Objective To analyze the potential causal relationship between sunscreen/ultraviolet protection and the risk of non-Hodgkin lymphoma using a two sample Mendelian randomization (MR) study method. Methods The summary data of genome-wide association study was used to select three types of non-Hodgkin lymphoma, namely diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, T/NK cell lymphoma, and sunscreen/ultraviolet protection highly correlated genetic loci, namely single nucleotide polymorphism (SNP), as instrumental variables. The reverse variance weighting method was used as the main method for MR analysis, MR Egger and MR-PRESO were used to detect level pleiotropy, and leave-one-out method was used for sensitivity analysis to ensure the robustness of the results. Results A total of 132 SNPs were included in the analysis. The results of the inverse variance weighted analysis showed that sunscreen/ultraviolet protection increased the incidence of DLBCL [odds ratio=2.439, 95% confidence interval (1.109, 5.362), P=0.027]. The heterogeneity test results showed that there was no heterogeneity in the causal relationship between sunscreen/ultraviolet protection and DLBCL (P>0.05). The results of the horizontal pleiotropy test showed that SNP did not exhibit horizontal pleiotropy (P>0.05). The leave-one-out method showed that no SNP with a significant impact on the results was found. There was no causal relationship between sunscreen/ultraviolet protection and follicular lymphoma and T/NK cell lymphoma. Conclusion There is a positive causal relationship between sunscreen/ultraviolet protection and the incidence of DLBCL.
ObjectiveThyroid nodules are an exceptionally common thyroid disorder. Past studies suggested a possible link between thyroid diseases and breast neoplasms. However, few studies have delved into the causal relationship between thyroid nodules and breast neoplasms. This study conducted a Mendelian randomization (MR) analysis to further investigate the causal relationship between them. MethodsThis study was conducted using data sourced from genome-wide association study (GWAS) summary datasets. The study focused on thyroid nodules, benign breast tumors, and malignant breast cancers as the research objects, and relevant single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs). The inverse-variance weighted (IVW) was primarily used to assess the causal relationship between thyroid nodules and breast neoplasms. Cochran’s Q test was employed to detect heterogeneity, while MR-Egger intercept and MR-PRESSO were used to test for pleiotropy. Sensitivity analysis was conducted using the leave-one-out method. ResultsThere was a significant causal relationship between thyroid nodules and malignant neoplasm of breast (OR=0.88, 95%CI 0.83 to 0.95, P<0.01), with no evidence of reverse causality between them (OR=1.01, 95%CI 0.99 to 1.03, P=0.16). No causal relationship was found between thyroid nodules and benign neoplasm of breast, as indicated by both forward MR analysis (OR=0.97, 95%CI 0.89 to 1.06, P=0.51) and reverse MR analysis (OR=0.97, 95%CI 0.92 to 1.04, P=0.40). Sensitivity analyses suggested that the study findings were accurate and reliable. ConclusionThe present study identifies thyroid nodules as a potential protective factor for malignant neoplasm of breast.
Objective To investigate the potential causal associations between 731 immune cell traits and atherosclerosis by Mendelian randomization (MR) analysis. Methods Using single nucleotide polymorphisms (SNPs) as instrumental variables, genome-wide association study (GWAS) summary statistics (GCST90001391 to GCST90002121) for 731 immune cell traits were obtained from the GWAS Catalog database, and the atherosclerosis dataset (finn-b-I9_CORATHER) was retrieved from the IEU database for MR analysis. The inverse variance weighted method, MR-Egger regression, weighted median, simple mode, and weighted mode approaches were employed to estimate the causal effects between the 731 immune cell traits and atherosclerosis, using odds ratio (OR) with 95% confidence interval (CI) as the effect size. Cochran Q test was used to assess heterogeneity. Horizontal pleiotropy was evaluated using the MR-Egger intercept test and the MR-PRESSO method. Leave-one-out analysis was conducted to examine the sensitivity of the causal estimates to individual SNPs. Results MR analysis revealed potential causal associations between 24 immune cell traits and atherosclerosis (P<0.05). Among them, human leucocyte antigen (HLA)-DR on plasmacytoid dendritic cells (DC) [OR=1.035, 95%CI (1.016, 1.054), P<0.001] and hematopoietic stem cell absolute count (HSCAC) [OR=1.049, 95%CI (1.021, 1.077), P<0.001] showed significant positive causal associations with atherosclerosis (P≤0.001), whereas CD86 on CD62L+ myeloid DC [OR=0.953, 95%CI (0.926, 0.981), P=0.001] exhibited a significant negative causal association with atherosclerosis (P≤0.001). The results of Cochran Q test, MR-Egger regression, and MR-PRESSO indicated P-values>0.05, suggesting no evidence of heterogeneity or horizontal pleiotropy in the causal estimates for these three immune cell traits. Reverse MR analysis, using the 24 immune cell traits as outcome variables, showed no evidence of causal association (P>0.05), supporting a unidirectional causal relationship from immune cells to atherosclerosis. Conclusion HLA-DR on plasmacytoid DC and HSCAC may serve as risk factors for atherosclerosis, while CD86 on CD62L+ myeloid DC may play a protective role against atherosclerosis.
Objective To investigate the potential causal relationship between specific oral microbiota and peptic ulcer disease (PUD) using a Mendelian randomization (MR) approach. Methods The genome-wide association study (GWAS) data from East Asian populations was utilized to perform a two-sample MR analysis to determine the causal relationship between oral microbiota and PUD. The MR analysis was primarily conducted using the inverse-variance weighted (IVW) method, supplemented by MR-Egger and weighted median methods. Heterogeneity and pleiotropy were assessed, and the leave-one-out method was employed to evaluate the stability of the MR results. Results There was a complex association between specific bacterial genera of the oral microbiota and PUD. Prevotella was found to potentially promote duodenal ulcers while exerting a protective effect against gastric ulcers. Campylobacter and Streptococcus demonstrated differing effects on gastric and duodenal ulcers. Furthermore, Fusobacterium and Haemophilus_A were positively associated with peptic ulcers, suggesting an increased risk of gastroduodenal ulcer development. Conclusion This study explores the causal relationship between oral microbiota and PUD, providing new insights into the prevention and treatment of PUD mediated by oral microbiota.
ObjectiveTo investigate the potential causal relationship between four types of reproductive behaviors and rheumatoid arthritis (RA), with the goal of establishing a theoretical foundation for clinical prevention and treatment strategies. MethodsPooled gene-wide association study (GWAS) data were obtained from large publicly searchable databases. Four characteristics like menarche, menopause, the age of first pregnancy and the age of last pregnancy, which related to reproductive behavior were selected as the exposure factors and RA as the outcome factors. Single nucleotide polymorphisms (SNPs), which were strongly correlated with the phenotype of the exposure factors, were screened as the instrumental variables, and two-sample Mendelian randomization analyses were used to assess the potential causal relationship between the exposure and the disease. Results① The Mendelian randomization analysis utilizing the inverse variance weighted method on two distinct samples revealed a significant negative correlation between the age of first pregnancy and last pregnancy with the risk of RA (OR=0.91, 95%CI 0.85 to 0.98, P=0.011; OR=0.54, 95%CI 0.31 to 0.93, P=0.026). Conversely, no causal relationship was observed between menarche and menopause with RA. Sensitivity analysis confirmed the robustness of the causal relationship, while MR Egger intercept analysis did not identify any potential horizontal pleiotropy (Page of first gestation -RA=0.169, Page of last gestation -RA=0.283). ② Reverse Mendelian randomization analysis revealed a significant positive causal association between RA and the age of first pregnancy, while no causal relationship was observed with the age of last pregnancy (OR=1.07, 95%CI 1.02 to 1.11, P=0.001). ③ Multivariate Mendelian randomization analysis demonstrated that both the age of first pregnancy and last pregnancy in women were inversely associated with the risk of RA (OR=0.88, 95%CI 0.80 to 0.97, P=0.010; OR=0.68, 95%CI 0.48 to 0.97, P=0.033). ④ There existed a negative correlation between the age of pregnancy in women and the risk of developing RA, suggesting a potential protective effect. ConclusionPregnancy age may have a negative causal relationship with the risk of RA, while menarche and menopause have no causal relationship with RA.
How to accurately identify factors of cancer occurrence and to provide intervention early are the key issues that urgently need to be addressed in cancer prevention and treatment. Mendelian randomization (MR) analysis uses genetic variants as instrument variables for exposures of interest, which compensates the shortcomings of traditional observational studies and clinical trials. This review introduced the current application status of MR analysis in cancer etiology and treatment researches in details, including assessment of cancer risk factors, exploration of cancer treatment targets, and evaluation of drug efficiency and adverse reactions. The scopes and dimensions of cancer etiology and treatment researches are greatly expanded because of various MR designs and abundant high-level omics data. As well, it provides a practical and feasible method for constructing cancer etiology networks and drug targeted databases, which are promising for supporting the development of precision cancer prevention and treatment.
Randomized controlled trial has been the "gold standard" for clinical trials, in which randomization serves as a fundamental principle of clinical trials and plays an important role in balancing covariates. The allocation probability in traditional design is fixed, while that in adaptive randomization can alter during the experiment according to the specified plan to achieve the purposes of balancing the sample size, maximizing the benefit of patient, or balancing covariates etc. In this study, the adaptive randomization methods applied in clinical trials are discussed to explore their advantages and disadvantages for providing reference for the randomization of clinical trials.
ObjectiveTo explore the causal association between venous thromboembolism (VTE) and cardiovascular disease (CVD) risks using a two-sample bidirectional Mendelian randomization (MR) study. MethodsThe single-nucleotide polymorphism (SNP) data associated with VTE and CVD from genome-wide association studies were obtained as instrumental variables. Inverse variance weighted (IVW) was used as the main MR method and other methods were used as supplementary methods. Cochran's Q test, the intercept term of MR-Egger, and MR-PRESSO were used to assess pleiotropy and heterogeneity to ensure the robustness of the results. ResultsThe IVW method suggested a causal association between VTE and atrial fibrillation (OR=1.033, 95%CI 1.009 to 1.058, P=0.008), but no association was identified between VTE and coronary artery disease (OR=0.994, 95%CI 0.974 to 1.023, P = 0.551), heart failure (OR=1.021, 95%CI 0.992 to 1.050, P=0.159) and myocardial infarction (OR=1.012, 95%CI 0.971 to 1.055, P=0.568). The results of Cochran's Q test showed that there was no heterogeneity in the MR analyses of VTE and CVD. The MR-Egger intercept analysis and the MR-PRESSO global testing did not detect potential horizontal pleiotropy, and the results were robust. Reverse MR analysis was used to verify the presence of reverse causal associations. The reverse MR analysis demonstrated that reverse causal associations between VTE and CVD were not evidenced. ConclusionThe results of the MR study demonstrated a causal association between VTE and atrial fibrillation, but not with coronary artery disease, heart failure or myocardial infarction.
Objective To explore the causal association between obstructive sleep apnea (OSA) and venous thromboembolism (VTE). Methods Using the summary statistical data from the FinnGen biological sample library and IEU OpenGWAS database, the relationship between OSA and VTE, including deep vein thrombosis (DVT) and pulmonary embolism, was explored through Mendelian randomization (MR) method, with inverse variance weighted (IVW) as the main analysis method. Results The results of univariate MR analysis using IVW method showed that OSA was associated with VTE and pulmonary embolism (P<0.05), with odds ratios and 95% confidence intervals of 1.204 (1.067, 1.351) and 1.352 (1.179, 1.544), respectively. There was no correlation with DVT (P>0.05). Multivariate MR analysis showed that after adjustment for confounding factors (smoking, diabetes, obesity and cancer), OSA was associated with VTE, DVT and pulmonary embolism (P<0.05), with odds ratios and 95% confidence intervals of 1.168 (1.053, 1.322), 1.247 (1.064, 1.491) and 1.158 (1.021, 1.326), respectively. Conclusion OSA increases the risk of VTE, DVT, and pulmonary embolism.
Objective To analyze the causal relationship between gut microbiota and childhood asthma based on Mendelian randomization (MR). Methods The human gut microbiota dataset was downloaded from the MiBioGen database, and 196 known bacterial groups (9 phyla, 16 classes, 20 orders, 32 families, and 119 genera) were retained as exposure factors. Single nucleotide polymorphisms (SNPs) that were strongly correlated with exposure factors and independent of each other were selected as effective instrumental variables. A childhood asthma dataset with 3 025 patients and 135 449 controls was downloaded from the genome-wide association studies database as the outcome variable. Two-sample MR analysis was performed using inverse variance weighted, weighted median, MR-Egger, weighted model and simple model methods, respectively. The causal association between gut microbiota and childhood asthma was evaluated by odds ratio (OR). Sensitivity analysis was performed by leave-one-out method. Horizontal pleiotropy was tested by MR-Egger intercept test and MR-PRESSO global test, and Cochran’s Q test was used for heterogeneity. Results A total of 15 out of 196 gut microbiota groups were found to have a causal association (P<0.05) with the risk of childhood asthma, with a total of 181 SNPs included in the analysis. Inverse variance weighted analysis showed that Mollicutes [OR=1.42, 95% confidence interval (CI) (1.10, 1.83), P=0.007], Escherichia-Shigella [OR=1.39, 95%CI (1.02, 1.90), P=0.036], Oxalobacter [OR=1.30, 95%CI (1.10, 1.54), P=0.002], Ruminococcaceae UCG-009 [OR=1.34, 95%CI (1.09, 1.64), P=0.006] and Tenericutes [OR=1.42, 95%CI (1.10, 1.83), P=0.007] were significantly positively correlated with childhood asthma. Actinobacteria [OR=0.76, 95%CI (0.58, 0.99), P=0.042], Bifidobacteriaceae [OR=0.76, 95%CI (0.58, 0.98), P=0.035], Eubacterium nodatum group [OR=0.81, 95%CI (0.70, 0.94), P=0.007], Bifidobacterales [OR=0.76, 95%CI (0.58, 0.98), P=0.035] and Actinobacteria [OR=0.74, 95%CI (0.56, 0.99), P=0.040] were negatively correlated with childhood asthma. In addition, the results of leave-one-out sensitivity analysis were stable, MR-Egger intercept test and MR-PRESSO global test showed no horizontal pleiotropy, and Cochran’s Q test showed no heterogeneity. Conclusions There is a causal relationship between gut microbiota and childhood asthma. Mollicutes, Escherichia-Shigella, Oxalobacter, Ruminococcaceae UCG-009 and Tenericutes may increase the risk of childhood asthma. Actinobacteria, Bifidobacteriaceae, Eubacterium nodatum group, Bifidobacterales and Actinobacteria can reduce the risk of childhood asthma.