Causal Effects of Asthma on Upper Airway Diseases and Allergic Diseases: A Two-Sample Mendelian Randomization.

INTRODUCTION: Asthma is associated with upper airway diseases and allergic diseases; however, the causal effects need to be investigated further. Thus, we performed this two-sample Mendelian randomization (MR) analysis to explore and measure the causal effects of asthma on allergic rhinitis (AR), vasomotor rhinitis (VMR), allergic conjunctivitis (AC), atopic dermatitis (AD), and allergic urticaria (AU). METHODS: The data for asthma, AR, VMR, AC, AD, and AU were obtained from large-scale genome-wide association studies summarized recently. We defined single-nucleotide polymorphisms satisfying the MR assumptions as instrumental variables. Inverse-variance weighted (IVW) approach under random-effects was applied as the dominant method for causal estimation. The weighted median approach, MR-Egger regression analysis, MR pleiotropy residual sum and outlier test, and leave-one-out sensitivity analysis were performed as sensitivity analysis. Horizontal pleiotropy was measured using MR-Egger regression analysis. Significant causal effects were attempted for replication and meta-analysis. RESULTS: We revealed that asthma had causal effects on AR (IVW, odds ratio [OR] = 1.93; 95% confidence interval [CI], 1.74-2.14; p < 0.001), VMR (IVW, OR = 1.40; 95% CI, 1.15-1.71; p < 0.001), AC (IVW, OR = 1.65; 95% CI, 1.49-1.82; p < 0.001), and AD (IVW, OR = 2.13; 95% CI, 1.82-2.49; p < 0.001). No causal effect of asthma on AU was observed. Sensitivity analysis further assured the robustness of these results. The evaluation of the replication stage and meta-analysis further confirmed the causal effect of asthma on AR (IVW OR = 1.81, 95% CI 1.62-2.02, p < 0.001), AC (IVW OR = 1.44, 95% CI 1.11-1.87, p < 0.001), and AD (IVW OR = 1.85, 95% CI 1.42-2.41, p < 0.001). CONCLUSIONS: We revealed and quantified the causal effects of asthma on AR, VMR, AC, and AD. These findings can provide powerful causal evidence of asthma on upper airway diseases and allergic diseases, suggesting that the treatment of asthma should be a preventive and therapeutic strategy for AR, VMR, AC, and AD.

Gastroesophageal reflux disease increases the risk of rheumatoid arthritis: a bidirectional two-sample Mendelian randomization study.

Rheumatoid arthritis (RA) is a common autoimmune disease, and some observational studies have indicated an association between Gastroesophageal Reflux Disease (GERD) and RA. However, the causal relationship between the two remains uncertain. We used Mendelian randomization (MR) to assess the causal relationship between GERD and RA. Two-sample Mendelian randomization analysis was performed using pooled data from large-scale genome-wide association studies. In addition, we performed multivariate MR analyses to exclude confounding factors between GERD and RA, including smoking quantity, drinking frequency, BMI, depression, and education attainment. The MR results for GERD on RA suggested a causal effect of the genetic susceptibility of GERD on RA (discovery dataset, IVW, odds ratio [OR] = 1.41, 95% confidence interval [CI] 1.22-1.63, p = 2.81 × 10-6; validation dataset, IVW, OR = 1.38, 95% CI 1.23-1.55, P = 1.76 × 10-8). Multivariate MR analysis also supports this result. But the results of the reverse MR analysis did not reveal compelling evidence that RA can increase the risk of developing GERD. Our bidirectional Two-Sample Mendelian randomization analysis and multivariate MR analysis provide support for the causal effect of GERD on RA. This discovery could offer new insights for the prevention and treatment of RA.

The role of herpes simplex virus infection in the etiology of head and neck cancer-a Mendelian randomization study.

Introduction: Head and neck cancer (HNC) is a complex disease, and multiple risk factors can lead to its progression. Observational studies indicated that herpes simplex virus (HSV) may be correlated with the risk of HNC. However, the causal effects and direction between them were still unclear. Methods: This study utilized a Mendelian randomization (MR) approach for causality assessment between HSV infection and Head and neck cancer based on the latest public health data and Genome-Wide Association Study (GWAS) data. The causal effects were estimated using IVW, weighted median, and MR-Egger. A reverse MR analysis was subsequently performed. Cochrans Q test, MR-Egger intercept test, leave one out analysis, and the funnel plot were all used in sensitivity analyses. Results: Genetically predicted higher level of HSV-1 IgG was causally related to HNC (OR=1.0019, 95%CI=1.0003-1.0036, p=0.0186, IVW) and oral and oropharyngeal cancer (OR=1.0018, 95%CI=1.0004-1.0033, p=0.0105, IVW). The reverse MR analysis did not demonstrate a reverse causal relationship between HSV and HNC. However, HSV-2 infection was not causally related to HNC data and oropharyngeal cancer data. Sensitivity analysis was performed and revealed no heterogeneity and horizontal pleiotropy. Conclusion: Collectively, a significant association was noted between HSV infection and increased risk of HNC, providing valuable insights into the etiology of this malignancy. Further in-depth study is needed to validate these findings and elucidate the underpinning mechanisms.

Smoking as a mediator in the association between major depressive disorder and schizophrenia on lung cancer risk: a bidirectional/multivariable and mediation Mendelian randomization study.

Background & Aims: Major depressive disorder and schizophrenia have been hypothesized to be closely associated with cancer. However, the associations between these psychiatric conditions and the development of lung cancer remain uncertain. This study aimed to explore the causal relationship among major depressive disorder, schizophrenia, and the risk of lung cancer. Methods: Two-sample bidirectional/multivariable and mediation Mendelian randomization (MR) analyses were conducted. Genome-wide summary data on major depressive disorder (N=500,199) and schizophrenia (N=127,906) were utilized. Data on the risk of lung cancer (overall, adenocarcinoma, and squamous cell) were collected from a cohort of individuals of European ancestry (N=27,209). Three smoking-related behaviors (smoking initiation, pack years of smoking, and cigarettes smoked per day) were included in the multivariable and mediation MR analyses. Results: Patients with schizophrenia had a significantly greater risk of developing lung cancer (odds ratio (OR) = 1.144, 95% confidence interval (95% CI): 1.048-1.248, P = 0.003). The number of cigarettes smoked per day partially mediated the relationship between schizophrenia and the overall risk of lung cancer (OR = 1.185, 95% CI: 1.112-1.264, P = 0.021, proportion of mediation effect: 61.033%). However, there is no reliable evidence indicating an association between major depressive disorder and the risk of lung cancer (overall, adenocarcinoma, and squamous cell cancer). Conclusions: The findings indicated an association between schizophrenia and an increased risk of lung cancer, with smoking served as a partial mediator. When smoking was included in the regression analysis, the explanatory power of schizophrenia diagnosis was reduced, suggesting that smoking may be an important causal contributor to lung cancer in this population. Given the high prevalence of smoking among individuals with schizophrenia, these results underscore the need for further research to explore the underlying mechanisms of smoking's impact. Consequently, greater emphasis should be placed on monitoring the respiratory health of individuals with schizophrenia and implementing early interventions to address smoking-related behaviors.

Role of inflammatory biomarkers in mediating the effect of lipids on spontaneous intracerebral hemorrhage: a two-step, two-sample Mendelian randomization study.

Background: Spontaneous intracerebral hemorrhage (sICH) is a form of stroke with high mortality rates and significant neurological implications for patients. Abnormalities in lipid metabolism have been implicated in various cardiovascular diseases, yet their relationship with sICH remains insufficiently explored, particularly concerning their association with inflammatory factors. Methods: Employing a two-sample, two-step Mendelian Randomization approach, combined with data from GWAS datasets, to investigate the causal relationship between plasma lipid levels and sICH. Additionally, the role of inflammatory factors in this relationship was examined, and sensitivity analyses were conducted to ensure the robustness of the results. Results: The results indicate a significant causal relationship between 19 plasma lipid metabolites and sICH. Furthermore, mediation analysis revealed that three distinct lipids, namely Sterol ester (27:1/20:2), Phosphatidylcholine (16:0_20:4), and Sphingomyelin (d34:1), exert their influence on sICH through inflammatory factors. TRAIL (OR: 1.078, 95% CI: 1.016-1.144, p = 0.013) and HGF (OR: 1.131, 95% CI: 1.001-1.279, p = 0.049) were identified as significant mediators. Conclusion: This study provides new evidence linking abnormalities in lipid metabolism with sICH and elucidates the role of inflammatory factors as mediators. These findings contribute to a better understanding of the pathogenesis of sICH and offer novel insights and therapeutic strategies for its prevention and treatment.

Comments on "sensitivity of estimands in clinical trials with imperfect compliance" by Chen and Heitjan.

Chen and Heitjan (Sensitivity of estimands in clinical trials with imperfect compliance. Int J Biostat. 2023) used linear extrapolation to estimate the population average causal effect (PACE) from the complier average causal effect (CACE) in multiple randomized trials with all-or-none compliance. For extrapolating from CACE to PACE in this setting and in the paired availability design involving different availabilities of treatment among before-and-after studies, we recommend the sensitivity analysis in Baker and Lindeman (J Causal Inference, 2013) because it is not restricted to a linear model, as it involves various random effect and trend models.

Differentiating Gliosarcoma from Glioblastoma: A Novel Approach Using PEACE and XGBoost to Deal with Datasets with Ultra-High Dimensional Confounders.

In this study, we used a recently developed causal methodology, called Probabilistic Easy Variational Causal Effect (PEACE), to distinguish gliosarcoma (GSM) from glioblastoma (GBM). Our approach uses a causal metric which combines Probabilistic Easy Variational Causal Effect (PEACE) with the XGBoost, or eXtreme Gradient Boosting, algorithm. Unlike prior research, which often relied on statistical models to reduce dataset dimensions before causal analysis, our approach uses the complete dataset with PEACE and the XGBoost algorithm. PEACE provides a comprehensive measurement of direct causal effects, applicable to both continuous and discrete variables. Our method provides both positive and negative versions of PEACE together with their averages to calculate the positive and negative causal effects of the radiomic features on the variable representing the type of tumor (GSM or GBM). In our model, PEACE and its variations are equipped with a degree d which varies from 0 to 1 and it reflects the importance of the rarity and frequency of the events. By using PEACE with XGBoost, we achieved a detailed and nuanced understanding of the causal relationships within the dataset features, facilitating accurate differentiation between GSM and GBM. To assess the XGBoost model, we used cross-validation and obtained a mean accuracy of 83% and an average model MSE of 0.130. This performance is notable given the high number of columns and low number of rows (code on GitHub).

Causality of immune cells on primary sclerosing cholangitis: a bidirectional two-sample Mendelian randomization study.

Background: Observational studies have indicated that immune dysregulation in primary sclerosing cholangitis (PSC) primarily involves intestinal-derived immune cells. However, the causal relationship between peripheral blood immune cells and PSC remains insufficiently understood. Methods: A bidirectional two-sample Mendelian randomization (MR) analysis was implemented to determine the causal effect between PBC and 731 immune cells. All datasets were extracted from a publicly available genetic database. The standard inverse variance weighted (IVW) method was selected as the main method for the causality analysis. Cochran's Q statistics and MR-Egger intercept were performed to evaluate heterogeneity and pleiotropy. Results: In forward MR analysis, the expression ratios of CD11c on CD62L+ myeloid DC (OR = 1.136, 95% CI = 1.032-1.250, p = 0.009) and CD62L-myeloid DC AC (OR = 1.267, 95% CI = 1.086-1.477, p = 0.003) were correlated with a higher risk of PSC. Each one standard deviation increase of CD28 on resting regulatory T cells (Treg) (OR = 0.724, 95% CI = 0.630-0.833, p < 0.001) and CD3 on secreting Treg (OR = 0.893, 95% CI = 0.823-0.969, p = 0.007) negatively associated with the risk of PSC. In reverse MR analysis, PSC was identified with a genetic causal effect on EM CD8+ T cell AC, CD8+ T cell AC, CD28- CD127- CD25++ CD8+ T cell AC, CD28- CD25++ CD8+ T cell AC, CD28- CD8+ T cell/CD8+ T cell, CD28- CD8+ T cell AC, and CD45 RA- CD28- CD8+ T cell AC. Conclusion: Our study indicated the evidence of causal effects between PSC and immune cells, which may provide a potential foundation for future diagnosis and treatment of PSC.

Bidirectional causality between the levels of blood lipids and endometriosis: a two-sample mendelian randomization study.

BACKGROUND: Observational studies have found a correlation between the levels of blood lipids and the development and progression of endometriosis (EM). However, the causality and direction of this correlation is unclear. This study aimed to examine the bidirectional connection between lipid profiles and the risk of EM using publicly available genome-wide association study (GWAS) summary statistics. METHODS: Eligible exposure variables such as levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were selected using a two-sample Mendelian randomization (MR) analysis method following a series of quality control procedures. Data on EM were obtained from the publicly available Finnish database of European patients. Inverse variance weighted (IVW), MR Egger, weighted median, and weighted mode methods were used to analyze the causal relationship between lipid exposure and EM, exclude confounders, perform sensitivity analyses, and assess the stability of the results. Reverse MR analyses were performed with EM as exposure and lipid results as study outcomes. RESULTS: IVW analysis results identified HDL as a protective factor for EM, while TG was shown to be a risk factor for EM. Subgroup analyses based on the site of the EM lesion identified HDL as a protective factor for EM of the uterus, while TG was identified a risk factor for the EM of the fallopian tube, ovary, and pelvic peritoneum. Reverse analysis did not reveal any effect of EM on the levels of lipids. CONCLUSION: Blood lipids, such as HDL and TG, may play an important role in the development and progression of EM. However, EM does not lead to dyslipidemia.

Causal effect of circulating cytokines on MRI markers of cerebral small vessel disease: A mendelian randomization study.

BACKGROUND: Previous observational studies have reported the correlation between circulating inflammatory cytokines and cerebral small vessel disease (CSVD). However, the causality of this association is uncertain. This study used Mendelian randomization to investigate the causal effect of circulating inflammatory cytokines on neuroimaging changes in CSVD. METHODS: This study utilized genetic variances of 41 inflammatory cytokines and 3 neuroimaging markers of CSVD from genome-wide association studies to assess the causal effects in a two-sample Mendelian randomization approach. Inverse variance weighted analysis was used as the main analytical method, and sensitivity analysis was used to further validate the robustness of the results. RESULTS: Increased IL-18 was associated with increased white matter hyperintensity (WMH) and mean diffusivity (MD) (ß = 0.034, 95 % CI 0.002, 0.065, P=0.038, ß = 0.157, 95 % CI 0.015, 0.299, P=0.030). However, increased IL-18 was associated with decreased fractional anisotropy (FA) (ß = -0.141, 95 % CI -0.279, -0.002, P=0.047). Increased monocyte chemotactic protein-1(MCP-1) was associated with decreased FA (ß = -0.278, 95 % CI -0.502, -0.054, P=0.015). Increased IL-10 levels and IL-2ra levels were associated with decreased risks of MD (ß = -0.228, 95 % CI -0.448, -0.009, p = 0.041; ß = -0.204, 95 % CI=-0.377, -0.031, p = 0.021). CONCLUSIONS: This study revealed that increased levels of IL-18 and MCP-1 were associated with white matter microstructural injury, and increased levels of IL-10 and IL-2ra were associated with decreased MD.

Physical activity initiated from midlife on risk of dementia and cognitive impairment: The Health and Retirement Study.

BACKGROUND: Physical activity is associated with lower risk of dementia and cognitive impairment, but existing randomized controlled trials have shown conflicting results. As cognitive decline occurs decades before the onset of dementia, physical activity interventions initiated in late life may have missed the potential window for prevention. An ideal trial of physical activity initiated from midlife and lasts till incident dementia and cognitive impairment in late life is not feasible. We aimed to estimate the effectiveness of a hypothetical physical activity intervention initiated from midlife on reducing dementia and cognitive impairment by emulating target trials using observational data. METHODS: The Health and Retirement Study was used to emulate target trials among noninstitutionalized participants aged 45 to 65 years with normal cognition who were physically inactive in the previous 2 years. Cognitive status was determined based on Langa-Weir classification of cognitive function (including immediate and delayed word recall tests, serial sevens subtraction, counting backward). Individuals were categorized as initiating physical activity or not, based on the self-reported physical activity. Intention-to-treat and per-protocol analysis were conducted with pooled logistic regression models with inverse-probability of treatment and censoring weights to estimate risk ratios (RRs), and 95% confidence intervals (95% CIs) were calculated with 200 sets of bootstrapping. RESULTS: Among 1505 participants (average age 57.6 ± 4.8 years, 67% women, 76.5% White), 72 cases of dementia and 409 cases of cognitive impairment occurred. After 12 years of follow-up, physical activity reduced dementia (RR = 0.70, 95% CI: 0.43, 0.99) for intention-to-treat analysis, and reduced dementia (RR = 0.51, 95% CI: 0.19, 0.99) and cognitive impairment (RR = 0.77, 95% CI: 0.61, 0.92) for per-protocol analysis. No significant reduction was found among older adults. CONCLUSIONS: Physical activity initiated during midlife may reduce dementia and cognitive impairment in late life, which highlights the importance of preventing cognitive outcomes at an earlier stage of life.

Immune-mediated inflammatory diseases and periodontal disease: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Previous observational studies have shown a bidirectional association between immune-mediated inflammatory disorders (IMID) and periodontal disease. However, evidence regarding the causal role of IMID and periodontal disease is still lacking. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) study to uncover the potential genetic causal effects between IMID and periodontal disease. METHODS: Bidirectional two-sample MR analysis was employed. Data for ten IMIDs were sourced from genome-wide association studies (GWAS) conducted by the FinnGen Consortium (range from 1023 to 36321 cases) and UK Biobank (UKB) (range from 150 to 17574 cases). Furthermore, GWAS data for periodontal disease were obtained from the FinnGen Consortium (87497 cases), UKB (458 cases), and Gene Lifestyle Interactions in Dental Endpoints (GLIDE) consortium (17,353 periodontitis cases). Subsequently, the causal relationships were analyzed by random effects inverse variance weighting, weighted median, and MR-Egger. Sensitivity analyses were performed using the Cochrane Q test, funnel plot, and Mr-Egger intercept test to ensure robustness. Eventually, replication analysis and meta-analysis across different databases were carried out. RESULTS: Systemic lupus erythematosus (SLE) [IVW: OR = 1.079 (95% CI: 1.032-1.128) and P < 0.001], Sjogren syndrome [IVW: OR = 1.082 (95% CI: 1.012-1.157) and P = 0.022] and hypothyroidism [IVW: OR = 1.52 (95% CI: 1.13-2.04) and P = 0.005] may increase the risk of periodontal disease. In addition, periodontal disease may reduce the risk of SLE [IVW: OR = 0.8079 (95% CI: 0.6764-0.9650) and P = 0.019] and hyperthyroidism [IVW: OR = 5.59*10-9 (95% CI: 1.43*10-15-2.18*10-2) and P = 0.014]. Meta-analysis indicated a causal correlation between SLE and an increased risk of periodontal disease: [OR = 1.08 (95% CI: 1.03-1.13), P = 0.0009]. No significant evidence suggests bilateral causal relationships between other IMIDs and periodontal disease. No significant estimation of heterogeneity or pleiotropy is detected. CONCLUSIONS: Our study has confirmed a genetic causal relationship between IMIDs and periodontal disease, thereby unveiling novel potential mechanisms underlying IMIDs and periodontal disease. This discovery is promising in fostering interdisciplinary collaboration between clinicians and stomatologists to facilitate appropriate and precise screening, prevention, and early treatment of IMIDs and periodontal disease.

Sensitivity analysis for principal ignorability violation in estimating complier and noncomplier average causal effects.

An important strategy for identifying principal causal effects (popular estimands in settings with noncompliance) is to invoke the principal ignorability (PI) assumption. As PI is untestable, it is important to gauge how sensitive effect estimates are to its violation. We focus on this task for the common one-sided noncompliance setting where there are two principal strata, compliers and noncompliers. Under PI, compliers and noncompliers share the same outcome-mean-given-covariates function under the control condition. For sensitivity analysis, we allow this function to differ between compliers and noncompliers in several ways, indexed by an odds ratio, a generalized odds ratio, a mean ratio, or a standardized mean difference sensitivity parameter. We tailor sensitivity analysis techniques (with any sensitivity parameter choice) to several types of PI-based main analysis methods, including outcome regression, influence function (IF) based and weighting methods. We discuss range selection for the sensitivity parameter. We illustrate the sensitivity analyses with several outcome types from the JOBS II study. This application estimates nuisance functions parametrically - for simplicity and accessibility. In addition, we establish rate conditions on nonparametric nuisance estimation for IF-based estimators to be asymptotically normal - with a view to inform nonparametric inference.

Serum 25-hydroxyvitamin D level and erectile dysfunction: a causal relationship? Findings from a two-sample Mendelian randomization study.

Background: Serum 25-hydroxyvitamin D level is associated with erectile dysfunction (ED) in observational studies. However, whether there is a causal association between them remains uncertain. Objective: Conduct a two-sample Mendelian randomization (MR) analysis to investigate the causal effect between serum 25-hydroxyvitamin D level and ED risk. Method: Genome-wide association study (GWAS) data of serum 25-hydroxyvitamin D levels comprising 6,896,093 single nucleotide polymorphisms (SNP) from 496,949 people of European ancestry were regarded as exposure for the MR analysis. Additional GWAS data involving 9,310,196 SNPs of 6,175 European ED cases and 217,630 controls were used as outcome data. The MR-Egger, inverse variance weighted (IVW) method, weighted median, simple mode, and weighted mode were employed to evaluate causal effects, among which IVW was the primary MR analysis method. The stability of the MR analysis results was confirmed by a heterogeneity test, a horizontal pleiotropy test, and the leave-one-out method. Result: There were 103 SNPs utilized as instrumental variables (p < 5 × 10-8). The results of MR analysis showed no causal effects of serum 25(OH) D concentration on ED risks (IVW; OR = 0.9516, 95% CI = 0.7994 to 1.1328, p = 0.5772). There was no heterogeneity and pleiotropy in the statistical models. Conclusion: The present MR study did not support a causal association for genetically predicted serum 25-hydroxyvitamin D concentration in the risk of ED in individuals of European descent.

Association of circulating vitamin levels with thyroid diseases: a Mendelian randomization study.

Background: Previous observational studies have shown conflicting results of vitamins supplementation for thyroid diseases. The causal relationships between vitamins and thyroid diseases are unclear. Therefore, we conducted a two-sample bidirectional Mendelian randomization (MR) study to explore association of circulating vitamin levels with thyroid diseases. Methods: We performed a bidirectional MR analysis using genome-wide association study (GWAS) data. Genetic tool variables for circulating vitamin levels include vitamins A, B9, B12, C, D, and E, Genetic tool variables of thyroid diseases include autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid nodules (TNs), and Thyroid cancer (TC). Inverse-variance weighted multiplicative random effects (IVW-RE) was mainly used for MR Analysis, weighted median (WM) and MR Egger were used as supplementary methods to evaluate the relationships between circulating vitamin levels and thyroid diseases. Sensitivity and pluripotency were evaluated by Cochran's Q test, MR-PRESSO, Radial MR, MR-Egger regression and leave-one-out analysis. Results: Positive MR evidence suggested that circulating vitamin C level is a protective factor in autoimmune hypothyroidism (ORIVW-RE=0.69, 95%CI: 0.58-0.83, p = 1.05E-04). Reverse MR Evidence showed that genetic susceptibility to autoimmune hyperthyroidism is associated with reduced level of circulating vitamin A(ORIVW-RE = 0.97, 95% CI: 0.95-1.00, p = 4.38E-02), genetic susceptibility of TNs was associated with an increased level of circulating vitamin D (ORIVW-RE = 1.02, 95% CI: 1.00-1.03, p = 6.86E-03). No causal and reverse causal relationship was detected between other circulating vitamin levels and thyroid diseases. Conclusion: Our findings provide genetic evidence supporting a bi-directional causal relationship between circulating vitamin levels and thyroid diseases. These findings provide information for the clinical application of vitamins prevention and treatment of thyroid diseases.

Exploring the causal relationship between immune cell and all-cause heart failure: a Mendelian randomization study.

Background and objectives: Heart failure (HF) is a disease with numerous genetic and environmental factors that affect it. The results of previous studies indicated that immune phenotypes are associated with HF, but there have been inconclusive studies regarding a causal relationship. Therefore, Mendelian randomization (MR) analyses were undertaken to confirm the causal connections between immune phenotypes and HF, providing genetic evidence supporting the association of immune cell factors with HF risk. Methods: We selected instrumental variables that met the criteria based on data from the results of genome-wide association studies (GWAS) of immune phenotype and all-cause HF. An evaluation of the causal association between 731 immune cell factors and HF risk was carried out using the inverse variance weighted (IVW), MR-Egger regression (MR-Egger), and weighted median (WM) analysis methods. To determine the horizontal pleiotropy, heterogeneity, and stability of the genetic variants, the MR-Egger intercept test, Cochran's Q test, MR-PRESSO, and leave-one-out sensitivity analysis were performed. Results: MR principal method (IVW) analysis showed that a total of 38 immune cell-related factors were significantly causally associated with HF. Further analyses combining three methods (IVW, MR-Egger and WME) showed that six exposure factors significantly associated with heart failure, as shown below. The effect of Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell% Dendritic cell, CD39+ CD8+ T cell% CD8+ T cell, CD3 on Central Memory CD4+ T cell on heart failure was positive. Whereas, a reverse effect was observed for CD14+ CD16+ monocyte% monocyte. Conclusion: We investigated the causal relationship between immune phenotypes and all-cause HF. According to the results, Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell% Dendritic cell, CD39+ CD8+ T cell% CD8+ T cell, CD3 on Central Memory CD4+ T cell aggravate HF, and the risk of HF is decreased by CD14+ CD16+ monocyte% monocyte. These phenotypes may serve as new biomarkers, providing new therapeutic insights for the prevention and treatment of all-cause HF.

The association of maternal smoking around birth with chronic respiratory diseases in adult offspring: A Mendelian randomization study.

INTRODUCTION: Maternal smoking during pregnancy disturbs fetal lung development, and induces in their offspring childhood respiratory diseases. Whether it has a continued impact on offspring adult lung health and exerts a casual effect of chronic respiratory diseases (CRDs), remains uncertain. We seek to determine the causal relationships between maternal smoking around birth and offspring adult CRDs, using summary data from previously described cohorts. METHODS: Mendelian randomization (MR) study was used to analyze the genome-wide associations of maternal smoking around birth and offspring adult CRDs, including respiratory insufficiency, chronic obstructive pulmonary disease (COPD), related respiratory insufficiency, emphysema, COPD, COPD hospital admissions, early onset of COPD, later onset of COPD, asthma, idiopathic pulmonary fibrosis (IPF), lung cancer (LC), small cell lung carcinoma (SCLC), and lung squamous cell carcinoma (LUSC). RESULTS: After removing single-nucleotide polymorphisms (SNPs) associated with smoking by the offspring, maternal smoking around birth was associated with increased risk of offspring adult respiratory diseases (OR=1.14; 95% CI: 1.013-1.284; p=0.030), respiratory insufficiency (OR=2.413; 95% CI: 1.039-5.603; p=0.040), COPD (OR=1.14; 95% CI: 1.013-1.284; p=0.003), and asthma (OR=1.336; 95% CI: 1.161-1.538; p<0.001). Besides, maternal smoking during pregnancy was associated with a greater risk of LUSC (OR=1.229; 95% CI: 0.992-1.523; p=0.059) than the risk of IPF (OR=1.001; 95% CI: 0.999-1.003; p=0.224), LC (OR=1.203; 95% CI: 0.964-1.501; p=0.103), or SCLC (OR=1.11; 95% CI: 0.77-1.601; p=0.577). CONCLUSIONS: In this MR analysis, maternal smoking around birth caused a strong risk factor for the offspring to develop lung problems and CRDs in adulthood. The policy related to smoking cessation for mothers during pregnancy should be encouraged.

Causal effect of physical activity and sedentary behavior on the risk of alcohol dependence: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Alcohol dependence, influenced by physical activity (PA) and sedentary behavior, lacks clear causal clarity. This study aims to clarify causal relationships by estimating these effects using bidirectional two-sample Mendelian randomization (MR). METHODS: A bidirectional multivariable two-sample MR framework was employed to assess the causal effects of PA and sedentary behavior on alcohol dependence. Summarized genetic association data were analyzed for four PA-related activity patterns-moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA), accelerometer-based physical activity with average acceleration (AccAve), and accelerometer-based physical activity with accelerations greater than 425 milli-gravities (Acc425)-and three sedentary behavior patterns-sedentary, TV watching, and computer use. The study was expanded to include the examination of the relationship between sedentary behavior or PA and general drinking behavior, quantified as drinks per week (DPW). We obtained summarized data on genetic associations with four PA related activity patterns (MVPA, VPA, AccAve and Acc425) and three sedentary behavior related behavior patterns (sedentary, TV watching and computer use). RESULTS: MR analysis found AccAve inversely associated with alcohol dependence risk (OR: 0.87; 95% CI: 0.80-0.95; p < 0.001), MVPA positively associated (OR: 2.86; 95%CI: 1.45-5.66; p = 0.002). For sedentary behavior and alcohol dependence, only TV watching was positively associated with the risk of alcohol dependence (OR: 1.43; 95%CI: 1.09-1.88; p = 0.009). No causal links found for other physical or sedentary activities. Reverse analysis and sensitivity tests showed consistent findings without pleiotropy or heterogeneity. Multivariate MR analyses indicated that while MVPA, AccAve and TV watching are independently associated with alcohol dependence, DPW did not show a significant causal relationship. CONCLUSIONS: Our results suggest that AccAve is considered a protective factor against alcohol dependence, while MVPA and TV watching are considered risk factors for alcohol dependence. Conversely, alcohol dependence serves as a protective factor against TV watching. Only TV watching and alcohol dependence might mutually have a significant causal effect on each other.

Estimating the Heterogeneous Causal Effects of Parent-Child Relationships among Chinese Children with Oppositional Defiant Symptoms: A Machine Learning Approach.

Oppositional defiant symptoms are some of the most common developmental symptoms in children and adolescents with and without oppositional defiant disorder. Research has addressed the close association of the parent-child relationship (PCR) with oppositional defiant symptoms. However, it is necessary to further investigate the underlying mechanism for forming targeted intervention strategies. By using a machine learning-based causal forest (CF) model, we investigated the heterogeneous causal effects of the PCR on oppositional defiant symptoms in children in Chinese elementary schools. Based on the PCR improvement in two consecutive years, 423 children were divided into improved and control groups. The assessment of oppositional defiant symptoms (AODS) in the second year was set as the dependent variable. Additionally, several factors based on the multilevel family model and the baseline AODS in the first year were included as covariates. Consistent with expectations, the CF model showed a significant causal effect between the PCR and oppositional defiant symptoms in the samples. Moreover, the causality exhibited heterogeneity. The causal effect was greater in those children with higher baseline AODS, a worse family atmosphere, and lower emotion regulation abilities in themselves or their parents. Conversely, the parenting style played a positive role in causality. These findings enhance our understanding of how the PCR contributes to the development of oppositional defiant symptoms conditioned by factors from a multilevel family system. The heterogeneous causality in the observation data, established using the machine learning approach, could be helpful in forming personalized family-oriented intervention strategies for children with oppositional defiant symptoms.