Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.177
Filtrar
1.
Z Gastroenterol ; 57(10): 1218-1225, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31610585

RESUMO

INTRODUCTION: Response to anti-TNF therapy is crucial for life expectancy and life quality in patients with severe Crohn's disease. We investigated if a previously reported gene expression profile predictive for infliximab response could be also applied to adalimumab response in an independent cohort. METHODS: Forty-seven Slovene Crohn's disease patients indicated for adalimumab therapy were enrolled in the study. Inflamed and non-inflamed colon biopsy samples were obtained during routine colonoscopy prior to adalimumab treatment. Response to adalimumab was measured with IBDQ. Gene expression in inflamed and non-inflamed colon biopsy samples was measured with RT-qPCR. Genotypes were extracted from previously available genotype data. Statistical analysis was performed with SPSS software. The R package e1071 was used to train bootstrap aggregated support vector machines (SVM). RESULTS: SVM prediction model analysis was used to analyze pooled, non-inflamed, and inflamed colon tissue datasets using IBDQ response after 4, 12, 20 and 30 weeks of adalimumab treatment. The bagging approach was used in an endeavor to obtain 100 % accuracy using 10 × 100 or 100 × 100 iterations. Average adalimumab response prediction accuracy is 75.5 % for pooled samples, 90.5 % for inflamed samples, and 100 % for non-inflamed samples. Moreover, models trained on selected SNPs from analyzed genes had an average accuracy of 92.8 %, confirming the involvement of genetic regions mapping the reported genes. Finally, using combined gene expression and SNP data we observed 100 % adalimumab response prediction accuracy for pooled, inflamed, and non-inflamed datasets. DISCUSSION: Our study supports the reported genetic anti-TNF response profile and extends it for adalimumab prediction.


Assuntos
Adalimumab , Doença de Crohn , Marcadores Genéticos , Adalimumab/uso terapêutico , Adulto , Anti-Inflamatórios/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Eslovênia
3.
Medicine (Baltimore) ; 98(23): e15913, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169706

RESUMO

We aimed to investigate the impact of the single nucleotide polymorphisms of rs34436714 of the NOD-like receptor protein 12 gene on the production of tumor necrosis factor-alpha (TNFα) in patients with inflammatory bowel disease (IBD)In a matched case-control study 90 patients with IBD, 56 with Crohn disease (CD) and 34 with ulcerative colitis, were genotyped and compared to 98 healthy comparators matched for age and gender. Expression level of TNFα, interleukin (IL)-6, IL-12, and soluble triggering receptor expressed on myeloid cells were measured in patients' sera. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated for TNFα production.Serum TNFα was greater among carriers of GT/TT genotypes than GG genotypes of rs34436714. Stimulated TNFα production was also higher in carriers of GT/TT genotypes. The frequency of CD with fistulizing behavior and with CD involving the small intestine was greater among carriers of GT/TT genotypes than of the GG genotype. Distribution of the GG, GT, and TT genotypes of rs34436714 were in Hardy-Weinberg equilibrium in both groups. The genotype distribution was the same in both groups.Carriage of minor frequency alleles of rs34436714 was accompanied by greater circulating levels of TNFα and by greater capacity for stimulated TNFα production by PBMCs. These alleles had an impact on the phenotype of patients with CD.


Assuntos
Doenças Inflamatórias Intestinais/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Idoso , Estudos de Casos e Controles , Colite Ulcerativa/genética , Colite Ulcerativa/fisiopatologia , Doença de Crohn/genética , Doença de Crohn/fisiopatologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Interleucina-12/biossíntese , Interleucina-6/biossíntese , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptor Gatilho 1 Expresso em Células Mieloides/biossíntese
4.
Artigo em Inglês | MEDLINE | ID: mdl-31052515

RESUMO

It is suggested that IL-23/IL-17 axis and single nucleotide polymorphisms (SNPs) of IL23R may have crucial role in pathogenesis of Crohn's disease (CD). Thus, we sought to assess the IL23R SNPs contribution to susceptibility and phenotype of CD. We recruited 117 CD subjects and 117 controls from Poland and 30 CD subjects and 30 controls from Bosnia and Herzegovina (B&H). Two common IL23R SNPs: rs1004819, rs7517847 were genotyped using TaqMan SNP assays. In the Polish population it was found that allele rs1004819: A increases the risk of CD, while allele rs7517847: A is protective against disease development. In Poles the co-carriage of two IL23R risk genotypes was associated with increased risk of CD. A significantly increased risk of CD early onset was observed in Poles carrying at least one rs7517847: G allele. It was also found that IL23R SNPs may be associated with structuring/penetrating CD behavior, as alleles rs1004819: A and rs7517847: G were significantly less frequent in patients without complications, from Poland and B&H, respectively. Allele rs1004819: A was also significantly more frequent in Poles with penetrating CD. These results confirm IL23R SNPs contribution to CD susceptibility in the Polish population and suggest their impact on early age of onset and more severe disease course.


Assuntos
Doença de Crohn/epidemiologia , Doença de Crohn/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Adulto , Alelos , Bósnia e Herzegóvina/epidemiologia , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polônia/epidemiologia
5.
Biomed Res Int ; 2019: 9537050, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093505

RESUMO

Background: Because of the similarity of intestinal tuberculosis and Crohn's disease in disease phenotype, differential diagnosis has always been a clinical problem. Arachidonic acid metabolites play an important role in the inflammatory response of intestinal tuberculosis and Crohn's disease. Recent studies have shown that the polymorphism locus in the promoter region of LTA4H gene affects LTB4 expression level and the susceptibility to extrapulmonary tuberculosis. Thus, we identified a total of 148 patients with intestinal tuberculosis, 145 with Crohn's disease, and 700 normal controls in this study. Methods: All the study participants were local Han people from Jiangxi Province in the past eleven years. DNA was extracted from the paraffin-embedded specimens or the whole blood. The LTA4H promoter SNP (rs17525495) was genotyped with TaqMan assay. Results: The T-alleles frequency was not significantly increased in patients with intestinal tuberculosis compared with healthy control group (p=0.630; OR=1.07; 95%CI=0.81-1.41), while patients with Crohn's disease have significantly increased T allele frequency compared with healthy population (p=0.032; OR=1.34; 95%CI=1.03-1.75). During treatment, the presence of the T allele significantly increased the proportion of Crohn's patients requiring glucocorticoids (p<0.05). Conclusions: The T allele of LTA4H gene SNP (rs17525495) is a risk factor for Crohn's disease instead of intestinal tuberculosis. More importantly, there may be a potential association of the different genotypes of rs17525495 with the treatment efficacy of 5-ASA and glucocorticoids in patients with Crohn's disease. The association between LTA4H polymorphism and drugs therapeutic effects might contribute to the practice of precision medicine and the prediction of clinical outcomes.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doença de Crohn/genética , Epóxido Hidrolases/genética , Grupos Étnicos/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Tuberculose Gastrointestinal/genética , Adulto , Doença de Crohn/enzimologia , Feminino , Frequência do Gene/genética , Humanos , Masculino , Modelos Genéticos , Tuberculose Gastrointestinal/enzimologia
6.
Adv Clin Exp Med ; 28(7): 955-960, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30929318

RESUMO

BACKGROUND: A common feature in the etiology of inflammatory bowel disease (IBD) and osteoporosis is a complex genetic background. Moreover, it has been shown that some of the susceptibility loci overlap for both diseases. One of the genes that may be involved in the pathogenesis of IBD as well as decreased bone mass is the vitamin D receptor (VDR) gene. OBJECTIVES: The aim of this study was to investigate the association of the TaqI polymorphism (rs731236, c.1056T >C) in the VDR gene with serum vitamin D concentration and bone mineral density (BMD) in patients with IBD. MATERIAL AND METHODS: A total of 172 IBD patients (85 with Crohn's disease (CD) and 87 with ulcerative colitis (UC)) and 39 healthy controls were enrolled in the study. Polymorphism was determined with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Bone mineral density was measured at the lumbar spine (L2-L4) and the femoral neck (FN) using dual-energy x-ray absorptiometry (DEXA). Serum concentrations of 25-hydroxyvitamin D were determined using electrochemiluminescence binding assay (ECLIA). RESULTS: Our studies revealed that serum vitamin D concentration in IBD patients was not lowered in comparison with healthy controls. Patients with CD presented more advanced osteopenia and osteoporosis. Individuals with UC carrying the TaqI tt genotype of VDR gene showed significantly higher FN BMD than carriers of TT and Tt genotypes (p = 0.02). Moreover, tt genotype was present with higher frequency in UC patients than in controls and CD patients (23% vs 7.7% and 16.5%, respectively). CONCLUSIONS: The tt genotype may have a protective effect on BMD in UC patients.


Assuntos
Densidade Óssea/genética , Doenças Ósseas Metabólicas/etiologia , Colo do Fêmur/diagnóstico por imagem , Doenças Inflamatórias Intestinais/complicações , Vértebras Lombares/diagnóstico por imagem , Receptores de Calcitriol/genética , Vitamina D/sangue , Absorciometria de Fóton , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/diagnóstico por imagem , Estudos de Casos e Controles , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Colite Ulcerativa/genética , Doença de Crohn/sangue , Doença de Crohn/complicações , Doença de Crohn/genética , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/genética , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Vitamina D/genética
7.
Int J Mol Med ; 43(6): 2291-2302, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017261

RESUMO

The main aim of the present study was to investigate the dual roles and mechanism of interleukin (IL)­18 in dextran sulfate sodium (DSS)­induced colitis. Firstly, meta­analysis was used to explore whether the levels of IL­18 were different in patients with colon cancer or inflammatory bowel disease. The results demonstrated that IL­18 (rs187238, ­137G/C) increased the incidence rate of colon cancer in patients, while IL­18 (rs187238, ­137G/C) decreased the incidence rate of ulcerative colitis or Crohn's disease in patients. Therefore, IL­18 (rs187238, ­137G/C) may have a dual function in colitis. Next, the functional role of IL­18 in colitis was further investigated, by use of a DSS­induced colitis mouse model. Pre­treatment of the mice with IL­18 increased body weight, augmented colon length, reduced inflammatory infiltration, promoted mucin (Muc)­2 expression, increased the function and quantity of goblet cells and increased the mRNA levels of resistin­like molecule (RELM) ß and trefoil factor family (TFF) 3 in mice with DSS­induced colitis, through the IL­22/STAT3 pathway. By contrast, treatment with IL­18 at later stages of the disease reduced body weight, decreased colon length, enhanced inflammatory infiltration and reduced Muc­2 expression, decreased the function and quantity of goblet cells and inhibited the mRNA levels of RELMß and TFF3 in mice with DSS­induced colitis. In conclusion, IL­18 served a dual function in colitis by regulating the function of goblet cells. The anti­inflammatory effects of IL­18 were observed in the early stage of colitis­induced inflammation, while the pro­inflammatory effects were observed in the later stages of the disease.


Assuntos
Colite/imunologia , Neoplasias do Colo/imunologia , Doença de Crohn/imunologia , Células Caliciformes/imunologia , Interleucina-18/imunologia , Animais , Colite/genética , Colite/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Doença de Crohn/genética , Doença de Crohn/patologia , Células Caliciformes/patologia , Humanos , Interleucina-18/genética , Interleucinas/imunologia , Masculino , Camundongos Endogâmicos C57BL , Taxa de Mutação , Polimorfismo de Nucleotídeo Único
8.
Oxid Med Cell Longev ; 2019: 5294105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019652

RESUMO

Aberrant microRNA (miRNA) expressions contribute to the development and progression of various diseases, including Crohn's disease (CD). However, the accurate mechanisms of miRNAs in CD are definitely unclear. We employed colonic tissue samples from normal volunteers and CD patients, an acute mice colitis model induced by 2,4,6-trinitro-benzene-sulfonic acid (TNBS), and a cellular oxidative stress model induced by H2O2 in HT-29 cells to determine the effects of oxidative stress on expressions of miR-122, selenium-binding protein 1 (SELENBP1, SBP1), p65 nuclear factor κB (p65NF-κB) signaling, and DNA methylation. We found that SBP1 was mainly located on epithelial cells and was significantly increased in patients with active CD. SBP1 was the target gene of miR-122. miR-122 expression was downregulated while SBP1 expression was upregulated under TNBS-induced colitis or oxidative stress. Pre-miR-122 or siRNA SBP1 (si-SBP1) treatment ameliorated acute TNBS-induced colitis and H2O2-induced oxidative stress. Cotreatment of pre-miR-122 and si-SBP1 enhanced these effects. Besides, pre-miR-122 and si-SBP1 obviously activated the p65NF-κB signaling by phosphorylation of IκBα. Bisulfite sequencing of the CpG islands in the promoter region of miR-122 showed that CpG methylation was significantly increased under oxidative stress. Treating cells with 5'-AZA which was well known as a DNA-demethylating agent significantly increased miR-122 expression. Our results suggest that oxidative stress-induced DNA methylation of miR-122 aggravates colitis targeting SELENBP1 partially by p65NF-κB signaling and may promote the progression of CD.


Assuntos
Colite/genética , Colite/patologia , Metilação de DNA/genética , MicroRNAs/metabolismo , Estresse Oxidativo/genética , Proteínas de Ligação a Selênio/metabolismo , Animais , Sequência de Bases , Doença de Crohn/genética , Doença de Crohn/patologia , Regulação para Baixo/genética , Células HT29 , Humanos , Peróxido de Hidrogênio/toxicidade , Camundongos , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Ácido Trinitrobenzenossulfônico
9.
Nat Commun ; 10(1): 1561, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952951

RESUMO

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUC5B with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn's disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors.


Assuntos
Estudo de Associação Genômica Ampla , Modelos Genéticos , Mucina-5B/genética , Simulação por Computador , Doença de Crohn/epidemiologia , Doença de Crohn/genética , Predisposição Genética para Doença , Humanos , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/genética , Incidência , Razão de Chances , Polimorfismo de Nucleotídeo Único , Análise de Regressão
10.
Mol Med Rep ; 19(5): 4500-4506, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896837

RESUMO

Genetic factors are crucial in the development of Crohn's disease (CD). Circular RNAs (circRNAs) are known to function as microRNA (miRNA) sponges and regulate a number of signalling pathways via circRNA­miRNA interactions. As competing endogenous RNAs, the functions of circRNAs in CD should be investigated. In the present study, colon biopsy tissues were collected from ileocolon (L3)­active CD patients and healthy controls. circRNA microarrays were performed with colon tissues from 3 CD patients and 3 controls. Subsequently, the candidate circRNAs were verified via reverse transcription­quantitative polymerase chain reaction using colon tissues from a further 10 CD patients and 10 controls. Targeted miRNAs, genes and pathways of candidate circRNAs were predicted and analysed. Arraystar circRNA microarrays demonstrated that there were 163 upregulated circRNAs targeting 435 miRNAs and 55 downregulated circRNAs targeting 207 miRNAs (fold­change >2 and P<0.01) in CD patients. As a candidate circRNA, hsa­circRNA­102685 was observed to putatively target hsa­miR­146b­5p, hsa­miR­182­5p and hsa­miR­146a­5p. Furthermore, Kyoto Encyclopaedia of Genes and Genomes pathway analysis predicted that hsa­circRNA­102685 potentially participated in apoptosis, and in the Toll­like receptor and p53 signalling pathways. Overall, the current study suggested that circRNA alterations serve an important role in the pathogenesis of CD. circRNAs, such as hsa­circRNA­102685, are involved in certain important signalling pathways of CD, and may be novel targets for diagnosis or treatment in this disease.


Assuntos
Colo/metabolismo , Doença de Crohn/patologia , RNA/metabolismo , Adulto , Análise por Conglomerados , Colo/patologia , Doença de Crohn/genética , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , RNA/genética , Transdução de Sinais , Receptores Toll-Like/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem
11.
Nat Genet ; 51(4): 592-599, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926968

RESUMO

Transcriptome-wide association studies (TWAS) integrate genome-wide association studies (GWAS) and gene expression datasets to identify gene-trait associations. In this Perspective, we explore properties of TWAS as a potential approach to prioritize causal genes at GWAS loci, by using simulations and case studies of literature-curated candidate causal genes for schizophrenia, low-density-lipoprotein cholesterol and Crohn's disease. We explore risk loci where TWAS accurately prioritizes the likely causal gene as well as loci where TWAS prioritizes multiple genes, some likely to be non-causal, owing to sharing of expression quantitative trait loci (eQTL). TWAS is especially prone to spurious prioritization with expression data from non-trait-related tissues or cell types, owing to substantial cross-cell-type variation in expression levels and eQTL strengths. Nonetheless, TWAS prioritizes candidate causal genes more accurately than simple baselines. We suggest best practices for causal-gene prioritization with TWAS and discuss future opportunities for improvement. Our results showcase the strengths and limitations of using eQTL datasets to determine causal genes at GWAS loci.


Assuntos
Predisposição Genética para Doença/genética , Transcriptoma/genética , Doença de Crohn/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Lipoproteínas LDL/genética , Locos de Características Quantitativas/genética , Esquizofrenia/genética
12.
Clin Chim Acta ; 494: 14-21, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30862513

RESUMO

BACKGROUD: CD(Crohn's Disease)is a chronic idiopathic inflammatory disorders of the GI tract. It is increasing worldwide and has become a global health problem. The key pathological mechanism for CD occurrence has not been identified, and present treatments are mostly anti-symptom therapy, which has limited efficacy. In this study, we investigate whether lncRNAs are involved in the pathogenesis of CD and how they may regulate the target genes in CD process. METHODS: CD patients were diagnosed in Zhongda Hospital of Southeast University between May 2017 and May 2018. Pathological and normal intestinal mucosa were collected and total RNA was extracted the expression of lncRNA and mRNA was profiled and analyzed by using lncRNA and mRNA gene chips. The lncRNAs and mRNAs with significant alternations (≥10 times and P < 0.05) were identified and verified. The co-expressed mRNAs with the differentially expressed lncRNAs were revealed by CNC analysis. The potential regulatory factors were determined by the Ce (cis/tans) mechanism analysis with the use of miRbase, Targetscan, and NCBI database. Finally, the lncRNA-miRNA/TF-mRNA expression network was predicted. RESULTS: Eight lncRNAs were found to be differentially expressed between the pathological mucosa and the normal mucosas in the ileal end. CNC analysis of the differentially expressed lncRNAs revealed fifty co-expressed mRNAs with positive or negative regulation. Base on the mRNAs KEGG pathway analysis, most of them appeared to be involved in cell signaling pathways. Six lncRNAs in the cytoplasm participated in the Ce mechanism, and the rest two lncRNAs in the nucleus participated in the cis/trans regulation mechanism. Finally, ternary relationship of lncRNAs-miRNAs and TFs-mRNAs was obtained by CNC,KEGG enrichment analysis and Ce (trans/cis) analysis. CONCLUSION: The differential expression of lncRNAs in CD mucosa indicated that lncRNAs were involved in immune reaction. These lncRNAs might contribute to the regulation of intestinal mucosa function through the genetic network of lncRNAs -miRNAs/TFs-mRNAs.


Assuntos
Doença de Crohn/genética , Mucosa Intestinal/metabolismo , RNA Longo não Codificante/genética , Doença de Crohn/diagnóstico , Doença de Crohn/metabolismo , Perfilação da Expressão Gênica , Humanos , RNA Mensageiro/genética
13.
PLoS One ; 14(1): e0211328, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30703110

RESUMO

BACKGROUND: Gene-microbiome interactions are important in aetiology and pathogenesis of inflammatory bowel disease, a chronic inflammatory disorder of the gastrointestinal tract consisting of Crohn's disease and ulcerative colitis. Scarce studies on gene-microbiome interactions show very little overlap in their results. Therefore, it is of utmost importance that gene-microbiome studies are repeated. We aimed to replicate the association between the SLC39A8 [Thr]391 risk allele and gut microbiome composition in patients with inflammatory bowel disease and healthy controls. METHODS: We collected faecal samples, peripheral blood and extensive phenotype data from 291 patients with inflammatory bowel disease and 476 healthy controls. Carrier status information was obtained from whole exome sequencing data, generated using the Illumina HiSeq. The gut microbiome composition was determined by tag-sequencing the 16S rRNA gene. Associations between carrier status and disease were tested using the Wilcoxon-Mann-Whitney test. Associations between carriers and gut microbiome composition were determined using principal coordinate analyses, variance explained, alpha diversity and additive general linear models in inflammatory bowel disease, healthy controls and all groups combined. RESULTS: Crohn's disease patients were more often carriers of the missense variant (21/171, 12.3%) than controls (30/476, 6.3%) (OR = 2.1, P = 0.01). We could not identify associations between carrier status and overall gut microbiome composition and microbial richness in all tested groups after correcting for potential confounding factors. We did identify 37 different operational taxonomical units to be associated with carrier status among the tested groups. Two of these 37 were identified before in the discovery study. CONCLUSIONS: We could confirm the genetic association of the SLC39A8 [Thr]391 risk allele with Crohn's disease but we could only limited replicate the association in gut microbiome composition. Independent replication of gene-microbiome studies is warranted to identify true biological mechanisms.


Assuntos
Bactérias/classificação , Proteínas de Transporte de Cátions/genética , Doença de Crohn/genética , Mutação de Sentido Incorreto , RNA Ribossômico 16S/genética , Análise de Sequência de DNA/métodos , Adulto , Idoso , Bactérias/genética , Bactérias/isolamento & purificação , Estudos de Casos e Controles , DNA Bacteriano/genética , DNA Ribossômico/genética , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Análise de Componente Principal
14.
Gastroenterology ; 156(8): 2254-2265.e3, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30779925

RESUMO

BACKGROUND & AIMS: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. METHODS: We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. RESULTS: We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. CONCLUSIONS: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.


Assuntos
Doença de Crohn/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana/métodos , Adolescente , Fatores Etários , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença de Crohn/sangue , Progressão da Doença , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Inflamação/genética , Masculino , América do Norte , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais
15.
JAMA ; 321(8): 773-785, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30806694

RESUMO

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Metiltransferases/metabolismo , Pirofosfatases/genética , Adolescente , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Grupo com Ancestrais do Continente Europeu , Exoma , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Contagem de Leucócitos , Masculino , Metiltransferases/genética , Metiltransferases/uso terapêutico , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Adulto Jovem
16.
Nat Rev Gastroenterol Hepatol ; 16(5): 296-311, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30787446

RESUMO

The IBDs, Crohn's disease and ulcerative colitis, are chronic inflammatory conditions of the gastrointestinal tract resulting from an aberrant immune response to enteric microbiota in genetically susceptible individuals. Disease presentation and progression within and across IBDs, especially Crohn's disease, are highly heterogeneous in location, severity of inflammation and other phenotypes. Current clinical classifications fail to accurately predict disease course and response to therapies. Genome-wide association studies have identified >240 loci that confer risk of IBD, but the clinical utility of these findings remains unclear, and mechanisms by which the genetic variants contribute to disease are largely unknown. In the past 5 years, the profiling of genome-wide gene expression, epigenomic features and gut microbiota composition in intestinal tissue and faecal samples has uncovered distinct molecular signatures that define IBD subtypes, including within Crohn's disease and ulcerative colitis. In this Review, we summarize studies in both adult and paediatric patients that have identified different IBD subtypes, which in some cases have been associated with distinct clinical phenotypes. We posit that genome-scale molecular phenotyping in large cohorts holds great promise not only to further our understanding of the diverse molecular causes of IBD but also for improving clinical trial design to develop more personalized disease management and treatment.


Assuntos
Colite Ulcerativa/diagnóstico , Colite Ulcerativa/genética , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Predisposição Genética para Doença , Fenótipo , Adulto , Criança , Colite Ulcerativa/classificação , Colite Ulcerativa/terapia , Doença de Crohn/classificação , Doença de Crohn/terapia , Marcadores Genéticos , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Medicina de Precisão
17.
Dig Dis ; 37(4): 284-290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799399

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) patients are reported to have lower bone density compared to healthy controls. There is limited consensus regarding factors affecting bone density among these patients. Our aim, therefore, was to determine clinical and genetic variables that contribute to lower bone mineral density (BMD) in IBD patients. METHODS: A cross-sectional study of IBD patients treated in a tertiary referral center was performed. Epidemiological and clinical data were collected, and genetic testing for the common mutations in Nucleotide-binding Oligomerization Domain-containing protein (NOD)2 was performed. We examined correlations between the different variables and BMD in the total hip, femoral neck, and lumbar spine. RESULTS: Eighty-nine patients (49% males, 67 Crohn's disease [CD]) participated in the study. 42Forty-two (63%) of the CD and 13 (59%) of the ulcerative colitis patients met the criteria for osteoporosis/osteopenia. Factors associated with lower Z scores were low body mass index (BMI; r = -0.307, p = 0.005), use of glucocorticoids (likelihood ratio [LR] 5.1, p = 0.028), and a trend for male gender (LR = 3.4, p = 0.079). Among CD patients, low bone density showed borderline significance for association with gastrointestinal surgery (LR = 4.1, p = 0.07) and smoking (LR = 3.58, p = 0.06). Low levels of 25OHD were not associated with low BMD, nor were mutations in NOD2. No increased rate of fractures was seen among patients with osteopenia or osteoporosis. CONCLUSION: In addition to the generally accepted risk factors for osteoporosis (glucocorticoids, low BMI, smoking), male IBD patients had a trend toward lower BMD. Carrying a mutaticon in NOD2 did not confer a risk for bone loss.


Assuntos
Índice de Massa Corporal , Densidade Óssea/fisiologia , Glucocorticoides/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/fisiopatologia , Fumar/efeitos adversos , Adulto , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/fisiopatologia , Colite Ulcerativa/complicações , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Colite Ulcerativa/fisiopatologia , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Doença de Crohn/fisiopatologia , Estudos Transversais , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Osteoporose/complicações , Osteoporose/fisiopatologia , Fatores de Risco
18.
Int J Mol Sci ; 20(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769939

RESUMO

The NOD2 gene, involved in innate immune responses to bacterial peptidoglycan, has been found to be closely associated with Crohn's Disease (CD), with an Odds Ratio ranging from 3⁻36. Families with three or more CD-affected members were related to a high frequency of NOD2 gene variations, such as R702W, G908R, and 1007fs, and were reported in the EPIMAD Registry. However, some rare CD multiplex families were described without identification of common NOD2 linked-to-disease variations. In order to identify new genetic variation(s) closely linked with CD, whole exome sequencing was performed on available subjects, comprising four patients in two generations affected with Crohn's disease without R702W and G908R variation and three unaffected related subjects. A rare and, not yet, reported missense variation of the NOD2 gene, N1010K, was detected and co-segregated across affected patients. In silico evaluation and modelling highlighted evidence for an adverse effect of the N1010K variation with regard to CD. Moreover, cumulative characterization of N1010K and 1007fs as a compound heterozygous state in two, more severe CD family members strongly suggests that N1010K could well be a new risk factor involved in Crohn's disease genetic susceptibility.


Assuntos
Doença de Crohn/genética , Predisposição Genética para Doença , Imunidade Inata/genética , Proteína Adaptadora de Sinalização NOD2/genética , Adolescente , Adulto , Alelos , Criança , Doença de Crohn/imunologia , Doença de Crohn/patologia , Feminino , Estudos de Associação Genética , Genótipo , Heterozigoto , Humanos , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Proteína Adaptadora de Sinalização NOD2/química , Proteína Adaptadora de Sinalização NOD2/imunologia , Peptidoglicano/imunologia , Polimorfismo de Nucleotídeo Único , Conformação Proteica , Sequenciamento Completo do Exoma
19.
Orv Hetil ; 160(5): 179-185, 2019 Feb.
Artigo em Húngaro | MEDLINE | ID: mdl-30686035

RESUMO

INTRODUCTION: Genetic polymorphism of thiopurine S-methyltransferase, the key enzyme in metabolism of thiopurines (azathioprine and 6-mercaptopurine) used in the treatment of inflammatory bowel disease, results in different enzyme activities. Decreased enzyme activity causes myelosuppression whereas abnormally high activity results in hepatotoxicity at standard thiopurine doses. Four allele variants (TMPT*2, TMPT*3A, TPMT*3B and TPMT*3C) account for decreased activity in more than 95% of cases. AIM: To evaluate the frequency of severe side effects, such as myelosuppression and hepatotoxicity, at standard or decreased azathioprine doses in children with inflammatory bowel disease who do not exhibit any of the four most common variant alleles. METHOD: Retrospective analysis of children with inflammatory bowel disease treated with azathioprine at a single tertiary referral center. RESULTS: 51 patients were identified (44: Crohn's disease, 7: ulcerative colitis; male ratio: 28/51; mean age at diagnosis: 12.4 years). Two patients discontinued azathioprine arbitrarily whereas in one patient it was stopped due to serious pancreatitis and in another one because of severe flu-like symptoms. None of the remaining 47 patients exhibited hepatotoxicity suggesting abnormally high thiopurine S-methyltransferase activity. Four patients (8.5%) had profound myelosuppression on less than 1 mg/kg/day azathioprine requiring discontinuation of the drug, and all of them showed complete bone marrow recovery subsequently. No myelosuppression occurred in the remaining 43 patients on 2.17 ± 0.31 mg/kg/day (mean ± SD) azathioprine treatment. CONCLUSIONS: Regular blood tests are necessary on thiopurine therapy despite normal thiopurine S-methyltransferase genotype because of the risk of myelosuppression. The four most common variant alleles were identified in routine genotyping only, therefore most likely rare variant allele(s) or polymorphism of other enzymes involved in thiopurine metabolism account for the aforementioned four cases with profound bone marrow suppression. Thiopurine metabolite monitoring is the key for individualized treatment when optimal dosing can be achieved with the least side effects. Orv Hetil. 2019; 160(5): 179-185.


Assuntos
Doenças Inflamatórias Intestinais/genética , Metiltransferases/genética , Polimorfismo Genético , Adolescente , Criança , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Doença de Crohn/genética , Feminino , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino
20.
Am J Med Sci ; 357(2): 134-142, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30665494

RESUMO

BACKGROUND: The aim of this study was to investigate the association of intestinal mucosa long noncoding RNA (lncRNA) antisense noncoding RNA in the INK4 locus (ANRIL) expression with disease risk, activity and inflammatory cytokines levels of Crohn's disease (CD). METHODS: Forty-two patients with active CD (A-CD), 59 patients with CD in remission (R-CD) and 67 controls were consecutively recruited. Intestinal mucosa samples were collected from all participants at baseline and from A-CD patients at 3-months after infliximab treatment. LncRNA ANRIL level, mRNA expression of tumor necrosis factor-α, interleukin (IL)-10, IL-17, IL-23 and interferon gamma were assessed by quantitative polymerase chain reaction. C-reactive protein, erythrocyte sedimentation rate and Crohn's disease activity index were used to evaluate the disease activity of CD. RESULTS: LncRNA ANRIL expression was decreased in patients with A-CD compared with patients with R-CD (P < 0.001) and controls (P < 0.001) and was also reduced in patients with R-CD compared with controls (P < 0.001). Receiver operating characteristic curves showed that lncRNA ANRIL expression distinguished CD, A-CD and R-CD from controls, as well as A-CD from R-CD. Additionally, lncRNA ANRIL expression was negatively associated with Crohn's disease activity index (P = 0.002), C-reactive protein (P < 0.001) and erythrocyte sedimentation rate (P = 0.001), and associated with tumor necrosis factor-α (P < 0.001), IL-17 (P < 0.001) and interferon gamma messenger RNA levels (P = 0.004) but positively associated with IL-10 messenger RNA level (P = 0.002). Furthermore, IncRNA ANRIL expression was increased after infliximab treatment compared with baseline in patients with A-CD that responded to treatment (P < 0.001) but remained stable in patients with A-CD that did not respond (P = 0.897). CONCLUSIONS: lncRNA ANRIL downregulation in intestinal mucosa correlates with increased disease risk, higher disease activity and elevated proinflammatory cytokines levels, and its change associates with infliximab treatment response in patients with CD.


Assuntos
Doença de Crohn/epidemiologia , Citocinas/metabolismo , Infliximab/uso terapêutico , Mucosa Intestinal/metabolismo , RNA Longo não Codificante/genética , Adulto , China , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Doença de Crohn/imunologia , Feminino , Humanos , Inflamação/etiologia , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , Fatores de Risco , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA