the lack of macular edema in uveitis patients. CONCLUSION: Our results clearly showed for the first time that two functional genetic variants of IRF5 may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies.


Assuntos
Predisposição Genética para Doença/genética , Fatores Reguladores de Interferon/genética , Edema Macular/genética , Polimorfismo de Nucleotídeo Único , Uveíte Anterior/complicações , Adulto , Alelos , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Edema Macular/complicações , Masculino , Pessoa de Meia-Idade , Fenótipo
12.
BMC Med Genet ; 14: 52, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23676143

RESUMO

BACKGROUND: Recently, different genetic variants located within the IL2/IL21 genetic region as well as within both IL2RA and IL2RB loci have been associated to multiple autoimmune disorders. We aimed to investigate for the first time the potential influence of the IL2/IL21, IL2RA and IL2RB most associated polymorphisms with autoimmunity on the endogenous non-anterior uveitis genetic predisposition. METHODS: A total of 196 patients with endogenous non-anterior uveitis and 760 healthy controls, all of them from Caucasian population, were included in the current study. The IL2/IL21 (rs2069762, rs6822844 and rs907715), IL2RA (2104286, rs11594656 and rs12722495) and IL2RB (rs743777) genetic variants were genotyped using TaqMan® allelic discrimination assays. RESULTS: A statistically significant difference was found for the rs6822844 (IL2/IL21 region) minor allele frequency in the group of uveitis patients compared with controls (P(-value)=0.02, OR=0.64 CI 95%=0.43-0.94) although the significance was lost after multiple testing correction. Furthermore, no evidence of association with uveitis was detected for the analyzed genetic variants of the IL2RA or IL2RB loci. CONCLUSION: Our results indicate that analyzed IL2/IL21, IL2RA and IL2RB polymorphisms do not seem to play a significant role on the non-anterior uveitis genetic predisposition although further studies are needed in order to clear up the influence of these loci on the non-anterior uveitis susceptibility.


Assuntos
Predisposição Genética para Doença , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/genética , Interleucina-2/genética , Interleucinas/genética , Polimorfismo Genético , Uveíte/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único
13.
Mol Vis ; 19: 638-43, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23559857

RESUMO

OBJECTIVE: Endogenous uveitis is a major cause of visual loss mediated by the immune system. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes a lymphoid-specific phosphatase that plays a key role in T-cell receptor (TCR) signaling. Two independent functional missense single nucleotide polymorphisms (SNPs) located within the PTPN22 gene (R263Q and R620W) have been associated with different autoimmune disorders. We aimed to analyze for the first time the influence of these PTPN22 genetic variants on endogenous non-anterior uveitis susceptibility. METHODS: We performed a case-control study of 217 patients with endogenous non-anterior uveitis and 718 healthy controls from a Spanish population. The PTPN22 polymorphisms (rs33996649 and rs2476601) were genotyped using TaqMan allelic discrimination assays. The allele, genotype, carriers, and allelic combination frequencies were compared between cases and controls with χ(2) analysis or Fisher's exact test. RESULTS: Our results showed no influence of the studied SNPs in the global susceptibility analysis (rs33996649: allelic P- value=0.92, odds ratio=0.97, 95% confidence interval=0.54-1.75; rs2476601: allelic P- value=0.86, odds ratio=1.04, 95% confidence interval=0.68-1.59). Similarly, the allelic combination analysis did not provide additional information. CONCLUSIONS: Our results suggest that the studied polymorphisms of the PTPN22 gene do not play an important role in the pathophysiology of endogenous non-anterior uveitis.


Assuntos
Substituição de Aminoácidos/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Uveíte Anterior/enzimologia , Uveíte Anterior/genética , Alelos , Estudos de Casos e Controles , Demografia , Feminino , Frequência do Gene/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Espanha
14.
Hum Immunol ; 74(2): 230-3, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23127549

RESUMO

OBJECTIVE: Signal-transducer and activator of transcription protein 3 (STAT3) gene encodes a transducer and transcription factor that plays an important role in many cellular processes such as cell growth, apoptosis and immune response. Several STAT3 genetic variants have been associated to different autoimmune diseases. Our aim was to reveal the possible STAT3 influence in other immune-mediated diseases such as psoriatic arthritis (PsA) and Behcet disease (BD). METHODS: The STAT3 rs744166 and rs2293152 polymorphisms were genotyped using predesigned TaqMan® assays in a total of 335 PsA patients, 217 BD patients, and 1844 ethnically matched healthy controls of Spanish Caucasian origin. RESULTS: A statistically significant association of the STAT3 rs744166(∗)G allele with PsA was observed (P-value=1.36×10(-3), OR 1.35). The detected effect was more evident when the rs744166(∗)GG homozygote frequencies were compared between PsA patients and controls (genotype P-value=9.77×10(-5), OR 1.82). In contrast, the allele and genotypic distributions of rs744166 polymorphism showed no significant differences between patients with BD and control subjects (allelic P-value=0.80, OR 1.03). Additionally, no evidence of association was detected between the rs2293152 genetic variant and both studied diseases. CONCLUSION: Our results suggest for the first time that the STAT3 gene might be involved in PsA but not in Behcet's disease predisposition.


Assuntos
Artrite Psoriásica/genética , Síndrome de Behçet/genética , Predisposição Genética para Doença , Polimorfismo Genético , Fator de Transcrição STAT3/genética , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
15.
J Rheumatol ; 39(12): 2294-302, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23027890

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan(®) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression.


Assuntos
Predisposição Genética para Doença , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Progressão da Doença , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Escleroderma Sistêmico/etnologia
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