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 | 2021 May
REPOSITORIES: biostudies-literature
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Assessing the protective role of allergic disease in gastrointestinal tract cancers using Mendelian randomization analysis.
Yuan Shuai S Vithayathil Mathew M Kar Siddhartha S Carter Paul P Mason Amy M AM Xie Shao-Hua SH Burgess Stephen S Larsson Susanna C SC
Allergy 20201021 5
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| S-EPMC10963466 | biostudies-literature
Project description:Morning chronotype has been associated with a reduced risk of prostate and breast cancer. However, few studies have examined whether chronotype is associated with digestive tract cancer risk. We conducted a Mendelian randomization (MR) study to assess the associations of chronotype with major digestive tract cancers. A total of 317 independent genetic variants associated with chronotype at the genome-wide significance level (P < 5 × 10-8 ) were used as instrumental variables from a genome-wide meta-analysis of 449 734 individuals. Summary-level data on overall and six digestive tract cancers, including esophageal, stomach, liver, biliary tract, pancreatic and colorectal cancers, were obtained from the UK Biobank (11 952 cases) and FinnGen (7638 cases) study. Genetic liability to morning chronotype was associated with reduced risk of overall digestive tract cancer and cancers of stomach, biliary tract and colorectum in UK Biobank. The associations for the overall digestive tract, stomach and colorectal cancers were directionally replicated in FinnGen. In the meta-analysis of the two sources, genetic liability to morning chronotype was associated with a decreased risk of overall digestive tract cancer (odds ratio [OR] 0.94, 95% confidence interval [CI]: 0.90-0.98), stomach cancer (OR 0.84, 95% CI: 0.73-0.97) and colorectal cancer (OR 0.92, 95% CI: 0.87-0.98), but not with the other studied cancers. The associations were consistent in multivariable MR analysis with adjustment for genetically predicted sleep duration, short sleep, insomnia and body mass index. The study provided MR evidence of inverse associations of morning chronotype with digestive tract cancer, particularly stomach and colorectal cancers.
| S-EPMC7613990 | biostudies-literature
Project description:The association between osteoarthritis (OA) and gastrointestinal disorders was found in observational studies. However, the causality is still elusive. A bidirectional Mendelian randomization (MR) analysis using genome wide association studies data was conducted to assess the causal association between OA and gastrointestinal diseases [including peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD), and inflammatory bowel disease (IBD)]. A two-step MR (TSMR) was conducted between OA, gastrointestinal diseases and drugs to explore the mediating effects of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids use. We used multivariable MR (MVMR) analysis to further validate the impact of prescription history on diseases. Results had statistical significance at a Bonferroni corrected P-value below 0.008. We observed that genetically predicted OA had a significant positive association with GORD [odds ratio (OR) = 1.26, P = 5e-05], but not with PUD or IBD. Regarding the other direction, gastrointestinal disorders as exposure had a null association with OA. Using TSMR, OA patients tended to increase the use of NSAIDs (OR = 1.45, P = 0.001) and opioids (OR = 1.77, P = 2e-05), but only the use of opioids increased the risk of GORD (OR = 1.43, P = 5e-09). Further MVMR analysis showed that the adverse effect of OA on GORD was significantly reduced after adjusting for opioids use (OR = 1.20, P = 0.038). This study provides evidence for the causal association between OA and increased risk of GORD, which is partly attributed to opioids use in OA patients but not NSAIDs.
| S-EPMC10638284 | biostudies-literature
Project description:BackgroundEpigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.MethodsWe conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.ResultsMeta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers.ConclusionsGrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.FundingFMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.
| S-EPMC9049976 | 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:BackgroundThe association between Parkinson's disease (PD) and gastrointestinal (GI) cancers remains unknown. This study aims to assess the causal effect of PD on colon cancer (CC), gastric cancer (GC), esophageal cancer (EC), and rectal cancer (RC) using the two-sample Mendelian randomization (MR) method.MethodsFive pairs of summary datasets of genome-wide association studies (GWAS) from publicly available studies [Integrative Epidemiology Unit (IEU) OpenGWAS project, FinnGen, and GWAS Catalog database] were enrolled. The inverse variance weighted (IVW) method was used as the primary outcome for MR analysis. Cochran Q-derived, MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods, and leave-one-out analysis were used to test heterogeneity and directional pleiotropy.ResultsFor the European population, no significant causal effect of PD on the risk of CC was found [odds ratio (OR) =0.9; 95%, confidence interval (CI): 1.00-1.11; P=0.42]. The same applied to the East Asian population (OR =1.05; 95% CI: 0.66-1.66; P=0.63). As for GC, no causal effect was found (OR =0.94, 95% CI: 0.89-0.99; P=0.22). Moreover, the genetic liability for PD was not associated with EC (OR =1.00; 95% CI: 0.99-1.00; P=0.32). Finally, no evidence was found for any causal effect of genetic liability for PD on an increased risk of RC (OR =1.00; 95% CI: 0.99-1.00; P=0.71).ConclusionsThere is no causal effect of genetic liability for PD on an increased risk of GI cancer.
| S-EPMC11399876 | biostudies-literature
Project description:Recent research has demonstrated a relationship between fruit and vegetable intake and gastrointestinal cancers, but the causality of these associations remains uncertain. This investigation sought to elucidate whether there is a potential causal relationship between the intake of fruits and vegetables and the risk of gastrointestinal cancers. Employing two-sample Mendelian randomization (MR), this research explored the causative influence of consuming fruits (fresh and dried) and vegetables (salads/raw and cooked) on the susceptibility to gastrointestinal cancers. The UK Medical Research Council-Integrative Epidemiology Unit (MRC-IEU) provided the summary statistics for these exposure variables, while the summary statistics for outcome data came from four other data sources. Univariable and multivariable MR were performed using inverse variance-weighted (IVW), MR-Egger, weighted media (WM), and Lasso model methods. Besides, multiple methods were employed for sensitivity analyses to guarantee the robustness of the findings, including MR-Egger intercept, Cochran's Q test, and MR-PRESSO. Furthermore, the Phenoscanner V2 database was employed to identify possible confounders. The main analysis of univariable MR found that dried fruit consumption provided protection against pancreatic and oral cavity/pharyngeal cancers. However, this correlation becomes non-significant when potential confounders such as smoking, drinking, and body mass index (BMI) are accounted for. Furthermore, neither univariate nor multivariate MR analyses revealed enough data to prove a causal relationship between the intake of fresh fruit, vegetables (including salad/raw and cooked), and gastrointestinal cancers. There is insufficient evidence for a causal association between the consumption of fruits and vegetables and the occurrence of gastrointestinal cancers. Further empirical research is needed to corroborate these dietary factors' role in the etiology of gastrointestinal cancers.
| S-EPMC11582617 | biostudies-literature
Project description:BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
| S-EPMC10724909 | biostudies-literature
Project description:Background Previous observational studies suggested inconsistent insights on the associations between meat intake and the risk of digestive tract cancers (DCTs). The causal effect of meat intake on DCTs is unclear. Methods Two-sample Mendelian randomization (MR) was performed based on genome-wide association studies (GWAS) summary data from UK Biobank and FinnGen to evaluate the causal effect of meat intake [processed meat, red meat (pork, beef, and lamb), and white meat (poultry)] on DCTs (esophageal, stomach, liver, biliary tract, pancreatic, and colorectal cancers). The causal effects were estimated using a primary analysis that employed inverse-variance weighting (IVW) and complementary analysis that utilized MR-Egger weighted by the median. A sensitivity analysis was conducted using the Cochran Q statistic, a funnel plot, the MR-Egger intercept, and a leave-one-out approach. MR-PRESSO and Radial MR were performed to identify and remove outliers. To demonstrate direct causal effects, multivariable MR (MVMR) was applied. In addition, risk factors were introduced to explore potential mediators of the relationship between exposure and outcome. Results The results of the univariable MR analysis indicated that genetically proxied processed meat intake was associated with an increased risk of colorectal cancer [IVW: odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.07–4.19; P = 0.031]. The causal effect is consistent in MVMR (OR = 3.85, 95% CI 1.14–13.04; P = 0.030) after controlling for the influence of other types of exposure. The body mass index and total cholesterol did not mediate the causal effects described above. There was no evidence to support the causal effects of processed meat intake on other cancers, except for colorectal cancer. Similarly, there is no causal association between red meat, white meat intake, and DCTs. Conclusions Our study reported that processed meat intake increases the risk of colorectal cancer rather than other DCTs. No causal relationship was observed between red and white meat intake and DCTs.
| S-EPMC9968810 | biostudies-literature
Project description:BackgroundType 2 diabetes mellitus (DM2) and osteoporosis (OP) are currently the two most significant causes of mortality and morbidity in older adults, according to clinical evidence. The intrinsic link between them is yet unknown, despite reports of their coexistence. By utilizing the two-sample Mendelian randomization (MR) approach, we sought to evaluate the causal impact of DM2 on OP.MethodsThe aggregate data of the whole gene-wide association study (GWAS) were analyzed. A two-sample MR analysis was performed using single-nucleotide polymorphisms (SNPs), which are strongly associated with DM2, as instrumental variables (IVs) to evaluate the causal analysis of DM2 on OP risk with OR values, using inverse variance weighting, MR-egger regression, and weighted median methods, respectively.ResultA total of 38 single nucleotide polymorphisms were included as tool variables. According to the results of inverse variance-weighted (IVW), we found that there was a causal relationship between DM2 and OP, in which DM2 had a protective effect on OP. For each additional case of DM2, there is a 0.15% decrease in the odds of developing OP (OR = 0.9985;95%confidence interval:0.9974,0.9995; P value = 0.0056). There was no evidence that the observed causal effect between DM2 and the risk of OP was affected by genetic pleiotropy (P = 0.299). Using Cochran Q statistics and MR-Egger regression in the IVW approach, the heterogeneity was calculated; P > 0.05 shows that there is a significant amount of heterogeneity.ConclusionA causal link between DM2 and OP was established by MR analysis, which also revealed that DM2 decreased the occurrence of OP.
| S-EPMC10236750 | biostudies-literature