Objective To explore the causal relationship between DNA copy number and the risk of Alzheimer disease (AD) using Mendelian randomization (MR) methods, as well as to investigate the potential mediating effects of immune cells. Methods The data related to 731 immune cell types, DNA copy number and AD from the Genome-Wide Association Study database were collected. A bidirectional MR analysis was conducted to explore the causal relationship between DNA copy number and AD, primarily using the inverse-variance weighted method and MR-Egger method. Additionally, a two-step mediation analysis was performed to identify potential mediating immune cells. Results A total of 134 single-nucleotide polymorphisms were included for bidirectional MR analysis. The MR methods results showed a negative causal relationship between DNA copy number and the risk of AD (P<0.05), while the reverse analysis showed no statistical significance. Sensitivity analysis confirmed the robustness of these results. The mediation analysis indicated that the immune cell phenotype (HVEM on CD45RA-CD4+) partially mediated the causal relationship between DNA copy numbers and the risk of AD, with a mediation effect proportion of 4.6%. Conclusion An increase in DNA copy numbers may reduce the risk of AD, and immune cells partially mediate this causal relationship.
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.
Objective To compare the balance of simple randomization, stratified blocked randomization and minimization. Methods Monte Carlo technique was employed to simulate the treatment allocation of simple randomization, stratified blocked randomization and minimization respectively, then the balance of treatment allocation in each group and the balance for every prognostic factor were compared. Results The simulation demonstrated that minimization provides the best performance to ensure balance in the number of patients between groups and prognostic factors. Balance in prognostic factors achieved with stratified blocked randomization was similar to that achieved with simple randomization. Conclusion Minimization offers the best balance in the number of patients and prognostic factors between groups.
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.
Objective To evaluate the potential causal relationship between asthma and the risk of gastroesophageal reflux disease (GERD) using a two-sample Mendelian randomization study. Methods A large sample of genome-wide association study was used to summarize the data, and the genetic loci [single nucleotide polymorphisms (SNPs)] closely related to asthma were selected as instrumental variables, and Mendelian randomization analysis was conducted by inverse variance weighting, weighted median and MR-Egger method, respectively. At the same time, the multi-effect of MR-Egger was detected and the sensitivity analysis was carried out by Leave-one-out method to ensure the robustness of the results. Results A total of 77 SNPs closely related to asthma were selected as instrumental variables. The results of inverse variance weighted analysis showed a significant positive correlation between asthma and the occurrence of gastroesophageal reflux disease [odds ratio (OR)=1.044, 95% confidence interval (CI) (1.006, 1.083), P=0.024]. Weighted median results showed similar causality [OR=1.075, 95%CI (1.021, 1.133), P=0.006]. The MR-Egger regression results showed that there was a positive correlation between asthma and GERD, but there was no statistical significance [OR=1.080, 95%CI (0.983, 1.187), P=0.115]. The heterogeneity test results showed that there was no heterogeneity in the causal relationship between asthma and GERD (P>0.05). The results of the horizontal pleiotropy test showed that there was no horizontal pleiotropy in SNPs (P>0.05). The results of the retention test showed that no SNPs with significant impact on the results were detected. Conclusion There is a positive causal relationship between asthma and GERD.
Mendelian randomization is a special type of instrumental variable analysis. Its application in the medical field increases in popularity because of its obvious advantages and the rapid development of genomics. This article aimed to introduce the basic concepts, principles, common methods, and limitations of Mendelian randomization. It is expected to provide guidance for researchers to conduct Mendelian randomization studies.
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.
Objective To analyze whether there is a causal association between psoriasis and Alzheimer disease (AD) by a two-sample two-way Mendelian randomization (MR) method. Methods In the forward study, the single nucleotide polymorphisms (SNPs) associated with psoriasis were obtained from the comprehensive statistical data of the genome-wide association study database as the instrumental variables, and AD as the outcome; in the reverse study, the SNPs associated with AD were taken as instrumental variables, and psoriasis as the outcome. Using two-sample two-way MR analysis, the odds ratio (OR) value and 95% confidence interval (CI) of regression models, namely inverse variance weighted (IVW) method, MR-Egger regression method, weighted median method, simple pattern method, and weighted pattern method, were used to evaluate the causal relationship between psoriasis and AD. Cochran’s Q test was used to assess the heterogeneity of genetic instrumental variables, MR-Egger intercept method was used to test the horizontal pleiotropy of the assessment, “leave-one-out” method was used to assess the sensitivity of a SNP to the effect of causality, and the symmetry of funnel plot was observed to assess bias. Results A total of 19 SNPs associated with psoriasis were included as instrumental variables in the forward study. The IVW analysis of the forward study showed that there was a causal correlation between psoriasis and AD [OR=1.032, 95%CI (1.014, 1.051), P<0.001], and MR-Egger regression method [OR=1.042, 95%CI (1.012, 1.073), P=0.013], weighted median [OR=1.048, 95%CI (1.023, 1.074), P<0.001], and weighted model [OR=1.046, 95%CI (1.020, 1.073), P=0.002] all supported this result. Heterogeneity test (IVW result: Q=13.752, P=0.745; MR-Egger regression result: Q=13.134, P=0.727), MR-Egger intercept method (Egger intercept=–0.004, P=0.442), the results of “leave-one-out” method and funnel plot showed that the results of MR analysis were reliable. A total of 127 AD-related SNPs were included as instrumental variables in the reverse study. In reverse research, there was no evidence to support the AD could increase the risk of psoriasis (P>0.05). Heterogeneity test (IVW result: Q=232.496, P<0.001; MR-Egger regression result: Q=232.119, P<0.001) suggested heterogeneity, but MR-Egger intercept method (Egger intercept=0.003, P=0.652), the results of “leave-one-out” method and funnel plot showed that the results of MR analysis were reliable. Conclusion There is a causal association between psoriasis and AD, and psoriasis may increase the risk of AD.
Objective To introduce the use of Central Randomization System in clinical trials. Methods We discussed the application of Central Randomization System in clinical trials from object management, drug management and user management, and made a brief description of minimization method. Results Central Randomization Systems can guarantee the nnplementation of the scheme of randomization, and can be used in clinical trials with minimization. Conclusion Central Randomization Systems are feasible in clinical trials especially in traditional Chinese medicine and open clinical trials.
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.