Objective To assess any potential associations between lung cancer and gut microbiota. Methods Mendelian randomization (MR) analysis was carried out by utilizing summary data from genome-wide association studies (GWAS) of the gut microbiota and lung cancer. The gut microbiota served as an exposure. Instrumental ariables (IVs) were identified from the GWAS of 18340 participants. The GWAS study of lung cancer from Europe served as an outcome, including 29 266 lung cancer patients and 56450 controls. We used the inverse-variance weighted (IVW) method as the primary analysis. Sensitivity analysis was used to test the reliability of MR analysis results. Results IVW results showed that Genus Parabacteroides (OR=1.258, 95%CI 1.034 to 1.531, P=0.022) and Phylum Bacteroidetes (OR=1.192, 95%CI 1.001 to 1.419, P=0.048) had a positive causal association with lung cancer, and there was a negative causal association between family Bifidobacteriaceae (OR=0.845, 95%CI 0.721 to 0.989, P=0.037) and order Bifidobacteriales (OR=0.865, 95%CI 0.721 to 0.989, P=0.037) with lung cancer. Sensitivity analysis showed no evidence of reverse causality, pleiotropy, and heterogeneity. Conclusion This study demonstrates that Genus Parabacteroides and Phylum Bacteroidetes are related to an increased risk of lung cancer, family Bifidobacteriaceae and order Bifidobacteriales can reduce the risk of lung cancer. Our thorough investigations provide evidence in favor of a potential causal relationship between a number of gut microbiota-taxa and lung cancer. To demonstrate how gut microbiota influences the development of lung cancer, further research is necessary.
Objective To explore the correlation between physical activity, sleep and aging using a two-sample Mendelian randomization (MR) method. Methods The data through genome-wide association studies was summarized. The single nucleotide polymorphisms (SNPs) related to physical activity and sleep as instrumental variables was selected. The inverse variance weighting method was used for the main analyses, complemented by the weighted median method and MR Egger regression, and then sensitivity analyses were carried out in terms of multiplicity, heterogeneity and leave-one-out method. Finally, multivariate Mendelian methods were applied to eliminate confounders and find mediators. Results A total of two types of physical activity (strong physical activity, physical inactivity) and three sleep conditions (daytime naps, short sleep duration, adequate sleep duration) were found to have a causal relationship with frailty index (P<0.05), while physical inactivity was found to have a causal relationship with telomere length (P<0.05). A total of 167 SNPs were included in the analysis. Strong physical activity [correlation coefficient (β)=?1.26, 95% confidence interval (CI) (?1.60, ?0.96), P<0.0001], adequate sleep duration [β=?0.17, 95%CI (?0.26, ?0.09), P<0.001] were negatively correlated with the frailty index. Physical inactivity [β=1.47, 95%CI (0.85, 2.08), P<0.001], daytime naps [β=0.25, 95%CI (0.12, 0.39), P=0.0002], and short sleep duration [β=0.20, 95%CI (0.13, 0.27), P<0.0001] were positively associated with frailty index. Physical inactivity [β=?0.38, 95%CI (?0.69, ?0.07), P=0.02] was negatively correlated with telomere length. Percentage body fat, body fat mass, waist circumference, body weight and body mass index partially mediated 25.52%, 23.52%, 10.08%, 17.6% and 10.08% of the effect between daytime naps and frailty index, respectively. Conclusion There is a causal relationship between physical activity, sleep, and aging.
Objective To analyze the causal relationship between educational attainment and the risk of systemic lupus erythematosus (SLE). Methods Based on the data from publicly available genome-wide association studies, we employed single nucleotide polymorphisms (SNPs) strongly associated with educational attainment as instrumental variables. Two-sample Mendelian randomization analysis was used to investigate the causal relationship between educational attainment and SLE. The primary analysis method used was the inverse variance weighted with multiplicative random effects. Validation methods included inverse variance weighted with fixed effects and MR-Egger methods. Additionally, sensitivity analysis was conducted using the leave-one-out approach. Results Finally, 433 SNPs were included. The inverse variance weighted with multiplicative random effects analysis indicated no causal effect of educational attainment on the risk of SLE [odds ratio =1.111, 95% confidence interval (0.813, 1.518), P=0.509]. Similarly, the other two methods did not find any evidence of a causal relationship (P>0.05); however, significant heterogeneity was observed. The MR-Egger regression analysis provided no evidence of horizontal pleiotropy among the included instrumental variables (P>0.05). The leave-one-out approach did not identify any individual SNP that had a significant impact on the overall effect estimate. ConclusionIn conclusion, this study does not support a causal effect of educational attainment on the risk of SLE.
ObjectiveTo investigate the causal relationship between 731 kinds of immune cell phenotypes and positive-human epidermal growth factor receptor (HER+), negative-human epidermal growth factor receptor (HER–), negative-human epidermal growth factor receptor 2 (HER2–) breast cancer. MethodsGenome-wide association data using immune cell phenotype and breast cancer were used with inverse variance weighting as the primary analytical method; horizontal pleiotropy was tested using MR-PRESSO and outliers were corrected; in addition, the reliability of the obtained data was verified using Cochran’s Q test, Mendelian randomization (MR)- Egger regression and leave-one-out method were used to verify the reliability of the obtained data. ResultsFor HER+ breast cancer, CD3 on CD39+CD4+T cell [ OR=0.940, 95%CI (0.913, 0.968), P=0.019] was protective factor. For HER– breast cancer, no immune cell phenotype was found to be correlated with it. For HER2– breast cancer, CD3 on CD39+CD4+ T cell [OR=0.951, 95%CI (0.930, 0.973), P=0.014], CD3 on secreting CD4 regulatory T cell [OR=0.949, 95%CI (0.925, 0.974), P=0.023] were protective factors. ConclusionThere is a causal association between certain immune cell phenotypes and breast cancer, which may be predictive markers for early diagnosis of breast cancer and development of new immunotherapies.
Objective To explore the potential causal relationship between thyroid dysfunction and osteoporosis (OP) through bidirectional two-sample Mendelian randomization (MR) analysis to provide genetic evidence for the risk association between thyroid dysfunction and OP, and provide reference for early prevention and treatment of OP. Methods Causal relationships were estimated based on data from genome-wide association studies for hypothyroidism (n=410141), hyperthyroidism (n=460499), Hashimoto thyroiditis (n=395640), and OP (n=212778). The inverse variance weighted method was used as the main analysis method, and the other four methods were used as the supplementary analysis methods to evaluate the causal effect of thyroid dysfunction and OP. Results The results of inverse variance weighted method showed that hypothyroidism [odds ratio (OR)=1.097, 95% confidence interval (CI) (1.017, 1.183), P=0.017], hyperthyroidism [OR=1.089, 95%CI (1.000, 1.186), P=0.049] and Hashimoto thyroiditis [OR=1.190, 95%CI (1.054, 1.343), P=0.005] were positively correlated with the causal effect of OP. The results of reverse MR analysis did not support that OP would increase the risk of hypothyroidism, hyperthyroidism or Hashimoto thyroiditis (P>0.05). In the bidirectional MR analyses, there was no heterogeneity in Cochran Q detection, MR-Egger intercept test results showed that there was no horizontal pleotropy, and the leave-one-out method analysis results showed that the MR analysis results were reliable. Conclusion Hypothyroidism, hyperthyroidism, and Hashimoto thyroiditis increase the risk of OP, while OP is not found to increase the risk of thyroid dysfunction in reverse studies.
ObjectiveA two-sample Mendelian randomization analysis was used to explore the causal associations between four basic body indices (basal metabolic rate, body fat percentage, BMI and hip circumference) and myasthenia gravis (MG). MethodsPooled gene-wide association study (GWAS) data were obtained from large publicly searchable databases, and four basic body indices were selected as the exposure factors and myasthenia gravis as the outcome factors, and 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 performed in order to assess the potential causal relationship between the exposure and the disease. ResultsInverse variance weighting (IVW) analysis showed that increased basal metabolic rate (OR=1.39, 95%CI 1.00 to 1.93, P=0.047), body fat percentage (OR=1.61, 95%CI 1.06 to 2.44, P=0.024), and hip circumference (OR=1.67, 95%CI 1.29 to 2.17, P<0.001) increased the risk of MG. But there was no significant causal relationship between BMI and MG. ConclusionBasal metabolic rate, body fat percentage and hip circumference have a positive causal relationship with MG, while BMI does not have a significant causal relationship with MG.
Objective To investigate the causal relationship between 91 circulating inflammatory proteins and respiratory tract infection by bidirectional Mendelian randomization. Methods single nucleotide polymorphisms (SNPs) for 91 inflammatory circulating proteins were derived from GWAS data from a genome-wide association study of 14 824 subjects of European ancestry on the Olink Target platform, and SNPs for acute bronchitis, acute bronchiolitis, and acute laryngitis and tracheitis were derived from GWAS pooled data in the FinnGen database. Inverse variance weighting method was used as the main research method to conduct bidirectional Mendelian randomization analysis, and Cochran’ IVW Q test, MR-Egger regression method and one by one elimination method were used to conduct sensitivity tests to evaluate heterogeneity and horizontal pleiotropy. In order to reduce the incidence of Class I errors and improve the feasibility of the study, Bonferroni correction was performed.ResultsLevels of C hemokine C-X-C motif ligand 6 (CXCL6), matrix metalloproteinase-1 (MMP-1), hepatocyte growth factor (HGF), interleukin-10 (IL-10), chemokine C-X3-C motif ligand 1 (CX3CL1), and TNF-related activation-induced cytokine (TRANCE) were causally associated with acute bronchitis. MMP-1 level [OR: 1.239 0, 95%CI: 1.111 6-1.382 2, P<0.000 5] had a significant causal relationship with acute bronchitiss and played a promoting role. Levels of macrophage inflammatory protein-1α (MIP-1α), signaling lymphocyte activating molecules, and FMS-associated tyrosine kinase 3 ligand (FIt3L) were potentially causally associated with acute bronchiolitis. There was a potential causal relationship between C-X-C motif chemokine 5 (CXCL5), T cell surface glycoprotein CD6 subtype (CD6), fibroblast growth factor 19 (FGF-19), C-C motif chemokine 23 (CCL23), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor ligand superfamily member 12 (TNFSF12) levels and acute laryngitis and tracheitis. In reverse Mendelian randomization analysis, there were no positive results between acute bronchitis, acute bronchiolitis and 91 inflammatory factors. Acute laryngitis and tracheitis [OR: 1.076 3,95%CI: 1.012 9-1.143 7, P=0.017 6] were potentially causally associated with FGF-19 levels. Conclusions MMP-1 level have a significant causal relationship with acute bronchitis. The levels of other inflammatory factors such as CXCL6, HGF, MIP-1 alpha, FIt3L, CXCL5, FGF-19 are potentially causally associated with respiratory tract infections. MMP-1 may be an important target for the prediction or treatment of acute bronchitis.
ObjectiveTo analyze the causal relationship between the intake of cheese or tea and the risk of gastroesophageal reflux disease (GERD). MethodsUsing a two-sample Mendelian randomization approach, single nucleotide polymorphisms (SNPs) associated with milk or tea intake were used as instrumental variables. The causal effect of milk or tea intake on the risk of GERD was investigated using the MR Egger method, the weighted median method, the inverse-variance weighted (IVW) random-effects model, and the IVW fixed-effects model. Multivariable analysis was conducted using the MR Egger method, and leave-one-out sensitivity analysis was performed to validate the reliability of the data. ResultsCheese intake could reduce the occurrence of GERD [IVW random-effects model β=–1.010, 95%CI (0.265, 0.502), P<0.05], while tea intake could lead to the occurrence of GERD [IVW random-effects model β=0.288, 95%CI (1.062, 1.673), P<0.05]. ConclusionCheese intake may have a positive causal relationship with reducing the risk of GERD occurrence, while tea intake may have a positive causal relationship with increasing the risk of GERD occurrence.
ObjectiveTo investigate the causal relationship between gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) with its typical symptoms (snoring and daytime sleepiness) by using Mendelian randomization (MR). MethodsThe inverse-variance weighted method was used as the main analysis method to assess the causal effect. Sensitivity and pleiotropy analyses were carried out using leave-one-out and MR-Egger analysis, and then heterogeneity tests were conducted. ResultsIn the MR analysis, genetically predicted GERD was associated with a greater risk of OSA (IVW: OR=1.528, 95%CI 1.374 to 1.699, P=5.315E?15). Additional MR results were consistent with the IVW results, and no pleiotropy or heterogeneity was found. We also discovered a significant causal relationship between GRED and snoring (IVW: OR=0.959, 95%CI 0.949 to 0.969, P=1.507E?15), and daytime sleepiness (IVW: OR=1.024, 95%CI 1.021 to 1.036, P=4.580E?5), with no evidence of pleiotropy. ConclusionThe MR study supports a causal effect between GERD and OSA with its typical symptoms (daytime sleepiness and snoring).
ObjectiveTo explore whether there is a causal relationship between intestinal flora and esophageal cancer. MethodsSummary statistics of intestinal flora and esophageal cancer were obtained from the genome-wide association studies (GWAS) database. Five methods, including inverse variance weighted (IVW), weighted median estimation, Mendelian randomization (MR)-Egger regression, single mode, and weighted mode, were used for analysis, with IVW as the main analysis method. Sensitivity analysis was used to evaluate the reliability of MR results. ResultsIn the IVW method, Oxalobacteraceae [OR=1.001, 95%CI (1.000, 1.002), P=0.023], Faecalibacterium [OR=1.001, 95%CI (1.000, 1.002), P=0.028], Senegalimassilia [OR=1.002, 95%CI (1.000, 1.003), P=0.006] and Veillonella [OR=1.001, 95%CI (1.000, 1.002), P=0.018] were positively correlated with esophageal cancer, while Burkholderiales [OR=0.999, 95%CI (0.998, 1.001), P=0.002], Eubacterium oxidoreducens [OR=0.998, 95%CI (0.997, 0.999), P=0.038], Romboutsia [OR=0.999, 95%CI (0.998, 1.000), P=0.048] and Turicibacter[OR=0.998, 95%CI (0.997, 0.999), P=0.013] were negatively correlated with esophageal cancer. Sensitivity analysis showed no evidence of heterogeneity, horizontal pleiotropy and reverse causality. ConclusionOxalobacteraceae, Faecalibacterium, Senegalimassilia and Veillonella increase the risk of esophageal cancer, while Burkholderiales, Eubacterium oxidoreducens, Romboutsia and Turicibacter decrease the risk of esophageal cancer. Further studies are needed to explore how these bacteria affect the progression of esophageal cancer.