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1.
Toxins (Basel) ; 13(8)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34437440

RESUMO

Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and its incidence is correlated with infections, chronic inflammation, diet, and genetic factors. An emerging aspect is that microbial dysbiosis and chronic infections triggered by certain bacteria can be risk factors for tumor progression. Recent data suggest that certain bacterial toxins implicated in DNA attack or in proliferation, replication, and death can be risk factors for insurgence and progression of CRC. In this study, we recruited more than 300 biopsy specimens from people undergoing colonoscopy, and we analyzed to determine whether a correlation exists between the presence of bacterial genes coding for toxins possibly involved in CRC onset and progression and the different stages of CRC. We also analyzed to determine whether CRC-predisposing genetic factors could contribute to bacterial toxins response. Our results showed that CIF toxin is associated with polyps or adenomas, whereas pks+ seems to be a predisposing factor for CRC. Toxins from Escherichia coli as a whole have a higher incidence rate in adenocarcinoma patients compared to controls, whereas Bacteroides fragilis toxin does not seem to be associated with pre-cancerous nor with cancerous lesions. These results have been obtained irrespectively of the presence of CRC-risk loci.

2.
Neurogastroenterol Motil ; : e14236, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34378841

RESUMO

BACKGROUND: Functional dyspepsia (FD) is a common gastrointestinal condition of poorly understood pathophysiology. While symptoms' overlap with other conditions may indicate common pathogenetic mechanisms, genetic predisposition is suspected but has not been adequately investigated. METHODS: Using healthcare, questionnaire, and genetic data from three large population-based biobanks (UK Biobank, EGCUT, and MGI), we surveyed FD comorbidities, heritability, and genetic correlations across a wide spectrum of conditions and traits in 10,078 cases and 351,282 non-FD controls of European ancestry. KEY RESULTS: In UK Biobank, 281 diagnoses were detected at increased prevalence in FD, based on healthcare records. Among these, gastrointestinal conditions (OR = 4.0, p < 1.0 × 10-300 ), anxiety disorders (OR = 2.3, p < 1.4 × 10-27 ), ischemic heart disease (OR = 2.2, p < 2.3 × 10-76 ), and infectious and parasitic diseases (OR = 2.1, p = 1.5 × 10-73 ) showed strongest association with FD. Similar results were obtained in an analysis of self-reported conditions and use of medications from questionnaire data. Based on a genome-wide association meta-analysis of genotypes across all cohorts, FD heritability was estimated close to 5% ( h SNP 2  = 0.047, p = 0.014). Genetic correlations indicate FD predisposition is shared with several other diseases and traits (rg  > 0.344), mostly overlapping with those also enriched in FD patients. Suggestive (p < 5.0 × 10-6 ) association with FD risk was detected for 13 loci, with 2 showing nominal replication (p < 0.05) in an independent cohort of 192 FD patients. CONCLUSIONS & INFERENCES: FD has a weak heritable component that shows commonalities with multiple conditions across a wide spectrum of pathophysiological domains. This new knowledge contributes to a better understanding of FD etiology and may have implications for improving its treatment.

3.
Nutrients ; 12(8)2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32784647

RESUMO

Epidemiologic studies have revealed inconsistent evidence of gene-diet interaction in relation to colorectal cancer (CRC). The aim of this study was to analyze them in a sample of cases and controls from the population-based bowel cancer screening program of the Osakidetza/Basque Health Service. This study analyzed dietetic, genetic, demographic, socioeconomic factors and lifestyles. In the present manuscript, the survey design, sampling, instruments, measurements and related quality management were presented. Moreover, we analyze differences between cases and controls in some data, especially those related to diet. The participants were 308 cases and 308 age- and sex-matched subjects as controls. Cases were more likely than controls to have overweight/obesity (67.5% vs. 58.1%, p < 0.05), a lower intake of vitamin B2 (0.86 ± 0.23 vs. 0.92 ± 0.23 mg/1000 kcal, p < 0.01) and calcium:phosphorus ratio (0.62 ± 0.12 vs. 0.65 ± 0.13, p < 0.01). A higher proportion of cases than controls did not meet the Nutritional Objectives for saturated fatty acids (85.7% vs. 67.5%, p < 0.001) or cholesterol (35.4% vs. 25.0%, p < 0.01). In conclusion, the present study provides valuable data for analyzing the complexity of gene-diet interaction in relation to CRC. The results presented here suggest that overweight/obesity and a high intake of certain dietary components, especially saturated fatty acids and cholesterol, are more frequent in cases than in controls.


Assuntos
Neoplasias Colorretais/epidemiologia , Dieta/estatística & dados numéricos , Detecção Precoce de Câncer/estatística & dados numéricos , Predisposição Genética para Doença/epidemiologia , Estado Nutricional/genética , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Dieta/efeitos adversos , Inquéritos sobre Dietas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos , Espanha/epidemiologia
4.
World J Gastroenterol ; 26(28): 4108-4125, 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32821073

RESUMO

BACKGROUND: The results obtained to date concerning food groups, diet quality and colorectal cancer (CRC) risk vary according to criteria used and the study populations. AIM: To study the relationships between food groups, diet quality and CRC risk, in an adult population of the Basque Country (North of Spain). METHODS: This observational study included 308 patients diagnosed with CRC and 308 age- and sex-matched subjects as controls. During recruitment, dietary, anthropometric, lifestyle, socioeconomic, demographic and health status information was collected. Adherence to the dietary recommendations was evaluated utilizing the Healthy Eating Index for the Spanish Diet and the MedDietScore. Conditional logistic regressions were used to evaluate the associations of food group intakes, diet quality scores, categorized in tertiles, with CRC risk. RESULTS: The adjusted models for potential confounding factors showed a direct association between milk and dairy products consumption, in particular high-fat cheeses [odds ratio (OR) third tertile vs first tertile = 1.87, 95% confidence intervals (CI): 1.11-3.16], and CRC risk. While the consumption of fiber-containing foods, especially whole grains (OR third tertile vs first tertile = 0.62, 95%CI: 0.39-0.98), and fatty fish (OR third tertile vs first tertile = 0.53, 95%CI: 0.27-0.99) was associated with a lower risk for CRC. Moreover, higher MD adherence was associated with a reduced CRC risk in adjusted models (OR third tertile vs first tertile = 0.40, 95%CI: 0.20-0.80). CONCLUSION: Direct associations were found for high-fat cheese, whereas an inverse relation was reported for fiber-containing foods and fatty fish, as well as adherence to a Mediterranean dietary pattern.


Assuntos
Neoplasias Colorretais , Dieta , Adulto , Animais , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Dieta/efeitos adversos , Fibras na Dieta , Humanos , Fatores de Risco , Espanha/epidemiologia
5.
Nutrients ; 12(5)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32423041

RESUMO

Celiac disease (CeD) is a complex immune-mediated inflammatory condition triggered by the ingestion of gluten in genetically predisposed individuals. Literature suggests that alterations in gut microbiota composition and function precede the onset of CeD. Considering that microbiota is partly determined by host genetics, we speculated that the genetic makeup of CeD patients could elicit disease development through alterations in the intestinal microbiota. To evaluate potential causal relationships between gut microbiota and CeD, we performed a two-sample Mendelian randomization analysis (2SMR). Exposure data were obtained from the raw results of a previous genome-wide association study (GWAS) of gut microbiota and outcome data from summary statistics of CeD GWAS and Immunochip studies. We identified a number of putative associations between gut microbiota single nucleotide polymorphisms (SNPs) associated with CeD. Regarding bacterial composition, most of the associated SNPs were related to Firmicutes phylum, whose relative abundance has been previously reported to be altered in CeD patients. In terms of functional units, we linked a number of SNPs to several bacterial metabolic pathways that seemed to be related to CeD. Overall, this study represented the first 2SMR approach to elucidate the relationship between microbiome and CeD.


Assuntos
Doença Celíaca/genética , Doença Celíaca/microbiologia , Microbioma Gastrointestinal/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética
6.
Sci Rep ; 9(1): 1298, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718669

RESUMO

The Human Leucocyte Antigen (HLA) locus and other DNA sequence variants identified in Genome-Wide Association (GWA) studies explain around 50% of the heritability of celiac disease (CD). However, the pathogenesis of CD could be driven by other layers of genomic information independent from sequence variation, such as DNA methylation, and it is possible that allele-specific methylation explains part of the SNP associations. Since the DNA methylation landscape is expected to be different among cell types, we analyzed the methylome of the epithelial and immune cell populations of duodenal biopsies in CD patients and controls separately. We found a cell type-specific methylation signature that includes genes mapping to the HLA region, namely TAP1 and HLA-B. We also performed Immunochip SNP genotyping of the same samples and interrogated the expression of some of the affected genes. Our analysis revealed that the epithelial methylome is characterized by the loss of CpG island (CGI) boundaries, often associated to altered gene expression, and by the increased variability of the methylation across the samples. The overlap between differentially methylated positions (DMPs) and CD-associated SNPs or variants contributing to methylation quantitative trait loci (mQTLs) is minimal. In contrast, there is a notable enrichment of mQTLs among the most significant CD-associated SNPs. Our results support the notion that DNA methylation alterations constitute a genotype-independent event and confirm its role in the HLA region (apart from the well-known, DQ allele-specific effect). Finally, we find that a fraction of the CD-associated variants could exert its phenotypic effect through DNA methylation.


Assuntos
Doença Celíaca/etiologia , Metilação de DNA , Epigenoma , Genótipo , Antígenos HLA/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Biópsia , Doença Celíaca/metabolismo , Doença Celíaca/patologia , Ilhas de CpG , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Antígenos HLA/imunologia , Humanos , Mucosa Intestinal/patologia , Masculino , Regiões Promotoras Genéticas
7.
Front Nutr ; 6: 187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31921880

RESUMO

Celiac disease (CD) patients present a loss of intestinal barrier function due to structural alterations in the tight junction (TJ) network, the most apical unions between epithelial cells. The association of TJ-related gene variants points to an implication of this network in disease susceptibility. This work aims to characterize the functional implication of TJ-related, disease-associated loci in CD pathogenesis. We performed an association study of 8 TJ-related gene variants in a cohort of 270 CD and 91 non-CD controls. The expression level of transcripts located in the associated SNP region was analyzed by RT-PCR in several human tissues and in duodenal biopsies of celiac patients and non-CD controls. (si)RNA-driven silencing combined with gliadin in the Caco2 intestinal cell line was used to analyze the implication of transcripts from the associated region in the regulation of TJ genes. We replicated the association of rs6962966*A variant [p = 0.0029; OR = 1.88 (95%1.24-2.87)], located in an intron of TJ-related MAGI2 coding gene and upstream of RP4-587D13.2 transcript, bioinformatically classified as a long non-coding RNA (lncRNA). The expression of both genes is correlated and constitutively downregulated in CD intestine. Silencing of lncRNA decreases the levels of MAGI2 protein. At the same time, silencing of MAGI2 affects the expression of several TJ-related genes. The associated region is functionally altered in disease, probably affecting CD-related TJ genes.

8.
Genes (Basel) ; 9(5)2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29748492

RESUMO

The aim of this study was to construct celiac co-expression patterns at a whole genome level and to identify transcription factors (TFs) that could drive the gliadin-related changes in coordination of gene expression observed in celiac disease (CD). Differential co-expression modules were identified in the acute and chronic responses to gliadin using expression data from a previous microarray study in duodenal biopsies. Transcription factor binding site (TFBS) and Gene Ontology (GO) annotation enrichment analyses were performed in differentially co-expressed genes (DCGs) and selection of candidate regulators was performed. Expression of candidates was measured in clinical samples and the activation of the TFs was further characterized in C2BBe1 cells upon gliadin challenge. Enrichment analyses of the DCGs identified 10 TFs and five were selected for further investigation. Expression changes related to active CD were detected in four TFs, as well as in several of their in silico predicted targets. The activation of TFs was further characterized in C2BBe1 cells upon gliadin challenge, and an increase in nuclear translocation of CAMP Responsive Element Binding Protein 1 (CREB1) and IFN regulatory factor-1 (IRF1) in response to gliadin was observed. Using transcriptome-wide co-expression analyses we are able to propose novel genes involved in CD pathogenesis that respond upon gliadin stimulation, also in non-celiac models.

9.
Gastroenterology ; 155(1): 168-179, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29626450

RESUMO

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.


Assuntos
Cromossomos Humanos Par 9/genética , Constipação Intestinal/genética , Síndrome do Intestino Irritável/genética , Menarca/genética , Adulto , Idoso , Constipação Intestinal/etiologia , Constipação Intestinal/fisiopatologia , Europa (Continente) , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Autorrelato , Fatores Sexuais , Suécia , Estados Unidos
10.
J Pediatr Gastroenterol Nutr ; 67(2): 225-231, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29601440

RESUMO

OBJECTIVE: The aim of the study is to identify additional celiac disease associated loci in the major histocompatibility complex (MHC) independent from classical HLA risk alleles (HLA-DR3-DQ2) and to characterize their potential functional impact in celiac disease pathogenesis at the intestinal level. METHODS: We performed a high-resolution single-nucleotide polymorphism (SNP) genotyping of the MHC region, comparing HLA-DR3 homozygous celiac patients and non-celiac controls carrying a single copy of the B8-DR3-DQ2 conserved extended haplotype. Expression level of potential novel risk genes was determined by RT-PCR in intestinal biopsies and in intestinal and immune cells isolated from control and celiac individuals. Small interfering RNA-driven silencing of selected genes was performed in the intestinal cell line T84. RESULTS: MHC genotyping revealed 2 associated SNPs, one located in TRIM27 gene and another in the non-coding gene HCG14. After stratification analysis, only HCG14 showed significant association independent from HLA-DR-DQ loci. Expression of HCG14 was slightly downregulated in epithelial cells isolated from duodenal biopsies of celiac patients, and eQTL analysis revealed that polymorphisms in HCG14 region were associated with decreased NOD1 expression in duodenal intestinal cells. CONCLUSIONS: We have successfully employed a conserved extended haplotype-matching strategy and identified a novel additional celiac disease risk variant in the lncRNA HCG14. This lncRNA seems to regulate the expression of NOD1 in an allele-specific manner. Further functional studies are needed to clarify the role of HCG14 in the regulation of gene expression and to determine the molecular mechanisms by which the risk variant in HCG14 contributes to celiac disease pathogenesis.


Assuntos
Doença Celíaca/genética , Predisposição Genética para Doença , Antígeno HLA-DR3/genética , Proteína Adaptadora de Sinalização NOD1/metabolismo , RNA Longo não Codificante/genética , Estudos de Casos e Controles , Doença Celíaca/metabolismo , Doença Celíaca/patologia , Criança , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único
11.
Clin Gastroenterol Hepatol ; 16(10): 1673-1676, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29408290

RESUMO

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).


Assuntos
Frequência do Gene , Genótipo , Síndrome do Intestino Irritável/genética , Síndrome do Intestino Irritável/patologia , Complexo Sacarase-Isomaltase/deficiência , Humanos , Prevalência
12.
J Immunol ; 199(2): 581-588, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28626066

RESUMO

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of inflammation. To further understand the interaction between inflammatory signaling pathways and lncRNAs, we characterized the function of cardiac and apoptosis-related lncRNA (Carlr), an lncRNA expressed in both mouse and human cells of diverse tissues. Carlr expression is increased following NF-κB signaling in macrophages, with concomitant translocation to, and enrichment of, the transcript in the cytoplasm. Knockdown of Carlr results in impaired expression of NF-κB pathway genes and influences the interaction between macrophages and intestinal cells in an inflammatory environment. In human celiac disease patient samples, increased levels of the Carlr transcript were detected in the cytoplasm, alongside elevated expression of NF-κB pathway genes. These findings suggest that increased Carlr expression and/or cytoplasmic localization is required for efficient NF-κB signaling and is associated with the inflamed tissue state observed in human celiac disease.


Assuntos
Citoplasma/genética , Regulação da Expressão Gênica , NF-kappa B/genética , NF-kappa B/metabolismo , RNA Longo não Codificante/genética , Animais , Apoptose , Doença Celíaca/imunologia , Doença Celíaca/metabolismo , Citoplasma/imunologia , Citoplasma/metabolismo , Expressão Gênica , Humanos , Inflamação , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , NF-kappa B/imunologia , Fosforilação , Transdução de Sinais
13.
Diabetes ; 66(4): 1022-1029, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28073828

RESUMO

Neonatal diabetes mellitus (NDM) is a rare form of diabetes diagnosed within the first 6 months of life. Genetic studies have allowed the identification of several genes linked to the development of NDM; however, genetic causes for ∼20% of the cases remain to be clarified. Most cases of NDM involve isolated diabetes, but sometimes NDM appears in association with other pathological conditions, including autoimmune diseases. Recent reports have linked activating mutations in STAT3 with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact of STAT3-activating mutations have not been characterized at the pancreatic ß-cell level. By using whole-exome sequencing, we identified a novel missense mutation in the binding domain of the STAT3 protein in a patient with NDM. The functional analyses showed that the mutation results in an aberrant activation of STAT3, leading to deleterious downstream effects in pancreatic ß-cells. The identified mutation leads to hyperinhibition of the transcription factor Isl-1 and, consequently, to a decrease in insulin expression. These findings represent the first functional indication of a direct link between an NDM-linked activating mutation in STAT3 and pancreatic ß-cell dysfunction.


Assuntos
Hipotireoidismo Congênito/genética , Diabetes Mellitus/genética , Células Secretoras de Insulina/metabolismo , Insulina/biossíntese , Fator de Transcrição STAT3/genética , Animais , Western Blotting , Linhagem Celular , Imunoprecipitação da Cromatina , Colite Colagenosa/complicações , Hipotireoidismo Congênito/complicações , Feminino , Humanos , Recém-Nascido , Proteínas com Homeodomínio LIM/metabolismo , Mutação , Mutação de Sentido Incorreto , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Fatores de Transcrição/metabolismo , Transfecção
14.
Eur J Hum Genet ; 24(12): 1831-1834, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27650971

RESUMO

To identify candidate genes in celiac disease (CD), we reanalyzed the whole Immunochip CD cohort using a different approach that clusters individuals based on immunoancestry prior to disease association analysis, rather than by geographical origin. We detected 636 new associated SNPs (P<7.02 × 10-07) and identified 5 novel genomic regions, extended 8 others previously identified and also detected 18 isolated signals defined by one or very few significant SNPs. To test whether we could identify putative candidate genes, we performed expression analyses of several genes from the top novel region (chr2:134533564-136169524), from a previously identified locus that is now extended, and a gene marked by an isolated SNP, in duodenum biopsies of active and treated CD patients, and non-celiac controls. In the largest novel region, CCNT2 and R3HDM1 were constitutively underexpressed in disease, even after gluten removal. Moreover, several genes within this region were coexpressed in patients, but not in controls. Other novel genes like KIF21B, REL and SORD also showed altered expression in active disease. Apart from the identification of novel CD loci, these results suggest that ancestry-based stratified analysis is an efficient strategy for association studies in complex diseases.


Assuntos
Doença Celíaca/genética , Loci Gênicos , Linhagem , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Doença Celíaca/metabolismo , Duodeno/metabolismo , Glutens/metabolismo , Humanos
15.
PLoS One ; 11(5): e0155603, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27176223

RESUMO

Endogenous retroviruses (ERVs) are proviral phases of exogenous retroviruses that have co-evolved with vertebrate genomes for millions of years. Previous studies have identified the envelope (env) protein genes of retroviral origin preferentially expressed in the placenta which suggests a role in placentation based on their membrane fusogenic capacity and therefore they have been named syncytins. Until now, all the characterized syncytins have been associated with three invasive placentation types: the endotheliochorial (Carnivora), the synepitheliochorial (Ruminantia), and the hemochorial placentation (human, mouse) where they play a role in the syncytiotrophoblast formation. The purpose of the present study was to evaluate whether EqERV env RNA is expressed in horse tissues as well and investigate if the horse, possessing an epitheliochorial placenta, has "captured" a common retroviral env gene with syncytin-like properties in placental tissues. Interestingly, although in the equine placenta there is no syncytiotrophoblast layer at the maternal-fetal interface, our results showed that EqERV env RNA is highly expressed at that level, as expected for a candidate syncytin-like gene but with reduced abundance in the other somatic tissues (nearly 30-fold lower) thus suggesting a possible role in the placental tissue. Although the horse is one of the few domestic animals with a sequenced genome, few studies have been conducted about the EqERV and their expression in placental tissue has never been investigated.


Assuntos
Retrovirus Endógenos/genética , Feto/virologia , Genes env , Cavalos/virologia , Placenta/virologia , Proteínas do Envelope Viral/genética , Animais , Feminino , Regulação Viral da Expressão Gênica , Gravidez , RNA Viral/genética , RNA Viral/metabolismo
16.
Virology ; 494: 119-28, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27107945

RESUMO

Endogenous retroviruses (ERVs) are remnants of retroviral infections that are present in a large number of vertebrate genomes. Based on the proposal that the rat could act as a reservoir of retroviruses, rat ERVs were analysed in silico using a whole-genome approach. To enrich the detected ERV groups, we applied an upgraded approach based on the hidden Markov model. We found 2637 elements that were classified into the following groups: 9 groups of Class I; 15 of Class II, 7 of them previously described; 1 of Class III; and 3 groups whose classification was unclear but were distantly related to Class I. Sixteen ERV groups seemed to be specific to rat. The high number of rat-specific groups might be related to the contact of rats with retroviruses and their role as a reservoir. In addition, the env gene of the more extended groups seemed to be undetectable.


Assuntos
Retrovirus Endógenos/genética , Genoma Viral , Estudo de Associação Genômica Ampla , Genômica , Animais , Mapeamento Cromossômico , Biologia Computacional , Retrovirus Endógenos/classificação , Evolução Molecular , Variação Genética , Genômica/métodos , Mamíferos , Camundongos , Anotação de Sequência Molecular , Filogenia , Polimorfismo de Nucleotídeo Único , Ratos , Sequências Repetidas Terminais
18.
PLoS One ; 10(9): e0135983, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26379185

RESUMO

While most patients affected by the influenza A(H1N1) pandemic experienced mild symptoms, a small fraction required hospitalization, often without concomitant factors that could explain such a severe course. We hypothesize that host genetic factors could contribute to aggravate the disease. To test this hypothesis, we compared the allele frequencies of 547,296 genome-wide single nucleotide polymorphisms (SNPs) between 49 severe and 107 mild confirmed influenza A cases, as well as against a general population sample of 549 individuals. When comparing severe vs. mild influenza A cases, only one SNP was close to the conventional p = 5×10-8. This SNP, rs28454025, sits in an intron of the GSK233 gene, which is involved in a neural development, but seems not to have any connections with immunological or inflammatory functions. Indirectly, a previous association reported with CD55 was replicated. Although sample sizes are low, we show that the statistical power in our design was sufficient to detect highly-penetrant, quasi-Mendelian genetic factors. Hence, and assuming that rs28454025 is likely to be a false positive, no major genetic factor was detected that could explain poor influenza A course.


Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/genética , Feminino , Frequência do Gene , Genômica , Genótipo , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Masculino , Polimorfismo de Nucleotídeo Único , RNA Viral/genética , Fatores de Risco , Índice de Gravidade de Doença
19.
Mol Immunol ; 63(2): 505-12, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25458311

RESUMO

The major histocompatibility complex (MHC)-containing genes are among the most polymorphic in vertebrates. MHC genes code for proteins that are critical in the immune system response. In this study, the polymorphism of the second exon of the MHC class II DRB gene was characterized in the Eastern woodchuck (Marmota monax). Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) represent the best available animal model for the study of chronic hepatitis B infection in humans. In the genotyped animals we found fifteen alleles, which were expressed in two independent loci and that were named DRB1A and DRB1B in this work. The 15 alleles investigated showed an elevated divergence. A significant excess of non-synonymous substitutions was detected, which could indicate that a historical positive selection is acting in the woodchuck DRB1 genes. This hypothesis was confirmed in our study by the high variability in or near the antigen binding sites (ABS) and by the results obtained in sequence variability analyses. This analysis identified the presence of a microsatellite sequence that is located at the start of the second intron, which could further allow the development of a fast and cheap semiautomatic sequencing method.


Assuntos
Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Hepatite B/imunologia , Hepatite B/virologia , Complexo Principal de Histocompatibilidade/genética , Alelos , Sequência de Aminoácidos , Animais , Clonagem Molecular , Primers do DNA/metabolismo , Modelos Animais de Doenças , Genótipo , Cadeias HLA-DRB1/química , Hepatite B/genética , Vírus da Hepatite B da Marmota/fisiologia , Humanos , Marmota , Dados de Sequência Molecular , Filogenia , Alinhamento de Sequência , Análise de Sequência de DNA
20.
Curr Genomics ; 15(4): 256-65, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25132796

RESUMO

Endogenous retroviruses (ERVs) are genomic elements that are present in a wide range of vertebrates. Although the study of ERVs has been carried out mainly in humans and model organisms, recently, domestic animals have become important, and some species have begun to be analyzed to gain further insight into ERVs. Due to the availability of complete genomes and the development of new computer tools, ERVs can now be analyzed from a genome-wide viewpoint. In addition, more experimental work is being carried out to analyze the distribution, expression and interplay of ERVs within a host genome. Cats, cattle, chicken, dogs, horses, pigs and sheep have been scrutinized in this manner, all of which are interesting species in health and economic terms. Furthermore, several studies have noted differences in the number of endogenous retroviruses and in the variability of these elements among different breeds, as well as their expression in different tissues and the effects of their locations, which, in some cases, are near genes. These findings suggest a complex, intriguing relationship between ERVs and host genomes. In this review, we summarize the most important in silico and experimental findings, discuss their implications and attempt to predict future directions for the study of these genomic elements.

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