RESUMO
Background: Emerging observational studies indicated an association between hyperthyroidism and gastrointestinal disorders. However, it remains unclear whether this association is causal, particularly in the case of gastroesophageal reflux (GERD) and esophageal cancer. Methods: To assess the potential causal relationship between hyperthyroidism and GERD or esophageal cancer, we conducted a bidirectional 2-sample Mendelian randomization study. Independent genetic instruments for hyperthyroidism from the UK Biobank (N case=3,545 and N control=459,388) and public genome-wide association study (GWAS) dataset (N case=3,731 and N control=480,867) were used to investigate the association with esophageal cancer in the UK Biobank study (N case=740 and N control=372,016) and GERD in the public GWAS database (N case=20,381 and N control=464,217). Four different approaches (inverse variance weighted (IVW), weighted mode, MR-Egger, and weighted median regression) were used to ensure that our results more reliable. Additional sensitivity analyses were also performed to validate our results. Results: When hyperthyroidism was considered as the exposure factor, it appeared to act as a protective factor for GERD (ORIVW = 0.88, 95% CI, 0.79-0.99, P = 0.039), while as a risk factor for esophageal cancer (ORIVW = 1.03, 95% CI, 1.01-1.06, P = 0.003). However, there is no evidence supporting a reverse causal relationship between genetic susceptibility to hyperthyroidism and GERD or esophageal cancer. Conclusion: Our findings provided genetic evidence supporting bidirectional causal relationships between hyperthyroidism and GERD or esophageal cancer. These results substantiate certain discoveries from previous observational studies on a causal level and provide insight into relevant genetic susceptibility factors.
Assuntos
Neoplasias Esofágicas , Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Hipertireoidismo , Análise da Randomização Mendeliana , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/etiologia , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/epidemiologia , Hipertireoidismo/genética , Hipertireoidismo/epidemiologia , Hipertireoidismo/complicações , Fatores de Risco , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , MasculinoRESUMO
OBJECTIVE: Early identification of modifiable risk factors is crucial for the prevention of constipation. This study systematically investigated the relationship between genetically predicted modifiable risk factors and constipation. METHODS: The inverse variance weighting (IVW) method was employed as the primary analytical approach. For similar exposure indicators, the multivariate Mendelian randomization (MVMR) method was used to adjust for potential biases in univariate MR analysis. The robustness of the results was further evaluated using the MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis. Bonferroni correction was applied to reduce the false positive rate in the results. RESULTS: The IVW analysis indicated a significant causal association between genetically predicted gastroesophageal reflux disease [OR (95% CI) = 1.192 (1.079-1.315), P = 0.0005], atorvastatin use [OR (95% CI) = 16.995 (3.327-86.816), P = 0.0007], and constipation. Additionally, there was a potential causal association between education level [OR (95% CI) = 0.859 (0.767-0.964), P = 0.009], major depressive disorder [OR (95% CI) = 1.206 (1.041-1.399), P = 0.013], hypothyroidism [OR (95% CI) = 2.299 (1.327-3.985), P = 0.003], and aspirin use [OR (95% CI) = 4.872 (1.174-20.221), P = 0.029] with constipation. No causal associations were found for the other included indicators. Sensitivity analysis demonstrated the absence of evidence for heterogeneity and pleiotropy in any positive results. CONCLUSION: This study identified several risk factors that could be targeted for the prevention of constipation, offering valuable insights for public health policies.
Assuntos
Constipação Intestinal , Análise da Randomização Mendeliana , Humanos , Constipação Intestinal/epidemiologia , Fatores de Risco , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/genética , Polimorfismo de Nucleotídeo Único , Escolaridade , Predisposição Genética para DoençaRESUMO
The aim is to investigate the evidence for shared genetic architecture between each of asthma, allergic rhinitis and eczema with gastro-esophageal reflux disease (GERD). Structural equation models (SEM) and polygenic risk score (PRS) analyses are applied to three Swedish twin cohorts (n = 46,582) and reveal a modest genetic correlation between GERD and asthma of 0.18 and bidirectional PRS and phenotypic associations ranging between OR 1.09-1.14 and no correlations for eczema and allergic rhinitis. Linkage disequilibrium score regression is applied to summary statistics of recently published GERD and asthma/allergic disease genome wide association studies and reveals a genetic correlation of 0.48 for asthma and GERD, and Genomic SEM supports a single latent factor. A gene-/gene-set analysis using MAGMA reveals six pleiotropic genes (two at 12q13.2) associated with asthma and GERD. This study provides evidence that there is a common genetic architecture unique to asthma and GERD that may explain comorbidity and requires further investigation.
Assuntos
Asma , Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Humanos , Refluxo Gastroesofágico/genética , Asma/genética , Feminino , Masculino , Predisposição Genética para Doença , Suécia/epidemiologia , Adulto , Pessoa de Meia-Idade , Herança Multifatorial , Hipersensibilidade/genética , Desequilíbrio de LigaçãoRESUMO
BACKGROUND: Gastroesophageal reflux disease (GERD) and cholecystitis share overlapping symptoms, including belching, acid reflux, and heartburn. Despite this, the causal relationship between these two conditions remains unclear. This study aimed to investigate the causal link between GERD and cholecystitis using a Mendelian randomization (MR) approach. METHODS: A two-sample MR analysis was conducted using the inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger method to assess the causal effects of GERD on the cholecystitis risk. Genome-wide association studies (GWASs) on GERD (N cases = 129080; N controls = 473524) and cholecystitis (N cases = 1930; N controls =359264) were obtained from the IEU Open GWAS project. Various techniques were employed to assess pleiotropy and heterogeneity. RESULTS: Seventy-seven single nucleotide polymorphisms from GERD GWASs were selected as instrumental variables (IVs). The primary IVW method revealed a significant association between GERD and an increased risk of cholecystitis (odds ratio = 1.004; 95% confidence interval = 1.003-1.005, p = 2.68 × 10- 9). The absence of heterogeneity and pleiotropy in the data supports the reliability of the results. CONCLUSIONS: GERD was positively associated with the risk of cholecystitis. This study provides insights into potential avenues for the development of prevention strategies and treatment options for cholecystitis in patients with GERD. These findings contribute to our understanding of the complex interplay between GERD and cholecystitis.
Assuntos
Colecistite , Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/complicações , Colecistite/genética , Predisposição Genética para Doença , Fatores de Risco , CausalidadeRESUMO
One Health and planetary health place emphasis on the common molecular mechanisms that connect several complex human diseases as well as human and planetary ecosystem health. For example, not only lung cancer (LC) and gastroesophageal reflux disease (GERD) pose a significant burden on planetary health, but also the coexistence of GERD in patients with LC is often associated with a poor prognosis. This study reports on the genetic overlaps between these two conditions using systems biology-driven bioinformatics and machine learning-based algorithms. A total of nine hub genes including IGHV1-3, COL3A1, ITGA11, COL1A1, MS4A1, SPP1, MMP9, MMP7, and LOC102723407 were found to be significantly altered in both LC and GERD as compared with controls and with pathway analyses suggesting a significant association with the matrix remodeling pathway. The expression of these genes was validated in two additional datasets. Random forest and K-nearest neighbor, two machine learning-based algorithms, achieved accuracies of 89% and 85% for distinguishing LC and GERD, respectively, from controls using these hub genes. Additionally, potential drug targets were identified, with molecular docking confirming the binding affinity of doxycycline to matrix metalloproteinase 7 (binding affinity: -6.8 kcal/mol). The present study is the first of its kind that combines in silico and machine learning algorithms to identify the gene signatures that relate to both LC and GERD and promising drug candidates that warrant further research in relation to therapeutic innovation in LC and GERD. Finally, this study also suggests upstream regulators, including microRNAs and transcription factors, that can inform future mechanistic research on LC and GERD.
Assuntos
Refluxo Gastroesofágico , Neoplasias Pulmonares , Aprendizado de Máquina , Biologia de Sistemas , Humanos , Neoplasias Pulmonares/genética , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/diagnóstico , Biologia de Sistemas/métodos , Algoritmos , Biologia Computacional/métodos , Simulação de Acoplamento Molecular , Redes Reguladoras de Genes , Perfilação da Expressão Gênica/métodosRESUMO
BACKGROUND: Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder. Recent studies indicate that GERD may exert systemic effects, potentially elevating the risk of severe infections, including sepsis. Nevertheless, the causal relationship between GERD and sepsis, as well as sepsis-related 28-day mortality, remains uncertain. AIM: The aim of this study is to investigate the causal relationship between GERD and the risk of sepsis, including 28-day mortality of sepsis. METHODS: This study utilized a two-sample Mendelian Randomization (MR) approach to analyze data from publicly available genome-wide association studies (GWAS) databases ( https://gwas.mrcieu.ac.uk/ ). The analysis comprised 129,080 cases and 473,524 controls for GERD; 11,643 patients and 474,841 controls for sepsis; and 1,896 patients and 484,588 controls for 28-day mortality from sepsis. The objective was to evaluate the causal impact of GERD on the risk of sepsis and 28-day sepsis mortality. Genetic variation data pertinent to GERD were obtained from the most recent genome-wide association studies (GWAS). The primary analysis employed the Inverse Variance Weighted (IVW) method. Sensitivity and pleiotropy analyses were performed to validate the robustness of the findings. RESULTS: MR analysis revealed a notable link between genetically predicted GERD and increased sepsis risk (odds ratio [OR] 1.37, 95% confidence interval [CI] 1.24-1.52; p = 2.79 × 10-9). Moreover, GERD correlated with elevated 28-day mortality of sepsis (OR 1.44, 95% CI 1.11-1.85; p = 5.34 × 10-3). These results remained consistent throughout various sensitivity analyses, indicating their resilience against potential pleiotropy and other biases. CONCLUSION: This study indicates that genetic predisposition to GERD may be linked to an elevated risk of sepsis and its associated 28-day mortality. However, the study does not establish a direct causal relationship for GERD itself, nor does it assess the impact of GERD treatment. Further research is needed to explore the underlying mechanisms and potential therapeutic interventions involved.
Assuntos
Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Sepse , Humanos , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/mortalidade , Sepse/genética , Sepse/mortalidade , Fatores de Risco , Predisposição Genética para Doença , Estudos de Casos e Controles , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Previous studies have suggested a potential association between irritability and the risk of various diseases. However, establishing a causal relationship has remained a significant challenge. To address this issue, we employed Mendelian randomization (MR), a sophisticated approach that leverages genotype data to emulate the conditions of randomized controlled trials. This method enables us to investigate the potential causal link between irritability and the susceptibility to esophageal diseases. METHODS: We conducted an extensive multivariable MR analysis using summary-level data from genome-wide association studies (GWAS) encompassing various esophageal diseases, including gastroesophageal reflux disease (GERD), esophageal cancer (EC), and Barrett's esophagus. Both univariable and multivariable MR analyses were performed to elucidate and confirm the causal association between genetically predicted irritability and the incidence of esophageal diseases. RESULTS: Based on our primary causal effects model utilizing MR analyses with the inverse-variance weighted (IVW) method, genetically predicted irritability was identified as a risk factor for GERD (OR = 2.413; 95 % CI: 1.678-3.470; P = 2.03E-06) and Barrett's esophagus (OR = 2.306; 95 % CI: 1.042-5.101; P = 0.039). However, irritability was not found to be associated with the risk of EC, even after adjusting for BMI, smoking initiation, and alcohol consumption. CONCLUSION: The multivariable MR analysis performed in this study demonstrated a causal relationship between irritability and esophageal diseases. It is imperative to acknowledge the need for further large-scale prospective studies to validate these findings.
Assuntos
Esôfago de Barrett , Neoplasias Esofágicas , Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Humor Irritável , Análise da Randomização Mendeliana , Humanos , Esôfago de Barrett/genética , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/epidemiologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/epidemiologia , Fatores de Risco , Doenças do Esôfago/genética , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença/genéticaRESUMO
BACKGROUND: Previous studies have shown that physical activity (PA) and leisure sedentary behaviors (LSB, including leisure television watching) are linked to gastroesophageal reflux disease (GERD). However, the associations between PA/LSB and GERD remain controversial. In this study, we aimed to reveal whether these associations reflect causal relationships and reveal the potential mechanisms of these relationships using bidirectional and two-step Mendelian randomization (MR) analyses. METHODS: We obtained genome-wide association study (GWAS) summary statistics for PA/LSB, four common risk factors (including cigarettes smoked per day, alcoholic drinks per week, triglycerides, total cholesterol) and GERD from published GWASs. A bidirectional MR analysis was performed to identify causal relationships between PA/LSB and GERD. Then, a series of sensitivity analyses were performed to verify the robustness of the results. Finally, a mediation analysis via two-step MR was conducted to investigate any effects explained by common risk factors in these relationships. RESULTS: Genetically predicted per 1-SD increase in leisure time television watching significantly increased the risk of GERD in the bidirectional MR analysis (OR = 1.33; 95% CI: 1.14-1.56; P = 2.71 × 10- 4). Sensitivity analyses successfully verified the robustness of the causal relationship. Further mediation analysis showed that this effect was partly mediated by increasing cigarettes smoked per day, with mediated proportions of 18.37% (95% CI: 11.94-39.79%). CONCLUSION: Our findings revealed a causal relationship between leisure television watching and an increased risk of GERD, notably, the causal effect was partially mediated by cigarettes smoked per day. These findings may inform prevention and management strategies directed toward GERD.
Assuntos
Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Atividades de Lazer , Análise da Randomização Mendeliana , Televisão , Humanos , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/etiologia , Fatores de Risco , Comportamento Sedentário , Exercício Físico , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked this relationship. METHODS: This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancer-related data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods such as inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding factors. RESULTS: GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known risk factors-including smoking, alcohol consumption, major depression, and body mass index (BMI)-these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer was (OR, 1.23; 95% CI: 1.14-1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03-1.36), for lung squamous cell carcinoma was (OR, 1.35; 95% CI: 1.19-1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI: 1.22-2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23-5.37). Mediation analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks. CONCLUSIONS: This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer prevention strategies.
Assuntos
Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Neoplasias , Polimorfismo de Nucleotídeo Único , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/complicações , Neoplasias/genética , Neoplasias/epidemiologia , Fatores de Risco , Biobanco do Reino Unido , Reino Unido/epidemiologiaRESUMO
Rheumatoid arthritis (RA) is a common autoimmune disease, and some observational studies have indicated an association between Gastroesophageal Reflux Disease (GERD) and RA. However, the causal relationship between the two remains uncertain. We used Mendelian randomization (MR) to assess the causal relationship between GERD and RA. Two-sample Mendelian randomization analysis was performed using pooled data from large-scale genome-wide association studies. In addition, we performed multivariate MR analyses to exclude confounding factors between GERD and RA, including smoking quantity, drinking frequency, BMI, depression, and education attainment. The MR results for GERD on RA suggested a causal effect of the genetic susceptibility of GERD on RA (discovery dataset, IVW, odds ratio [OR] = 1.41, 95% confidence interval [CI] 1.22-1.63, p = 2.81 × 10-6; validation dataset, IVW, OR = 1.38, 95% CI 1.23-1.55, P = 1.76 × 10-8). Multivariate MR analysis also supports this result. But the results of the reverse MR analysis did not reveal compelling evidence that RA can increase the risk of developing GERD. Our bidirectional Two-Sample Mendelian randomization analysis and multivariate MR analysis provide support for the causal effect of GERD on RA. This discovery could offer new insights for the prevention and treatment of RA.
Assuntos
Artrite Reumatoide , Refluxo Gastroesofágico , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Artrite Reumatoide/genética , Humanos , Refluxo Gastroesofágico/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Razão de ChancesRESUMO
PURPOSE: Clinical studies suggested associations between obstructive sleep apnea (OSA) and gastrointestinal tract disorders. This study aims to investigate the genetic causal relationship between OSA and gastrointestinal tract disorders, specifically gastroesophageal reflux disease (GERD) and inflammatory bowel disease (IBD). METHODS: In this study, we employed two-sample Mendelian Randomization (MR) analysis to investigate the potential relationships between OSA and GERD, and between OSA and IBD. More specifically, the primary analysis utilized inverse variance weighting (IVW). Weighted median, MR Egger, and MR PRESSO were applied to complicate potential violations of MR assumptions. Also, sensitivity analysis was evaluated and similar analysis was performed again after outliers were removed. Additionally, multivariable MR (MVMR) was conducted for associated pairs to adjust for obesity. RESULTS: Genetically predicted risk of GERD increased OSA risk by approximately 60% (ORIVW = 1.62, 95%CI = [1.43,1.84]) which was also stable by other complicated approaches, and even with BMI adjusted by MVMR (ORadjBMI[95%CI] = 1.26 [1.15,1.37]). Besides, OSA showed a mild causal effect on increased GERD risk after adjusting for obesity (ORadjBMI[95%CI] = 1.05 [1.02,1.08]). Additionally, OSA increased the risks for IBD (ORIVW[95%CI] = 1.36 [1.12,1.65]), including a higher risk of CD (ORIVW[95%CI] = 1.41 [1.08,1.83]), and a trend for increasing UC risk (ORIVW[95%CI] = 1.29 [0.99,1.67]). CONCLUSION: GERD exerts a substantial causality on increasing the risk of OSA. Conversely, the potential for a causal relationship that OSA contributes to the development of GERD or IBD remains probable. These findings support the crosstalk between gastrointestinal tract disorders and OSA.
Assuntos
Refluxo Gastroesofágico , Análise da Randomização Mendeliana , Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/epidemiologia , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/complicações , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/epidemiologia , Gastroenteropatias/genética , Gastroenteropatias/epidemiologia , Gastroenteropatias/diagnóstico , Obesidade/genética , Obesidade/epidemiologiaRESUMO
Introduction: Despite observational studies suggest hypotheses indicating a potential link, the precise causal connection between sarcopenia and digestive system illnesses has not been clearly defined. Methods: We first use Linkage Disequilibrium Score Regression (LDSC) testing to determine the genetic correlation of traits associated with sarcopenia and 10 specific gastrointestinal diseases. Subsequently, we performed a set of bidirectional Mendelian Randomization (MR) analyses to gauge the genetic inclination towards sarcopenia-related traits in relation to each gastrointestinal condition, individually, across the FinnGen, UK Biobank, and other extensive collaborative consortia. The analytical outcomes were synthesized using a fixed-effects meta-analytic model. For outcomes indicating substantial causal impacts, mediation MR analyses were executed. Additionally, a battery of sensitivity analyses was conducted to evaluate the study's strength and dependability. Results: Our findings established a strong causal link between appendicular lean mass and gastroesophageal reflux disease (OR = 0.8607; 95% CI: 0.8345-0.8877; p < 0.0001) and a noteworthy correlation with nonalcoholic fatty liver disease (OR = 0.7981; 95% CI: 0.7281-0.8749; p < 0.0001), as per the meta-analysis data. We also evaluated the intermediary role of metabolic disorders in the association between appendicular lean mass and the aforementioned diseases. The intermediary effect towards gastroesophageal reflux disease is quantified as 0.0087 (95% CI, 8e-04, 0.0183), accounting for 5.9398% (95% CI, 0.5462, 12.4940%) of the overall effect. For non-alcoholic fatty liver, the intermediary impact is 0.0150 (95% CI, 0.0050, 0.0270), representing 19.7808% (95% CI, 6.5936, 35.6055%) of the total effect. Conclusion: The findings posit that augmenting muscle mass may serve as a preventative strategy against gastroesophageal reflux disease and non-alcoholic fatty liver, highlighting the critical role of metabolic disorder management in reducing the risks of these sarcopenia-related conditions.
Assuntos
Análise da Randomização Mendeliana , Sarcopenia , Humanos , Sarcopenia/genética , Doenças do Sistema Digestório/genética , Desequilíbrio de Ligação , Masculino , Feminino , Refluxo Gastroesofágico/genéticaRESUMO
The clinical incidence of sjogren's syndrome combined with gastroesophageal reflux disease is high. Existing observational studies have shown inconsistent results in the association between gastroesophageal reflux disease (GERD) and Sjogren's syndrome (SS).We observed that the symptoms of SS patients also improved after receiving GERD-related treatment. Therefore, we aimed to investigate the relationship between GERD and SS through a bidirectional two-sample Mendelian randomization (MR) study. Independent SNPs associated with GERD and SS were selected from a genome-wide association study (GWAS) as instrumental variables to conduct a bidirectional two-sample Mendelian analysis of GERD and SS. Genetic data were obtained from two databases for the following two outcomes: Gastroesophageal reflux (IEU Open GWAS) [sample size = 602,604 (patients = 129,080; nonpatients = 473,524)] and SS (FinnGen) [sample size = 392,423 (patients = 2,495; nonpatients = 389,928)]. Statistical methods for the MR analysis included the inverse-variance weighting method, weighted median, simple mode and weighted mode, as well as heterogeneity and sensitivity analyses using the Cochran Q statistic, MRâEgger regression, outlier detection methods (MR-PRESSO). In addition, Steiger Test was conducted to test the direction of causality. MR analysis showed a positive correlation between GERD and SS risk [odds ratio (OR) = 1.3279 (95% confidence interval 1.0312-1.7099, P = 0.0280)]. However, in contrast, no significant causal effect of SS on GERD was observed [OR = 1.0024 (95% CI 0.9651-1.0412; P = 0.8995)]. This bidirectional two-sample Mendelian randomization study confirmed a causal relationship between SS and GERD, and suggested that GERD is a risk factor for SS, while SS does not affect GERD.
Assuntos
Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Síndrome de Sjogren , Humanos , Refluxo Gastroesofágico/genética , Síndrome de Sjogren/genética , Síndrome de Sjogren/complicações , Predisposição Genética para Doença , FemininoRESUMO
Accumulating evidence from observational studies have suggested an association between gastroesophageal reflux disease (GERD) and non-alcoholic fatty liver disease (NAFLD). However, due to that such studies are prone to biases, we imported Mendelian randomization (MR) to explore whether the causal association between two diseases exsit. Hence, we aimed to analysis the potential association with MR. The single nucleotide polymorphisms (SNPs) of GERD were retrieved from the genome-wide association study dataset as the exposure. The SNPs of NAFLD were taken from the FinnGen dataset as the outcome. The relationship was analyzed with the assistance of inverse variance weighted, MR-Egger, and weighted median. We also uitilized the MR-Egger intercept, Cochran's Q test, leave-one-out analysis, MR-PRESSO, and Steiger directionality test to evaluate the robustness of the causal association. The meta-analysis were also implemented to give an overall evaluation. Finally, our analysis showed a causal relationship between GERD and NAFLD with aid of MR and meta-analysis (OR 1.71 95% CI 1.40-2.09; P < 0.0001).
Assuntos
Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Hepatopatia Gordurosa não Alcoólica , Polimorfismo de Nucleotídeo Único , Hepatopatia Gordurosa não Alcoólica/genética , Humanos , Refluxo Gastroesofágico/genética , Predisposição Genética para DoençaRESUMO
BACKGROUND: Observational studies have preliminarily revealed an association between smoking and gastroesophageal reflux disease (GERD). However, little is known about the causal relationship and shared genetic architecture between the two. This study aims to explore their common genetic correlations by leveraging genome-wide association studies (GWAS) of smoking behavior-specifically, smoking initiation (SI), never smoking (NS), ever smoking (ES), cigarettes smoked per day (CPD), age of smoking initiation(ASI) and GERD. METHODS: Firstly, we conducted global cross-trait genetic correlation analysis and heritability estimation from summary statistics (HESS) to explore the genetic correlation between smoking behavior and GERD. Then, a joint cross-trait meta-analysis was performed to identify shared "pleiotropic SNPs" between smoking behavior and GERD, followed by co-localization analysis. Additionally, multi-marker analyses using annotation (MAGMA) were employed to explore the degree of enrichment of single nucleotide polymorphism (SNP) heritability in specific tissues, and summary data-based Mendelian randomization (SMR) was further utilized to investigate potential functional genes. Finally, Mendelian randomization (MR) analysis was conducted to explore the causal relationship between the smoking behavior and GERD. RESULTS: Consistent genetic correlations were observed through global and local genetic correlation analyses, wherein SI, ES, and CPD showed significantly positive genetic correlations with GERD, while NS and ASI showed significantly negative correlations. HESS analysis also identified multiple significantly associated loci between them. Furthermore, three novel "pleiotropic SNPs" (rs4382592, rs200968, rs1510719) were identified through cross-trait meta-analysis and co-localization analysis to exist between SI, NS, ES, ASI, and GERD, mapping the genes MED27, HIST1H2BO, MAML3 as new pleiotropic genes between SI, NS, ES, ASI, and GERD. Moreover, both smoking behavior and GERD were found to be co-enriched in multiple brain tissues, with GMPPB, RNF123, and RBM6 identified as potential functional genes co-enriched in Cerebellar Hemisphere, Cerebellum, Cortex/Nucleus accumbens in SI and GERD, and SUOX identified in Caudate nucleus, Cerebellum, Cortex in NS and GERD. Lastly, consistent causal relationships were found through MR analysis, indicating that SI, ES, and CPD increase the risk of GERD, while NS and higher ASI decrease the risk. CONCLUSION: We identified genetic loci associated with smoking behavior and GERD, as well as brain tissue sites of shared enrichment, prioritizing three new pleiotropic genes and four new functional genes. Finally, the causal relationship between smoking behavior and GERD was demonstrated, providing insights for early prevention strategies for GERD.
Assuntos
Refluxo Gastroesofágico , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fumar , Refluxo Gastroesofágico/genética , Humanos , Fumar/genética , Genômica , MultiômicaRESUMO
BACKGROUND: Previous cross-sectional studies have identified multiple potential risk factors for functional dyspepsia (FD). However, the causal associations between these factors and FD remain elusive. Here we aimed to fully examine the causal relationships between these factors and FD utilizing a two-sample MR framework. METHODS: A total of 53 potential FD-related modifiable factors, including those associated with hormones, metabolism, disease, medication, sociology, psychology, lifestyle and others were obtained through a comprehensive literature review. Independent genetic variants closely linked to these factors were screened as instrumental variables from genome-wide association studies (GWASs). A total of 8875 FD cases and 320387 controls were available for the analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach to assess the relationship between genetic variants of risk factors and the FD risk. Sensitivity analyses were performed to evaluate the consistency of the findings using the weighted median model, MR-Egger and MR-PRESSO methods. RESULTS: Genetically predicted depression (OR 1.515, 95% confidence interval (CI) 1.231 to 1.865, p = 0.000088), gastroesophageal reflux disease (OR 1.320, 95%CI 1.153 to 1.511, p = 0.000057) and years of education (OR 0.926, 95%CI 0.894 to 0.958, p = 0.00001) were associated with risk for FD in univariate MR analyses. Multiple medications, alcohol consumption, poultry intake, bipolar disorder, mood swings, type 1 diabetes, elevated systolic blood pressure and lower overall health rating showed to be suggestive risk factors for FD (all p<0.05 while ≥0.00167). The positive causal relationship between depression, years of education and FD was still significant in multivariate MR analyses. CONCLUSIONS: Our comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.
Assuntos
Dispepsia , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Dispepsia/genética , Dispepsia/epidemiologia , Fatores de Risco , Depressão/genética , Depressão/epidemiologia , Depressão/complicações , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/complicações , Polimorfismo de Nucleotídeo Único , Predisposição Genética para DoençaRESUMO
BACKGROUND: Observational studies have previously shown a potential link between psycho-emotional disorders, such as mood swings, highly strung, anxious feelings, and gastroesophageal reflux disease (GERD). However, the credibility of these associations could be influenced by various confounding factors. Consequently, our study sought to employ a Mendelian randomization (MR) approach to elucidate a potential causal relationship between psycho-emotional disorders and GERD. METHOD: Information on independent genetic variants linked to mood swings, highly strung, and anxious feelings was gathered from European populations participating in the IEU Open GWAS research. The FinnGen Consortium provided the genome-wide association study (GWAS) summary statistics for GERD. Our analysis employed the inverse variance weighted (IVW) method under the random effects model as the main analytical method. To further bolster our findings, we employed the weighted median and MR Egger methods. In addition, we conducted a series of sensitivity analyses. RESULTS: Our study supports the existence of a causal relationship between psycho-emotional disorders and GERD. Mood swings, highly strung, and anxious feelings adversely affected GERD risk (mood swings: OR 2.21, 95% CI 1.19-5.59, p = 3.09 × 10-2; highly strung: OR 5.63, 95% CI 1.77-17.94, p = 3.42 × 10-3; anxious feelings: OR 2.48, 95% CI 1.08-4.33, p = 2.89 × 10-2). CONCLUSION: This Mendelian randomization study provides robust support for the notion that mood swings, highly strung and anxious feelings, are associated with an increased risk of developing GERD.
Assuntos
Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/psicologia , Ansiedade/genética , Polimorfismo de Nucleotídeo Único , Predisposição Genética para DoençaRESUMO
Background: In observational studies, gastroesophageal reflux disease (GERD) is linked to atrial fibrillation (AF). It is uncertain whether the relationship is due to GERD-induced AF or GERD caused by AF, or confusion with factors related to GERD and AF such as obesity and sleep-disordered breathing. We applied bidirectional Mendelian randomization (MR), in which genetic variations are used as instrumental variables to resolve confounding and reverse causation issues, to determine the causal effect between GERD and AF. Methods: Using summary data from the GERD and AF genome-wide association study (GWAS), a bidirectional MR was performed to estimate the causative impact of GERD on AF risk and AF on GERD risk. The GWAS of GERD meta-analysis comprised 78707 cases and 288734 controls. GWAS summary data for AF, including 45766 AF patients and 191924 controls, were used to genetically predicted AF. The inverse variance weighted (IVW) method was the major MR approach used. MR-PRESSO was implemented to detect heterogeneity and correct the effect of outliers. Weighted median and MR-Egger regression were applied to test heterogeneity and pleiotropy. Results: The genetic instruments of GERD related to increasing the risk of AF, with an OR of 1.339 (95% CI: 1.242-1.444, p < 0.001). However, after removing the outlier 8 SNPs, genetically predicted AF was not associated with an elevated risk of GERD (p = 0.351). Conclusions: Our result suggested that GERD had a causal effect on AF. However, no evidence was identified that AF elevated the risk of GERD.
Assuntos
Fibrilação Atrial , Refluxo Gastroesofágico , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/epidemiologia , Fibrilação Atrial/genética , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Predisposição Genética para Doença , Fatores de RiscoRESUMO
Previous literature has demonstrated that COronaVIrus Disease of 2019 (COVID-19) impacts an individual gastrointestinal tract (GIT), causing symptoms like nausea, diarrhea, and loss of appetite. Severe acute respiratory syndrome coronavirus RNA has been discovered in the stool of infected individuals in earlier research. It was discovered that severe acute respiratory syndrome coronavirus was significantly expressed in the GIT, indicating that the virus can also infect the digestive system. Angiotensin-converting enzyme 2 functions as the viral receptor. The chronic illness known as gastroesophageal reflux disease (GERD) is typified by frequent reflux of stomach acid into the esophagus. By triggering the sensitized esophageal-bronchial neuronal circuit or aspirating into the airways (microaspiration), GER exacerbates respiratory diseases. Aspiration is a well-known risk to be considered when treating patients in intensive care units. Strong genetic correlations have been identified between COVID-19 infection and GERD susceptibility, suggesting a shared genetic basis for both conditions. Nonetheless, even though GERD, extraesophageal reflex, and COVID-19 have a number of significant risk factors and exhibit similar symptoms, the relationship between these illnesses has not yet been examined in depth. This review is the first of its kind to critically examine the association between the COVID-19 epidemic and GER and its associated diseases. The key objective of this work is to promote the creation of prevention plans, treatment plans, and guidelines while also enhancing and optimizing our understanding of the relationship between COVID-19 and GERs.
Assuntos
COVID-19 , Refluxo Gastroesofágico , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , COVID-19/genética , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/patologia , Refluxo Gastroesofágico/virologia , Quarentena , Fatores de Risco , SARS-CoV-2/fisiologiaRESUMO
Background: The association between air pollution, lung function, gastroesophageal reflux disease, and Non-alcoholic fatty liver disease (NAFLD) remains inconclusive. Previous studies were not convincing due to confounding factors and reverse causality. We aim to investigate the causal relationship between air pollution, lung function, gastroesophageal reflux disease, and NAFLD using Mendelian randomization analysis. Methods: In this study, univariate Mendelian randomization analysis was conducted first. Subsequently, Steiger testing was performed to exclude the possibility of reverse association. Finally, significant risk factors identified from the univariate Mendelian analysis, as well as important factors affecting NAFLD from previous observational studies (type 2 diabetes and body mass index), were included in the multivariable Mendelian randomization analysis. Results: The results of the univariable Mendelian randomization analysis showed a positive correlation between particulate matter 2.5, gastroesophageal reflux disease, and NAFLD. There was a negative correlation between forced expiratory volume in 1 s, forced vital capacity, and NAFLD. The multivariable Mendelian randomization analysis indicated a direct causal relationship between gastroesophageal reflux disease (OR = 1.537, p = 0.011), type 2 diabetes (OR = 1.261, p < 0.001), and NAFLD. Conclusion: This Mendelian randomization study confirmed the causal relationships between air pollution, lung function, gastroesophageal reflux, and NAFLD. Furthermore, gastroesophageal reflux and type 2 diabetes were identified as independent risk factors for NAFLD, having a direct causal connection with the occurrence of NAFLD.