Causal relationship between 14 site‐specific cancers and venous thromboembolism
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ABSTRACT:
SUBMITTER: Chen X
PROVIDER: S-EPMC10686126 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe association between educational attainment (EA) and arterial thrombotic disease has been reported, but the causal relationship between EA and venous thromboembolism (VTE) is not clear. We aimed to assess the causal effect of EA on VTE using the two-sample mendelian randomization (MR) method.MethodsData mining was conducted on the genome wide association studies (GWAS), with exposure factor EA and outcome factor VTE. Two-sample Mendelian Randomization (TSMR) analysis was conducted, with the results obtained from the random effects inverse variance weighted method (IVW). Use the MR-Egger method for pleiotropy analysis and leave one method for sensitivity analysis to verify the reliability of the data.ResultsGenetically predicted decreased EA was associated with a decreased risk of VTE in both the FinnGen consortium and UK Biobank (FinnGen-VTE: OR = 0.848; 95% CI 0.776-0.927; P = 2.84 × 10-4; UKB-VTE OR = 0.996; 95% CI 0.994-0.999; P = 0.008) under a multiplicative random-effects IVW model. Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected.ConclusionsThe MR technique instructed a potential inverse causative relationship between EA and occurrence of VTE. Therefore, patients with low EA should be more vigilant about the occurrence of VTE.
| S-EPMC11803988 | biostudies-literature
Project description:Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02-1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30-1.93 per standard deviation increase in BMI, P = 5.8 × 10-6). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.
| S-EPMC5531049 | biostudies-literature
Project description:BackgroundPeople with cancer experience high rates of venous thromboembolism (VTE). Risk of subsequent cancer is also increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer.MethodsWe used data from large genome-wide association study meta-analyses to perform bidirectional Mendelian randomization analyses to estimate causal associations between genetic liability to VTE and risk of 18 different cancers.ResultsWe found no conclusive evidence that genetic liability to VTE was causally associated with an increased incidence of cancer, or vice versa. We observed an association between liability to VTE and pancreatic cancer risk [odds ratio for pancreatic cancer: 1.23 (95% confidence interval: 1.08-1.40) per log-odds increase in VTE risk, P = 0.002]. However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence to suggest a causal relationship.ConclusionsThese findings do not support the hypothesis that genetic liability to VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesize evidence for these mechanisms.
| S-EPMC10859161 | biostudies-literature
Project description:BackgroundPeople with cancer experience high rates of venous thromboembolism (VTE). Additionally, risk of subsequent cancer is increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer.MethodsWe used data from large genome-wide association study meta-analyses to perform bi-directional Mendelian randomisation analyses to estimate causal associations between genetically-proxied lifetime risk of VTE and risk of 18 different cancers.ResultsWe found no conclusive evidence that genetically-proxied lifetime risk of VTE was causally associated with an increased incidence of cancer, or vice-versa. We observed an association between VTE and pancreatic cancer risk (odds ratio for pancreatic cancer 1.23 (95% confidence interval 1.08 - 1.40) per log-odds increase in risk of VTE, P = 0.002). However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence from Mendelian randomisation to suggest a causal relationship.ConclusionsThese findings do not support the hypothesis that genetically-proxied lifetime risk of VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesise evidence for these mechanisms.
| S-EPMC10246038 | biostudies-literature
Project description:BackgroundVenous thromboembolism (VTE) is the abnormal coagulation of blood in deep veins, which impairs venous return and includes deep vein thrombosis (DVT) and pulmonary embolism (PE). The incidence of VTE is increasing, leading to severe complications and sequelae. Despite the widespread application of multi-omics analyses in vascular disease research, identifying the specific links between various metabolic products, cytokines, and VTE, as well as their potential mediating roles, requires further validation due to confounding factors.MethodsSummary statistics for 1,091 metabolites, 309 metabolite ratios (8,299 individuals), and 41 inflammatory cytokines (8,293 individuals) were obtained from the largest genome-wide association studies (GWAS). Summary statistics for VTE (21,021 cases, 391,160 controls), DVT (6,501 cases, 357,111 controls), and PE (10,046 cases, 401,128 controls) were derived from the FinnGen R10 dataset. We initially examined causal relationships using two-sample MR analysis, followed by Two-step Mendelian Randomization (TSMR) and Multivariable Mendelian Randomization (MVMR) to identify potential mediating mechanisms.ResultsWe identified causal associations for 78 blood metabolites with VTE, 79 with DVT, and 81 with PE. Among all 41 inflammatory cytokines included, only platelet-derived growth factor BB (PDGF-BB) levels showed a causal relationship with increased risks of VTE, DVT, and PE. MVMR analysis revealed that the associations between glycocholate levels and VTE, DVT, and PE were mediated by PDGF-BB, accounting for 14.54% (p=2.84E-04), 17.10% (p=3.64E-05), and 10.44% (p=1.39E-02), respectively. Furthermore, the associations between dodecanedioate (C12:1-DC) levels and VTE and DVT were also mediated by PDGF-BB, accounting for 12.79% (p=6.10E-04) and 12.17% (p=2.13E-04), respectively.ConclusionThis study reveals significant associations between specific blood metabolites and the risks of VTE, DVT, and PE, with some associations potentially mediated by PDGF-BB.
| S-EPMC11471515 | biostudies-literature
Project description:BackgroundPrevious studies have indicated that lower lung function is related to a higher risk of venous thromboembolism (VTE). However, causal inferences may be affected by confounders, coheritability or reverse causality. We aimed to explore the causal association between lung function and VTE.MethodsSummary data from public genome-wide association studies (GWAS) for lung function and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly related to exposure were filtered as proxy instruments. We adopted linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomization (MR) analyses to infer the genetic backgrounds and causal associations between different lung functions and VTE events.ResultsLDSC showed a genetic correlation between forced expiratory volume in one second (FEV1) and deep vein thrombosis (DVT) (rg = - 0.189, P = 0.005). In univariate MR (UVMR), there was suggestive evidence for causal associations of genetically predicted force vital capacity (FVC) with DVT (odds ratio (OR) 0.774; 95% confidence interval (CI) 0.641-0.934) via forwards analysis and genetically predicted pulmonary embolism (PE) with FVC (OR 0.989; 95% CI 0.979-0.999) via reverse analysis. Multivariate MR (MVMR) analyses of lung function-specific SNPs suggested no significant direct effects of lung function on VTE, and vice versa. Of note is the borderline causal effect of PE on FEV1 (OR 0.921; 95% CI 0.848-1.000).ConclusionsOur findings identified a coheritability of FEV1 (significant) and FVC (suggestive) with DVT. There was no convincing causal relationship between lung function and the risk of VTE events. The borderline causal effect of PE on FEV1 and the significant genetic correlation of FEV1 with DVT may have clinical implications for improving the quality of existing prevention and intervention strategies.
| S-EPMC9885683 | biostudies-literature
Project description:BackgroundVenous thromboembolism (VTE) is still one of the most severe health issues, increasing mortality and lengthening hospital stays. Different abundances of gut microbiota have been clinically linked to VTE and coagulopathy. However, whether gut microbiota affected VTE formation remained uncertain.MethodsThe causative links between VTE and 211 gut microbiota at phylum, class, order, family and genus level were separately investigated using two-sample Mendelian Randomization (MR) analysis. Firstly, single nucleotide polymorphisms (SNPs) locus-wide significantly (P < 1.0 × 10- 5) related with gut microbiome abundance were extracted from large genome-wide analysis (GWAS) meta-analysis summary data. Instrumental variables (IVs) without pleiotropy were selected using the PhenoScanner and MR PRESSO test. Then, the MR analysis was implemented using the inverse variance weighted (IVW) method. Moreover, weighted median method, MR Egger method, simple median method and MR PRESSO were conducted to validate the causal associations. The reliability of the results was also assessed utilizing various sensitivity analyses, reverse MR analysis and multivariate Mendelian Randomization analysis (MVMR).ResultsWe found the phylum Firmicutes was robustly protective against VTE with MR analysis. Moreover, five taxa of Actinobacteria phylum (Bifidobacteriales order, Actinomycetales order, Bifidobacteriaceae family, Actinomycetaceae family, Slackia genus) and two taxa of Firmicutes phylum (Bacillales order, Lachnospiraceae UCG-010 genus) were suggestively protective for VTE. While three taxa of Firmicutes phylum (Bacilli class, Lactobacillales order and Lactococcus genus) might suggestively increase the risk of VTE. Sensitivity analyses indicated no significant horizontal pleiotropy, heterogeneity, or reverse causal associations. Furthermore, MVMR analysis unveiled independently positive causal association of Firmicutes phylum and Lachnospiraceae UCG-010 genus with risk of VTE.ConclusionTwo taxa of gut microbes (Firmicutes phylum and Lachnospiraceae UCG-010 genus) were independently protective against VTE, which suggests a potential avenue for developing new cost-effective strategies with minor side effects for VTE prevention and treatment.
| S-EPMC11841150 | biostudies-literature
Project description:PurposeMajor depressive disorder (MDD) and venous thromboembolism (VTE) may be linked in observational studies. However, the causal association remains ambiguous. Therefore, this study investigates the causal associations between them.MethodsWe performed a two-sample univariable and multivariable bidirectional Mendelian randomization (MR) analysis to evaluate the associations between MDD and VTE. The summary genetic associations of MDD statistics were obtained from the Psychiatric Genomics Consortium and UK Biobank. Information on VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE) were obtained from the FinnGen Biobank. Inverse-variance weighting was used as the main analysis method. Other methods include weighted median, MR-Egger, Simple mode, and Weighted mode.ResultsUnivariable MR analysis revealed no significant associations between MDD and VTE risk (odds ratio (OR): 0.936, 95% confidence interval (CI): 0.736-1.190, p = 0.590); however, after adjusting the potential relevant polymorphisms of body mass index and education, the multivariable MR analysis showed suggestive evidence of association between them (OR: 1.163, 95% CI: 1.004-1.346, p = 0.044). Univariable MR analysis also revealed significant associations between MDD and PE risk (OR: 1.310, 95% CI: 1.073-1.598, p = 0.008), but the association between them was no longer significant in MVMR analysis (p = 0.072). We found no significant causal effects between MDD and DVT risk in univariable or multivariable MR analyses. There was also no clear evidence showing the causal effects between VTE, PE, or DVT and MDD risk.ConclusionWe provide suggestive genetic evidence to support the causal association between MDD and VTE risk. No causal associations were observed between VTE, PE, or DVT and MDD risk. Further validation of these associations and investigations of potential mechanisms are required.
| S-EPMC11231919 | biostudies-literature
Project description:BackgroundThe risk of venous thromboembolism (VTE) by cancer site is uncertain.ObjectiveTo estimate VTE risk by tumor site.MethodsWe enumerated observed active cancers by cancer site for Olmsted County, MN residents with incident VTE over the 13-year period, 1988-2000 (n = 345 of 1417). We used 1988-2000 Iowa State Surveillance, Epidemiology, and End Results (SEER) data to estimate the expected age-specific prevalence of cancer by cancer site for all VTE cases; standardized Morbidity Ratios (SMR) for each cancer site were estimated by dividing the observed number of cancers in the VTE incident cohort by the expected number. Relative risk regression was used to model the observed number of cancers of each site, adjusting for the expected value based on SEER prevalence data, using generalized linear regression with a Poisson error and the natural log of the age- and sex-group expected count as an offset.ResultsFor men and women with VTE, all cancer sites had an increased SMR, ranging from 4.1 for head neck cancer to 47.3 for brain cancer. Among women, the SMR for breast, ovarian and other gynecologic cancers were 8.4, 13.0 and 8.4, respectively; for men, prostate cancer SMR was 7.9. Adjusting for age and sex, the relative risk (RR) of cancer in VTE cases was associated with cancer site in a multivariable model (p < 0.001). Adjusting for age and sex, pancreatic, brain, other digestive cancers, and lymphoma had significantly higher RRs than the grouped comparison cancers.ConclusionsIncident VTE risk can be stratified by cancer site.
| S-EPMC4339484 | biostudies-literature
Project description:BackgroundThe risk of extracolonic cancer is increased in inflammatory bowel disease (IBD) patients, but it is not clear whether there is a causal relationship. We aimed to systematically estimate the causal relationship between IBD and extracolonic cancers.MethodsIndependent genetic variants strongly associated with IBD were extracted as instrumental variables from genome-wide association study (GWAS) conducted by the International IBD Genetics Consortium including 12,882 IBD patients, 5956 Crohn's disease (CD) patients, and 6968 ulcerative colitis (UC) patients. Three sources of cancer GWAS were selected as outcome data. Two-sample Mendelian randomization (MR) analysis was conducted to assess the causal effects of IBD on 32 extracolonic cancers. The meta-analysis was applied to assess the combined causal effect with multiple MR results.ResultsIBD, CD, and UC have potential causal associations with oral cavity cancer (IBD: OR = 1.180, 95% CI: 1.059 to 1.316, P = 0.003; CD: OR = 1.112, 95% CI: 1.008 to 1.227, P = 0.034; UC: OR = 1.158, 95% CI: 1.041 to 1.288, P = 0.007). Meta-analysis showed a significant positive causal relationship between IBD and breast cancer (OR = 1.059; 95% CI: 1.033 to 1.086; P < 0.0001) as well as a potential causal relationship between CD and breast cancer (OR = 1.029; 95% CI: 1.002 to 1.055; P = 0.032) based on combining multiple MR results.ConclusionsThis comprehensive MR analysis suggested that genetically predicted IBD, as well as its subtypes, may be a risk factor in the development of oral cavity and breast cancer.
| S-EPMC10566178 | biostudies-literature