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OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications, but their use can be associated with a number of adverse reactions, including upper gastrointestinal lesions. The aim of the study was to identify clinical and pharmacogenetic factors associated with upper gastrointestinal lesions, including those linked to NSAIDs, in patients at a multidisciplinary hospital. METHODS: The study included 92 patients (mean age 59.4±16.5 years; 47 women), who underwent esophagogastroduodenoscopy during inpatient treatment. Patients' intake of NSAIDs and gastroprotectors during the year before hospitalization was considered. Demographic, clinical, laboratory data of patients were compared between groups, including genotyping for CYP2C9*2 rs179985, CYP2C9*3 rs1057910, CYP2C8*3 rs11572080, CYP2C8*3 rs10509681, PTGS-1 rs10306135, PTGS-1 rs12353214, and PTGS-2 rs20417 using real-time PCR. RESULTS: In NSAIDs+ patients, PTGS1 rs10306135 AT+TT genotypes increased the chance of developing gastrointestinal complications by 5.4 times (95â¯% CI=1.30-22.27). In total sample, smoking (OR=3.12, 95â¯% CI=1.15-8.46), and alcohol intake (OR=4.09, 95â¯% CI=1.05-15.87) increased odds of gastrointestinal damage. In NSAIDs+ patients omeprazole, famotidine and both famotidine and omeprazole during the last year were as ineffective as not taking gastroprotectors; in total sample famotidine (OR=0.19, 95â¯% CI=0.04-0.93) and two gastroprotectors (OR=0.13, 95â¯% CI=0.02-0.75) reduced the chance of upper gastrointestinal lesions. CONCLUSIONS: Pharmacogenetic features of patients may significantly contribute to the development NSAIDs-induced upper gastrointestinal injuries.
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Anti-Inflamatórios não Esteroides , Gastroenteropatias , Humanos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/genética , Adulto , Genótipo , Citocromo P-450 CYP2C9/genética , Trato Gastrointestinal Superior/efeitos dos fármacos , Trato Gastrointestinal Superior/patologia , Farmacogenética , Endoscopia do Sistema Digestório , Citocromo P-450 CYP2C8/genética , Ciclo-Oxigenase 1RESUMO
Mendelian randomization method is a powerful tool in epidemiological research. The core idea is to use genetic variation as a tool to assess the causal relationship between risk factors and specific diseases. Confounding factors are important interference factors for causal inference in epidemiological studies, and genetic variation in Mendelian randomization studies follows the principle of random distribution of alleles to offspring, which is similar to randomized controlled trials. Mendel 's randomization method can effectively avoid the confounding factors, reverse causality in observational studies and the representativeness and feasibility of randomized controlled trials. Previous observational studies have reported a relationship between negative emotions and upper gastrointestinal disease. However, whether this relationship is causal remains unclear. We aimed to evaluate the causal relationship between negative emotions and upper gastrointestinal diseases using two-sample Mendelian randomization (MR). Three sets of genetic instruments from the database were obtained for analysis, including 12 anxiety-related single nucleotide polymorphisms (SNPs), 46 depression-related SNPs, and 58 nervous-related SNPs. SNPs were filtered using the Phenoscanner website, and the inverse variance weighted method, weighted median method, MR-Egger regression, MR pleiotropy residual sum, and outlier test were used for analysis. In inverse variance weighted analysis, anxiety and depression had an effect on gastroduodenal ulcer (p = 2.849×10-3, ß = 4.908, 95% CI = 1.684-8.132; and p = 6.457×10-4, ß = 1.767, 95% CI = 0.752-2.782, respectively). Additionally, depression had an effect on diseases of the esophagus, stomach, and duodenum (p = 3.498×10-5, ß = 0.926, 95% CI = 0.487-1.364). Cochran's Q-derived p-values were 0.457, 0.603, and 0.643, and MR-Egger intercept-derived p-values were 0.697, 0.294, and 0.362, respectively. Here, we show that anxiety and depression have a causal relationship with gastroduodenal ulcers, and depression has a causal relationship with diseases of the esophagus, stomach, and duodenum.
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Emoções , Gastroenteropatias , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Gastroenteropatias/psicologia , Gastroenteropatias/genética , Depressão/genética , Ansiedade , Predisposição Genética para DoençaRESUMO
Infections with gastrointestinal nematodes (GINs) reduce the economic efficiency of sheep operations and compromise animal welfare. Understanding the host's response to GIN infection can help producers identify animals that are naturally resistant to infection. The objective of this study was to characterize the hepatic transcriptome of sheep that had been naturally exposed to GIN parasites. The hepatic transcriptome was studied using RNA-Sequencing technology in animals characterized as high (n = 5) or medium (n = 6) based on their innate immune acute-phase (AP) response phenotype compared with uninfected controls (n = 4), and with biased antibody-mediated (AbMR, n = 5) or cell-mediated (CMR, n = 5) adaptive immune responsiveness compared to uninfected controls (n = 3). Following the assessment of sheep selected for innate responses, 0, 136, and 167 genes were differentially expressed (DE) between high- and medium-responding animals, high-responding and uninfected control animals, and medium-responding and uninfected control animals, respectively (false discovery rate (FDR) < 0.05, and fold change |FC| > 2). When adaptive immune responses were assessed, 0, 53, and 57 genes were DE between antibody- and cell-biased animals, antibody-biased and uninfected control animals, and cell-biased and uninfected control animals, respectively (FDR < 0.05, |FC| > 2). Functional analyses identified enriched gene ontology (GO) terms and metabolic pathways related to the innate immune response and energy metabolism. Six functional candidate genes were identified for further functional and validation studies to better understand the underlying biological mechanisms of host responses to GINs. These, in turn, can potentially help improve decision making and management practices to increase the overall host immune response to GIN infection.
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Imunidade Inata , Fígado , Infecções por Nematoides , Doenças dos Ovinos , Transcriptoma , Animais , Ovinos/parasitologia , Fígado/parasitologia , Fígado/metabolismo , Fígado/imunologia , Infecções por Nematoides/veterinária , Infecções por Nematoides/genética , Infecções por Nematoides/imunologia , Infecções por Nematoides/parasitologia , Doenças dos Ovinos/parasitologia , Doenças dos Ovinos/genética , Doenças dos Ovinos/imunologia , Imunidade Inata/genética , Nematoides/patogenicidade , Imunidade Adaptativa/genética , Gastroenteropatias/genética , Gastroenteropatias/parasitologia , Gastroenteropatias/imunologia , Gastroenteropatias/veterináriaRESUMO
BACKGROUND: Chronic enteropathy associated with SLCO2A1 gene (CEAS) results from loss-of-function variants in SLCO2A1, which encodes the prostaglandin transporter (PGT). CEAS follows an autosomal recessive inheritance pattern. To date, approximate 30 pathogenic variants have been reported in CEAS. METHODS: We performed whole exome sequencing (WES) to screen for potential pathogenic variants in a patient suspected of having CEAS, and confirmed a variant in SLCO2A1 using Sanger sequencing. We established an in vitro minigene model to compare splicing between wild type (WT) and mutant transcripts. Quantitative polymerase chain reaction (qPCR) was used to evaluate SLCO2A1 transcription in the stomach and colon tissues from the patient and a healthy control (HC). The transcripts were further cloned and sequenced. RESULTS: The patient had a novel, homozygous, recessive c.929A > G variant in exon 7 of SLCO2A1, which has not been previously reported in CEAS or PHO. This variant altered splicing, resulting in an exon 7-truncated transcript lacking 16 bases. No normal transcript was detected in the patient's stomach or colon tissue. qPCR also showed significantly decreased SLCO2A1 transcription compared to HC. CONCLUSION: A previously unreported variant caused defective SLCO2A1 splicing and reduced mRNA levels in a patient with CEAS and PHO. This research enhances understanding of CEAS and PHO pathophysiology and aids genetic counseling and diagnosis.
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Transportadores de Ânions Orgânicos , Osteoartropatia Hipertrófica Primária , Humanos , Osteoartropatia Hipertrófica Primária/genética , Transportadores de Ânions Orgânicos/genética , Masculino , Gastroenteropatias/genética , Feminino , Sequenciamento do Exoma , Mutação/genética , Povo Asiático/genética , População do Leste AsiáticoRESUMO
Studies suggest links between diabetes and gastrointestinal (GI) traits; however, their underlying biological mechanisms remain unclear. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and GI disorders. Our study demonstrates a significant positive global genetic correlation of T2D with peptic ulcer disease (PUD), irritable bowel syndrome (IBS), gastritis-duodenitis, gastroesophageal reflux disease (GERD), and diverticular disease, but not inflammatory bowel disease (IBD). We identify several positive local genetic correlations (negative for T2D - IBD) contributing to T2D's relationship with GI disorders. Univariable and multivariable Mendelian randomisation analyses suggest causal effects of T2D on PUD and gastritis-duodenitis and bidirectionally with GERD. Gene-based analyses reveal a gene-level genetic overlap between T2D and GI disorders and identify several shared genes reaching genome-wide significance. Pathway-based study implicates leptin (T2D - IBD), thyroid, interferon, and notch signalling (T2D - IBS), abnormal circulating calcium (T2D - PUD), cardiovascular, viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. These findings support a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared biological pathways with putative causality for certain T2D - GI pairs, and identify targets for further investigation.
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Diabetes Mellitus Tipo 2 , Gastroenteropatias , Estudo de Associação Genômica Ampla , Diabetes Mellitus Tipo 2/genética , Humanos , Gastroenteropatias/genética , Predisposição Genética para Doença , Análise da Randomização MendelianaRESUMO
INTRODUCTION: Outer membrane protein (OMP) of Helicobacter pylori (H. pylori) i.e., blood group antigen binding adhesin (babA) is responsible for the attachment of H. pylori in the gastric epithelium. Its adherence is causative for gastric pathology such as gastritis, peptic ulcer disease (PUD), or digestive tract disorders like erosive reflux disease (ERD) and (NERD) non-erosive reflux disease and together called Gastroesophageal reflux disease (GERD). BabA manifests rapid and varied selection via substitution of amino acid in its Leb-carbohydrate binding domain (CBD) which enables better binding preferences for distinct human populations and ABO blood group phenotypes. The positive evolutionary selection of the pathogenic factor of this genetically diverse bacterium has enabled it to adapt to the host gastric environment. Analyzing the association of virulent genes (cagA, vacA) and babA will help us better understand bacteria's pathogenicity. METHOD: 109 H. pylori strains from patients with distinct gastrointestinal diseases were genotyped using Polymerase Chain Reaction(PCR) for cagA, vacA, and babA followed by Sanger sequencing and phylogenetic analysis. RESULT: In the babA + ve genotype, a statistically significant association with p = 0.04 and < 0.0001 is seen in gastritis and ERD respectively. A significant association of genotype vacAs1m2 (p = 0.0002) was seen in gastritis, vacAs1m1 (p = 0.02) in NERD, vacAs1m1 (p < 0.0001) and vacAs1m2 (p = 0.002) in ERD. This relationship helps to detect gastritis or ERD where BabA gene can be used as an independent marker for detecting their presence. CONCLUSION: The appearance of variants within distinct disease categories is due to local genetic variation.
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Adesinas Bacterianas , Infecções por Helicobacter , Helicobacter pylori , Filogenia , Humanos , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Helicobacter pylori/isolamento & purificação , Adesinas Bacterianas/genética , Infecções por Helicobacter/microbiologia , Índia , Masculino , Gastrite/microbiologia , Feminino , Gastroenteropatias/microbiologia , Gastroenteropatias/genética , Antígenos de Bactérias/genética , Genótipo , Adulto , Pessoa de Meia-Idade , Proteínas de Bactérias/genéticaRESUMO
OBJECTIVE: This study aimed to establish the association between HLA-A, B, DR genotypes and gastrointestinal variables in patients with SpA without inflammatory bowel disease (IBD). METHODS: Retrospective study of 91 patients with SpA and 401 healthy controls, with typing by Illumina Sequencing/PacBio and LIFECODES HLA-PCR/SSO multiplex sequencing technology. The presence of gastrointestinal symptoms was evaluated by administering a survey, and those who presented 2 or more symptoms were taken for clinical evaluation by rheumatology and gastroenterology, colonoscopy and histopathological study. (Ethics committee approval). RESULTS: The 59,3% of the patients were men, with a mean age of 43,9±11.4 years; 80,2% were classified as ankylosing spondylitis. 14, 28 and 19 genotypes for the HLA-A*, HLA-B* and HLA-DR* loci were identified in both groups, of which a relationship with gastrointestinal symptoms was identified: A*26, A*29 and B*27 were associated to abdominal pain, DRB1*11 and DRB1*16 with abdominal distention, A*30, B*38, DRB1*13 and DRB1*14 with weight loss, B*40 with diarrhea >4 weeks, and presence of mucus in the stools with A*02 and DRB1*11 (p<0.05). Furthermore, the presence of B*15 had a statistical relationship with intolerance to some food, highlighting the B*27 genotype in relation to grains and dairy products, A*23 with grains, vegetables and meats, and B*49 with vegetables and dairy (p<0.05). Regarding the endoscopic variables, macroscopic changes were found in the ileum mucosa related to A*02, B*48, DRB1*14 and the relationship between B*27 and ulcers at this level should be highlighted. Macroscopic changes in the sigmoid colon with B*48 and the rectum with A*30. In microscopic changes, inflammatory alterations of the ileum are mentioned with genotypes DRB1*07, DRB1*13 and DRB1*14, a genotype that is related to changes in the ileum both endoscopically and histologically (p<0.05). CONCLUSIONS: These findings indicate a potential genetic predisposition related to HLA genotypes that may increase the likelihood of food intolerance, gastrointestinal symptoms, and even visible and microscopic changes, specifically in the ileal tissue. The study highlights the presence of B*27 and other noteworthy HLA class I and class II genes (such as DRB1*14) in the diverse Colombian population.
OBJETIVO: Establecer la asociación entre genotipos HLA-A, B, DR y variables gastrointestinales en pacientes con EspA, sin enfermedad inflamatoria intestinal (EII). MÉTODOS: Estudio retrospectivo de 91 pacientes con EspA y 401 controles sanos, con tipificación por tecnología de secuenciación Illumina Sequencing/PacBio, y LIFECODES HLA-PCR/SSO multiplex. Se evaluó la presencia de síntomas gastrointestinales por aplicación de una encuesta, y, aquellos que presentaran dos o más síntomas, fueron llevados a valoración clínica por reumatología y gastroenterología, colonoscopia y estudio histopatológico. (Aprobación del Comité de Ética, HMC, 2022 - 2020). RESULTADOS: El 59,3% de los pacientes fueron hombres, con edad media de 43,9 ± 11,4 años. El 80,2% se clasificó como espondilitis anquilosante. Se identificaron en ambos grupos 14, 28 y 19 genotipos para los loci HLA-A*, HLA-B* y HLA-DR*, de los cuales se identificó relación con síntomas gastrointestinales: A*26, A*29 y B*27, con dolor abdominal; DRB1*11 y DRB1*16, con distensión abdominal; A*30, B*38, DRB1*13 y DRB1*14, con pérdida de peso; B*40, con diarrea >4 semanas y presencia de moco en las deposiciones con A*2 y DRB1*11 (p<0,05). Además, la presencia de B*15, tuvo relación estadística con intolerancia a algún tipo de alimento, a resaltar el genotipo B*27, en relación con granos y lácteos; A*23 con granos, verduras y carnes; y el B*49, con verduras y lácteos (p<0,05). Frente a las variables endoscópicas, se encontraron cambios macroscópicos en la mucosa de íleon relacionados con A*02, B*48, DRB1*14 y, a destacar, la relación B*27 con úlceras a este nivel. Cambios macroscópicos en colon sigmoides con B*48 y en recto con A*30. En cambios microscópicos, se mencionan alteraciones inflamatorias de íleon con genotipos DRB1*07, DRB1*13 y DRB1*14, genotipos que se relaciona a cambios en íleon tanto endoscópica e histológicamente (p<0,05). CONCLUSIONES: Estos resultados sugieren una posible susceptibilidad genética asociada al HLA, con genotipos que pueden predisponer a intolerancia alimentaria, síntomas gastrointestinales, e incluso, a cambios macroscópicos e histológicos, particularmente en tejido de íleon, entre los cuales está presente el B*27, pero resaltan otros interesantes en HLA clase I, como clase II (DRB1*14), en una población de alto mestizaje como la colombiana.
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Gastroenteropatias , Genótipo , Espondilartrite , Humanos , Masculino , Feminino , Adulto , Estudos Retrospectivos , Gastroenteropatias/genética , Gastroenteropatias/etiologia , Espondilartrite/genética , Espondilartrite/complicações , Pessoa de Meia-Idade , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/complicações , Antígenos HLA/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genéticaRESUMO
BACKGROUND: Cystic fibrosis (CF) is a rare and debilitating autosomal recessive disorder. It hampers the normal function of various organs and causes severe damage to the lungs, and digestive system leading to recurring pneumonia. Cf also affects reproductive health eventually may cause infertility. The disease manifests due to genetic aberrations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This study aimed to screen for CFTR gene variants in Pakistani CF patients representing variable phenotypes. METHODS: Clinical exome and Sanger sequencing were performed after clinical characterization of 25 suspected cases of CF (CF1-CF25). ACMG guidelines were followed to interpret the clinical significance of the identified variants. RESULTS: Clinical investigations revealed common phenotypes such as pancreatic insufficiency, chest infections, chronic liver and lung diseases. Some patients also displayed symptoms like gastroesophageal reflux disease (GERD), neonatal cholestasis, acrodermatitis, diabetes mellitus, and abnormal malabsorptive stools. Genetic analysis of the 25 CF patients identified deleterious variants in the CFTR gene. Notably, 12% of patients showed compound heterozygous variants, while 88% had homozygous variants. The most prevalent variant was p. (Met1Thr or Met1?) at 24%, previously not reported in the Pakistani population. The second most common variant was p. (Phe508del) at 16%. Other variants, including p. (Leu218*), p. (Tyr569Asp), p. (Glu585Ter), and p. (Arg1162*) were also identified in the present study. Genetic analysis of one of the present patients showed a pathogenic variant in G6PD in addition to CFTR. CONCLUSION: The study reports novel and reported variants in the CFTR gene in CF patients in Pakistani population having distinct phenotypes. It also emphasizes screening suspected Pakistani CF patients for the p. (Met1Thr) variant because of its increased observance and prevalence in the study. Moreover, the findings also signify searching for additional pathogenic variants in the genome of CF patients, which may modify the phenotypes. The findings contribute valuable information for the diagnosis, genetic counseling, and potential therapeutic strategies for CF patients in Pakistan.
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Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Mutação , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Sequenciamento do Exoma/métodos , Gastroenteropatias/genética , Hepatopatias/genética , Mutação/genética , Paquistão , FenótipoRESUMO
BACKGROUND: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. METHODS: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 × 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. FINDINGS: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. INTERPRETATION: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases. FUNDING: Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).
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Exercício Físico , Gastroenteropatias , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Comportamento Sedentário , Humanos , Gastroenteropatias/genética , Gastroenteropatias/etiologia , Gastroenteropatias/epidemiologia , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Fatores de RiscoRESUMO
BACKGROUND: The two-way communications along the gut-lung axis influence the immune function in both gut and lung. However, the shared genetic characteristics of lung function with gastrointestinal tract (GIT) diseases remain to be investigated. METHODS: We first investigated the genetic correlations between three lung function traits and four GIT diseases. Second, we illustrated the genetic overlap by genome-wide pleiotropic analysis (PLACO) and further pinpointed the relevant tissue and cell types by partitioning heritability. Furthermore, we proposed pleiotropic genes as potential drug targets by drug database mining. Finally, we evaluated the causal relationships by epidemiologic observational study and Mendelian randomization (MR) analysis. RESULTS: We found lung function and GIT diseases were genetically correlated. We identified 258 pleiotropic loci, which were enriched in gut- and lung-specific regions marked by H3K4me1. Among these, 16 pleiotropic genes were targets of drugs, such as tofacitinib and baricitinib targeting TYK2 for the treatment of ulcer colitis and COVID-19, respectively. We identified a missense variant in TYK2, exhibiting a shared causal effect on FEV1/FVC and inflammatory bowel disease (rs12720356, PPLACO=1.38 × 10- 8). These findings suggested TYK2 as a promising drug target. Although the epidemiologic observational study suggested the protective role of lung function in the development of GIT diseases, no causalities were found by MR analysis. CONCLUSIONS: Our study suggested the shared genetic characteristics between lung function and GIT diseases. The pleiotropic variants could exert their effects by modulating gene expression marked by histone modifications. Finally, we highlighted the potential of pleiotropic analyses in drug repurposing.
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Gastroenteropatias , Pulmão , Análise da Randomização Mendeliana , Volume Expiratório Forçado/genética , Trato Gastrointestinal , Estudo de Associação Genômica Ampla , Pulmão/fisiopatologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Humanos , Gastroenteropatias/genética , Gastroenteropatias/fisiopatologiaRESUMO
BACKGROUND: To explore the underlying causality between leukocyte telomere length (LTL) and four gastrointestinal diseases, we designed a two-sample bidirectional Mendelian randomization study. METHODS: Two-sample Mendelian randomization (MR) was used to explore genetic causality between LTL and four gastrointestinal diseases, including irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), gastrointestinal ulcers disease (GUD), and nonalcoholic fatty liver disease (NAFLD). We utilized inverse-variance weighted (IVW) as the primary method for MR analysis. Supplementary analyses were conducted using methods such as MR-Egger regression, weighted-median, Maximum Likelihood (MaxLik), Robust adjusted profile score (MR-RAPS), Contamination mixture (ConMix), and MR-mix. Cochran's Q was calculated to check for heterogeneity. The MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) were detected for pleiotropy. RESULTS: The IVW analysis suggests that there may be a potential causal relationship between LTL and two diseases (odds ratio (OR): 1.062; 95% confidence interval (CI): 1.003, 1.124; p = 0.038 for IBS and OR: 0.889; 95% CI: 0.798, 0.990; p = 0.032 for GERD). However, other methods do not entirely align with the results of the IVW analysis. In the reverse MR analysis, we did not find statistically significant associations between LTL and these four diseases. CONCLUSION: The current evidence does not definitively rule out a causal relationship between LTL and these four gastrointestinal diseases but suggests a potential association between LTL and IBS, or LTL and GERD. Exploring the relationship between gastrointestinal diseases and LTL may offer new insights into the onset, progression, and treatment of these diseases.
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Refluxo Gastroesofágico , Gastroenteropatias , Síndrome do Intestino Irritável , Humanos , Síndrome do Intestino Irritável/genética , Análise da Randomização Mendeliana , Gastroenteropatias/genética , Leucócitos , TelômeroRESUMO
INTRODUCTION: Gastrointestinal (GI) motility disorders comprise a wide range of different diseases affecting the structural or functional integrity of the GI neuromusculature. Their clinical presentation and burden of disease depends on the predominant location and extent of gut involvement as well as the component of the gut neuromusculature affected. AREAS COVERED: A comprehensive literature review was conducted using the PubMed and Medline databases to identify articles related to GI motility and functional disorders, published between 2016 and 2023. In this article, we highlight the current knowledge of molecular and genetic mechanisms underlying GI dysmotility, including disorders of gut-brain interaction, which involve both GI motor and sensory disturbance. EXPERT OPINION: Although the pathophysiology and molecular mechanisms underlying many such disorders remain unclear, recent advances in the assessment of intestinal tissue samples, genetic testing with the application of 'omics' technologies and the use of animal models will provide better insights into disease pathogenesis as well as opportunities to improve therapy.
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Gastroenteropatias , Animais , Humanos , Gastroenteropatias/diagnóstico , Gastroenteropatias/genética , Motilidade Gastrointestinal/genética , Encéfalo , CabeçaRESUMO
Fatores genéticos, imunológicos e ambientais estão envolvidos na patogênese de doenças gastrintestinais. Situado no braço curto do cromossomo 6, o sistema HLA se destaca pelo seu polimorfismo e capacidade de conferir susceptibilidade ou resistência a vários distúrbios imunomediados. De acordo com a patologia e, algumas vezes, com o grupo étnico-racial estudado, existem variações na associação HLA x doença. Acredita-se que moléculas de histocompatibilidade possam influenciar na idade de surgimento, resposta ao tratamento e no curso clínico de algumas enfermidades. O surgimento de novos métodos para tipificação dos alelos HLA assim como as mudanças em sua nomenclatura têm permitido um melhor entendimento desse sistema. Infelizmente, esse conhecimento não tem sido adequadamente veiculado na literatura clínica. Esta revisão tem porobjetivo abordar a estrutura e função do sistema HLA, seus métodos de detecção, nomenclatura e associação com doença celíaca, doença de Crohn, hepatite autoimune, pancreatite auto-imune e úlceras orais recorrentes.
Los factores genéticos, inmunológicos y ambientales están envueltos en la patogénesis de las enfermedades gastrointestinales. Situado en el brazo corto del cromosoma 6, el sistema HLA se destaca por su polimorfismo y capacidad de conferir susceptibilidad o resistencia a varios disturbios inmunomediados. De acuerdo con la patología y algunas veces con el grupo étnico-racial estudiado, existen variaciones en la asociación HLA yenfermedades. El surgimiento de nuevos métodos para tipificación de los alelos así como los cambios en su Nomenclatura ha permitido un mejor entendimiento de este sistema. Infelizmente, ese conocimiento no ha sido adecuadamente vehiculazado en la literatura clínica. Esta revisión tiene por objeto abordar la estructura y función del sistema HLA, sus métodos de detección, nomenclatura y asociación con la enfermedad celíaca, enfermedad de Crohn, hepatitis auto-inmune, pancreatitis auto-inmune y úlceras orales-recurrentes.
Genetic, immunological and environmental factors are involved in the pathogenesis of the gastrointestinal diseases. Situated on the short arm of the chromosome 6, the HLA system is very polymorphic and has the capacity to confer susceptibility or resistance to different diseases. The relationship HLA vs. disease differs with the disease and, sometimes, with the ethnic-racial group studied. Histocompatibility molecules could determine the age of onset, the treatment response and the clinical course for some diseases. The recent discovery of new methods to typify HLA alleles and the changes in its nomenclature has contributed to a better understanding of this system. Nevertheless, has not thoroughly widespread. The aim of this review is to discuss the HLA structure and function, methods of detection, nomenclature and its association with celiac disease, Crohns disease, autoimmune hepatitis, autoimmune pancreatitis and oral recurrent ulcers.