Assessing the protective role of allergic disease in gastrointestinal tract cancers using Mendelian randomization analysis.
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ABSTRACT:
SUBMITTER: Yuan S
PROVIDER: S-EPMC8411419 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDespite early attempts, the relationship between immune characteristics and gastrointestinal tract cancers remains incompletely elucidated. Hence, rigorous and further investigations in this domain hold significant clinical relevance for the development of novel potential immunotherapeutic targets.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis using the tools available in the "TwoSampleMR" R package. The GWAS data for these 731 immune traits were sourced from the GWAS Catalog database. Concurrently, data on gastrointestinal tract cancers, encompassing malignant tumors in the esophagus, stomach, small intestine, colon, and rectum, were extracted from the FinnGen database. The immune traits subjected to MR analysis predominantly fall into four categories: median fluorescence intensities (MFI), relative cell (RC), absolute cell (AC), and morphological parameters (MP). To ensure the reliability of our findings, sensitivity analyses were implemented to address robustness, account for heterogeneity, and alleviate the impact of horizontal pleiotropy.ResultsA total of 78 immune traits causally linked to gastrointestinal tract cancers were identified, encompassing esophageal cancer (12 traits), gastric cancer (13 traits), small intestine cancer (22 traits), colon cancer (12 traits), and rectal cancer (19 traits). Additionally, 60 immune traits were recognized as protective factors associated with gastrointestinal tract cancers, distributed across esophageal cancer (14 traits), gastric cancer (16 traits), small intestine cancer (7 traits), colon cancer (14 traits), and rectal cancer (9 traits). Furthermore, it was observed that seven immune traits are causally related to gastrointestinal tract cancers in at least two locations. These traits include "CCR2 on CD14- CD16+ monocyte," "CD19 on IgD+ CD38-," "CD19 on IgD+ CD38- naive," "CD25hi CD45RA+ CD4 not Treg AC," "CD27 on unsw mem," "CD28 on CD39+ activated Treg," and "CD45 on CD4+."ConclusionThis study elucidates a causal link between immune cells and gastrointestinal tract cancers at various sites through genetic investigation. The findings of this research open up new perspectives and resources for exploring tumor prevention strategies and immunotherapeutic targets.
| S-EPMC10963466 | biostudies-literature
Project description:BackgroundAdiponectin is an important adipocytokine and has been associated with the risks of gastrointestinal cancers (GICs). Mendelian randomization (MR) analysis is needed to assess the causal relationships between adiponectin and GICs.MethodsWe retrieved the summary data of genome-wide association studies for adiponectin and six types of GICs in East Asians. A series of quality control steps were performed to select the eligible genetic instrumental tools. Horizontal pleiotropy and between-SNP heterogeneity were tested to choose the primary MR method. We also conducted sensitivity analyses to test the robustness of the main findings.ResultsWe detected neither heterogeneity nor horizontal pleiotropy for the eligible SNPs in all of the MR analyses. Inverse variance weighted (IVW) was therefore used as the primary method, and suggested that per 10% increase in log-transformed adiponectin level was significantly associated with a decreased risk of gastric cancer (odds ratio [OR] = 0.88, 95% CI 0.81, 0.96), whereas with an increased risk of hepatocellular carcinoma (OR = 1.26, 95% CI 1.09, 1.44) and of biliary tract cancer (OR = 1.54, 95% CI 1.12, 2.12). However, only the association between adiponectin and HCC risk was statistically significant after correction for multiple testing. No statistically significant association was detected between adiponectin and esophageal (OR = 1.05, 95% CI 0.89, 1.23), pancreatic (OR = 1.04, 95% CI 0.78, 1.37), and colorectal cancers (OR = 1.00, 95% CI 0.93, 1.07). Sensitivity analyses did not find contradictory results.ConclusionHigh level of adiponectin may have a causal effect on and can serve as a biomarker for the carcinogenesis of gastric cancer, hepatocellular carcinoma, and biliary tract cancer.
| S-EPMC9189470 | biostudies-literature
Project description:Endometrial cancer is the most commonly diagnosed gynecological cancer in developed countries. Based on evidence from observational studies which suggest selenium inhibits the development of several cancers (including lung and prostate cancer), selenium supplementation has been touted as a potential cancer preventative agent. However, randomized controlled trials have not reported benefit for selenium supplementation in reducing cancer risk. For endometrial cancer, limited observational studies have been conducted assessing whether selenium intake, or blood selenium levels, associated with reduced risk, and no randomized controlled trials have been conducted. We performed a two-sample Mendelian randomization analysis to examine the relationship between selenium levels (using a composite measure of blood and toenail selenium) and endometrial cancer risk, using summary statistics for four genetic variants associated with selenium levels at genome-wide significance levels (P < 5 × 10-8), from a study of 12,906 endometrial cancer cases and 108,979 controls, all of European ancestry. Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in endometrial cancer development (OR per unit increase in selenium levels Z-score = 0.99, 95% CI = 0.87-1.14). Similar results were observed for sensitivity analyses robust to the presence of unknown pleiotropy (OR per unit increase in selenium levels Z-score = 0.98, 95% CI 0.89-1.08 for weighted median; OR per unit increase in selenium levels Z-score = 0.90, 95% CI = 0.53-1.50 for MR-Egger). In conclusion, these results do not support the use of selenium supplementation to prevent endometrial cancer.
| S-EPMC6445879 | biostudies-literature
Project description:ObjectivesAllergic diseases and Meniere's disease found to have a possible link in observational study. However, the potential causal relationship between the two is unclear. Therefore, we aimed to explore the causal relationship between allergic diseases and Meniere's disease using a new data analysis technique called bidirectional Mendelian randomization study.MethodSummary-level statistics for Meniere's disease and three allergic diseases (asthma, allergic rhinitis, eczema/dermatitis) were obtained from large-scale genome-wide association studies. The inverse variance weighted method was used as the primary measure, supplemented by MR-Egger regression and the weighted median method. To ensure the reliability of the conclusions, Cochran's Q, MR-Egger intercept, MR-PRESSO test, leave-one-out test, and MR Steiger test were used.ResultsInverse-variance weighted method showed asthma (p = 0.008, OR = 3.908, 95% CI 1.424-10.724, adjust_p = 0.024), allergic rhinitis (p = 0.026, OR = 24.714, 95% CI 1.479-412.827, adjust_p = 0.026) and eczema/dermatitis (p = 0.019, OR = 3725.954, 95% CI 3.795 to 3,658,399.580, adjust_p = 0.029) all had a significant effect on Meniere's disease. Reverse Mendelian randomization studies have shown that Meniere's disease does not increase the risk of three allergic diseases. Sensitivity analysis showed no horizontal pleiotropy and heterogeneity for each trait.ConclusionOur Mendelian randomization analysis supports a positive causal relationship between three allergic diseases (asthma, allergic rhinitis, eczema/dermatitis) and Meniere's disease. This suggests that physicians should pay more attention to the Meniere's patient's allergy history and consider allergy avoidance as part of their treatment plan.Level of evidenceMendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.
| S-EPMC11338938 | biostudies-literature
Project description:Genome-wide association studies, which typically report regression coefficients summarizing the associations of many genetic variants with various traits, are potentially a powerful source of data for Mendelian randomization investigations. We demonstrate how such coefficients from multiple variants can be combined in a Mendelian randomization analysis to estimate the causal effect of a risk factor on an outcome. The bias and efficiency of estimates based on summarized data are compared to those based on individual-level data in simulation studies. We investigate the impact of gene-gene interactions, linkage disequilibrium, and 'weak instruments' on these estimates. Both an inverse-variance weighted average of variant-specific associations and a likelihood-based approach for summarized data give similar estimates and precision to the two-stage least squares method for individual-level data, even when there are gene-gene interactions. However, these summarized data methods overstate precision when variants are in linkage disequilibrium. If the P-value in a linear regression of the risk factor for each variant is less than 1×10??, then weak instrument bias will be small. We use these methods to estimate the causal association of low-density lipoprotein cholesterol (LDL-C) on coronary artery disease using published data on five genetic variants. A 30% reduction in LDL-C is estimated to reduce coronary artery disease risk by 67% (95% CI: 54% to 76%). We conclude that Mendelian randomization investigations using summarized data from uncorrelated variants are similarly efficient to those using individual-level data, although the necessary assumptions cannot be so fully assessed.
| S-EPMC4377079 | biostudies-other
Project description:BACKGROUND AND AIMS:Studying the consequences of addictive behaviours is challenging, with understanding causal relationships from observational data being particularly difficult. For example, people who smoke or drink excessively are often systematically different from those who do not, are less likely to participate in research and may misreport their behaviours when they do. Furthermore, the direction of causation between an addictive behaviour and outcome may be unclear. Mendelian randomization (MR) offers potential solutions to these problems. METHODS:We describe MR's principles and the criteria under which it is valid. We identify challenges and potential solutions in its application (illustrated using two applied examples) and describe methodological extensions in its application. RESULTS:MR is subject to certain assumptions, and requires the availability of appropriate genetic data, large sample sizes and careful design and conduct. However, it has already been applied successfully to the addiction literature. The relationship between alcohol consumption (proxied by a variant in the ADH1B gene) and cardiovascular risk has been investigated, finding that alcohol consumption increases risk, with no evidence of a cardioprotective effect at moderate consumption levels. In addition, heaviness of smoking (proxied by a variant in the CHRNA5-A3-B4 gene cluster) and risk of depression and schizophrenia have been investigated, with no evidence of a causal effect of smoking on depression but some evidence of a causal effect on schizophrenia. CONCLUSIONS:Mendelian randomization analyses are already producing robust evidence for addiction-related practice and policy. As genetic variants associated with addictive behaviours are identified, the potential for Mendelian randomization analyses will grow. Methodological developments are also increasing its applicability.
| S-EPMC5873430 | biostudies-literature
Project description:BackgroundArsenic exposure affects >100 million people globally and increases risk for chronic diseases. One possible toxicity mechanism is epigenetic modification. Previous epigenome-wide association studies (EWAS) have identified associations between arsenic exposure and CpG-specific DNA methylation. To provide additional evidence that observed associations represent causal relationships, we examine the association between genetic determinants of arsenic metabolism efficiency (percent dimethylarsinic acid, DMA%, in urine) and DNA methylation among individuals from the Health Effects of Arsenic Longitudinal Study (n = 379) and Bangladesh Vitamin E and Selenium Trial (n = 393).MethodsWe used multivariate linear models to assess the association of methylation at 221 arsenic-associated CpGs with DMA% and measures of genetically predicted DMA% derived from three SNPs (rs9527, rs11191527, and rs61735836). We also conducted two-sample Mendelian randomization analyses to estimate the association between arsenic metabolism efficiency and CpG methylation.ResultsAmong the associations between DMA% and methylation at each of 221 CpGs, 64% were directionally consistent with associations observed between arsenic exposure and the 221 CpGs from a prior EWAS. Similarly, among the associations between genetically predicted DMA% and each CpG, 62% were directionally consistent with the prior EWAS results. Two-sample Mendelian randomization analyses produced similar conclusions.ConclusionOur findings support the hypothesis that arsenic exposure effects DNA methylation at specific CpGs in whole blood. Our novel approach for assessing the impact of arsenic exposure on DNA methylation requires larger samples in order to draw more robust conclusions for specific CpG sites.
| S-EPMC7147391 | biostudies-literature
Project description:BackgroundObservational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). It remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to evaluate the causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertensive drugs (AHDs), ALS, and their corresponding genome-wide association study (GWAS) summary datasets were obtained from the most recent studies with the largest sample sizes. The inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods were used for sensitivity analyses. To exclude the interference between SBP and DBP, a multivariable MR approach was used.ResultsWe found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960-0.996, P = 0.017) and that increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003-1.025, P = 0.015), which is supported by sensitivity analyses. The use of calcium channel blocker (CCB) showed a causal relationship with ALS (OR = 0.985, 95% CI 0.971-1.000, P = 0.049). No evidence was revealed that ALS caused changes in BP.ConclusionsThis study provides genetic support for a causal effect of BP and ALS that increased DBP has a protective effect on ALS, and increased SBP is a risk factor for ALS, which may be related to sympathetic excitability. Blood pressure management is essential in ALS, and CCB may be a promising candidate.
| S-EPMC8848798 | biostudies-literature
Project description:The causality of the association between depression and gastrointestinal diseases is undetermined. We conducted Mendelian randomization (MR) analyses to systematically explore the associations of depression with 24 gastrointestinal diseases. Independent genetic variants associated with depression at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analysis was conducted to explore the mediation effects of body mass index, cigarette smoking, and type 2 diabetes. After multiple-testing corrections, genetic liability to depression was associated with an increased risk of irritable bowel syndrome, non-alcohol fatty liver disease, alcoholic liver disease, gastroesophageal reflux, chronic pancreatitis, duodenal ulcer, chronic gastritis, gastric ulcer, diverticular disease, cholelithiasis, acute pancreatitis, and ulcerative colitis. For the causal effect of genetic liability to depression on non-alcoholic fatty liver disease, a substantial proportion was mediated by body mass index. Genetic predisposition to smoking initiation mediated half of effect of depression on acute pancreatitis. This MR study suggests that depression may play a causal role in many gastrointestinal diseases.
| S-EPMC10160129 | biostudies-literature
Project description:Upper gastrointestinal tract malignancies are among the most challenging cancers with regard to response to treatment and prognosis. Cancers of the esophagus, stomach, pancreas, liver, and biliary tree have dismal 5-year survival, and very modest improvements in this rate have been made in recent times. Oncolytic viruses are being developed to address these malignancies, with a focus on high safety profiles and low off-target toxicities. Each viral platform has evolved to enhance oncolytic potency and the clinical response to either single-agent viral therapy or combined viral treatment with radiotherapy and chemotherapy. A panel of genomic alterations, chimeric proteins, and pseudotyped capsids are the breakthroughs for vector success. This article revisits developments for each viral platform to each tumor type, in an attempt to achieve maximum tumor selectivity. From the bench to clinical trials, the scope of this review is to highlight the beginnings of translational oncolytic virotherapy research in upper gastrointestinal tract malignancies and provide a bioengineering perspective of the most promising platforms.
| S-EPMC5870634 | biostudies-literature