Strong Causal Relationship Research Articles

Association between immune cells and urticaria: a bidirectional Mendelian randomization study

Urticaria is characterized by transient itchy symptoms on the skin, usually accompanied by swelling, which is caused by mast cell activation leading to increased vascular permeability and dilation of the dermis. Urticaria involves recurrent activation of mast cells, T cells, eosinophils, and other immune cells around lesioned venules, with complex regulatory systems affecting mast cell functions, potentially contributing to urticaria pathogenesis. The direct causal relationship between immune cells and urticaria is currently unclear. To address this, our study utilized a bidirectional Mendelian randomization analysis, employing instrumental variables (IVs) associated with immune cells and urticaria, to investigate this causal relationship. First, by utilizing Genome-wide Association Study (GWAS) data, we identified 31 immunophenotypes associated with urticaria risk, with 18 increasing and 13 decreasing the risk. Through rigorous criteria, we identified 4 immunophenotypes that have a strong causal relationship with urticaria. Notably, HLA DR+ CD4+AC, CD45 on CD8br, and HLA DR on plasmacytoid dendritic cells were associated with an increased risk, while CD8dim NKT %lymphocyte was identified as a protective factor. Sensitivity analyses, including the MR-Egger intercept test, scatter plots, funnel plots, and leave-one-out analysis, supported the robustness of the findings. Reverse MR analysis suggested an inverse causal effect of urticaria on CD8dim NKT %lymphocyte, reinforcing the potential bidirectional nature of the relationship between urticaria and immune cell phenotypes. Our research substantiates the bidirectional causal relationship between immune cells and urticaria, thus benefiting for urticaria-targeted therapy development.

Causal relationship between hyperthyroidism and cataracts: a two-sample bi-directional mendelian randomization study

Clinical studies and meta-analyses have suggested a link between thyroid dysfunction and lens opacification. The objective of this study is to investigate the causal relationship between hyperthyroidism and the development of cataracts using the Mendelian randomization approach, with the aim of filling the gap in knowledge about the systemic effects of hyperthyroidism on ocular health. Leveraging genetic variants as instrumental variables, the analysis used extensive datasets from the UK Biobank and the FinnGen Database and employed three common approaches for causal inference (the Inverse Variance Weighted method, a regression based method the Weighted Median estimator, and MR-Egger regression) and accompanying sensitivity analyses to ensure robustness. The results demonstrate that there is a strong likely causal relationship, with hyperthyroidism increasing the risk of developing senile cataracts (OR = 361.09, 95%CI 5.024 to 2.60 × 104, P = 0.007). A sensitivity analysis provided no evidence of horizontal pleiotropy and no significant outliers, suggesting the results are robust. In conclusion, our study established a significant causal relationship between hyperthyroidism and increased risk of cataract development, underscoring the importance of considering the systemic effects of hyperthyroidism in clinical and public health interventions and policies. Future research should focus on elucidating the molecular mechanisms underlying this association, exploring the potential benefits of early intervention in hyperthyroidism to prevent cataract development, and investigating whether these findings translate across different ethnic populations. Additionally, further GWAS studies aimed at identifying genetic variants associated with both hyperthyroidism and cataracts are warranted to confirm and expand upon our results.

The impact of sleep problems on cerebral aneurysm risk is mediated by hypertension: a mediated Mendelian randomization study.

Cerebral aneurysm (CA) is a common vascular disease. The risk factors of CA include hypertension, smoking, and a family history of genetic predisposition. Although sleep-related problems have been found to have a strong association with cardiovascular disease, there is a lack of research regarding the causal relationship with cerebral aneurysms. In this study, we investigated the causal relationship between four sleep-related problems, including snoring, insomnia, narcolepsy, and napping during the day, and CA using a two-sample Mendelian randomization (MR) analysis. Moreover, the potential confounders before sleep problems and CA were further analyzed by multivariate MR (MVMR). The causal relationship between insomnia and CA was obtained analytically by means of sixMR analyses. There was a strong causal effect relationship between insomnia and CA, which suggests this as a potential risk factor [odds ratio (OR) = 8.35, 95% confidence interval (CI) = 2.422-28.791, p = 7.772e-04]. On this basis, hypertension was identified as a mediator between insomnia and CA by MVMR, with a mediating effect of 52.538% (OR = 3.05, 95% CI = 1.549-4.55, p = 0.015). The causal relationship between insomnia and CA was predicted using genetic variance data, and insomnia was found to be a potential risk factor. Furthermore, hypertension is a mediator between insomnia and CA. Therefore, focusing on sleep problems and improving sleep quality may be an active and effective strategy to prevent CA.

A MR-PheWAS and bidirectional Mendelian randomization study: Exploring for causal relationships of pancreatic cancer.

It is unknown what causes pancreatic cancer. We conducted a phenome-wide Mendelian randomization analysis (MR-pheWAS), a bidirectional Mendelian study, and a systematic review of research in order to thoroughly investigate any causal association between pancreatic cancer and Atlas. We used phenome-wide Mendelian randomization analysis to test for associations between pancreatic cancer and 776 phenotypes (n = 452,264) of Atlas in the UK Biobank. Causality is confirmed by two-sample Mendelian randomization (MR) analysis using correlation found by false discovery rate correction. Simultaneously, a comprehensive evaluation of pancreatic cancer MR studies was conducted in order to complement our findings and harmonize the existing evidence. According to the inverse-variance-weighted model, a total of 41 out of 776 phenotypes had a nominal significance level (P < .05) genetic prediction association with pancreatic cancer. Only genetically predicted pancreatic cancer was shown to be linked with elevated eosinophil counts following false discovery rate correction (P = .031) when several tests were taken into account. Pancreatic cancer and eosinophils were shown to be positively causally associated to one another, establishing a self-loop, according to two-sample MR validation in the IEU database (OR = 1.011, 95% CI: 1.002-1.020, P = .010) (OR = 1.229, 95% CI: 1.037-1.458, P = .017). Although MR-pheWAS found a strong causal relationship between eosinophils and pancreatic cancer, it also found a negative exclusion value for each phenotype and a significant number of suggestive association phenotypes that offered guidance for further research.

Environmental Enteropathy (EE): A Critical Challenge in Indian Public Health

There is strong causal relationship between stunting and Environmental Enteropathy, a subclinical condition of the small intestines. The biological plausibility for Environmental Enteropathy being a strong causal pathway for stunting has important policy implication in improving WASH in India, which has the highest incidence of stunting in the world. Four states of India namely, Uttar Pradesh, Jharkhand, Bihar and Assam have high incidence of stunting. This paper focuses on the association of WASH with stunting in these states. Review of literature and statistical analysis of data from IMIS of the MDWS, GOI provide certain critical findings in this respect. It was observed that all these states have low sanitation facilities and low coverage of piped water supply. Also, there is little surveillance of bacteriological quality of water in these states. Further, sanitary survey of the water sources to assess the risk of contamination of the sources have also been very poor. It is likely that children in these states face higher incidence of Environmental Enteropathy, which being asymptotic makes it difficult to identify the children living in such condition for child specific interventions.

Temporal and spatial convergence: the major depressive disorder burden attributed to intimate partner violence against women

ABSTRACT Background: There is a strong causal relationship between intimate partner violence and major depressive disorder, which partly endangers women's safety across the life course and potentially affects the development of future generations. The international community has placed a high priority on addressing the intimate partner violence and the resulting burden of mental illness. Data collection needs to be captured across the temporal trend and spatial distribution for major depressive disorder attributed to intimate partner violence, to reflect the priorities and expectations of survivors. Method: This research obtained raw disability-adjusted life years (DALYs) information for major depressive disorder attributed to intimate partner violence from the Global Burden of Disease 2019. Using estimated annual percentage change and two-way fixed effects models, a secondary spatio-temporal analysis of the age-standardized DALYs rate from 1990 to 2019 was performed. Results: In 2019, DALYs lost among women experiencing major depressive disorder (3.16 million) accounted for 37.18% of the DALYs lost worldwide due to intimate partner violence. The age-standardized DALYs rate of major depressive disorder attributed to intimate partner violence was 108.57 per 100,000. The highest was concentrated in the menopausal transition (45-55), with 133.61 per 100,000, and particularly distributed in Uganda (429.31 per 100,000). The early reproductive period (15–19) showed the increasing age-standardized DALYs rate from 1990 to 2019, which was mainly driven by Malaysia (3.73% per year). Furthermore, countries with higher initial levels of the age-standardized DALYs rate were growing faster than those with lower levels. Conclusions: The burden of major depressive disorder attributed to intimate partner violence showed biological and spatial inequality, prioritized intervention should be targeted at vulnerable stage women in their early reproductive period and menopausal transition. Combined political, socio-cultural as well as medical measures to prevent violence and treat major depressive disorder should be implemented and developed.

Surprisingly good fit of pressure-based cropland condition map and bird census data at the national scale

As the world is struggling to halt the rapid decline of biodiversity, the assessment and mapping of ecosystem condition is getting ever increasing attention. Croplands are artificial ecosystems, but as they occupy a large portion of land, they significantly influence biodiversity. Yet, there is a knowledge gap about their suitability to support and maintain wildlife on a national scale. Large-scale condition mapping is meant to address this gap; the good condition of croplands includes their ability to support biodiversity. However, the lack of suitable databases is often a challenge when creating such maps. As there is a strong causal relation between pressures on the ecosystem and its condition, pressure indicators can be used as proxies to approximate condition when more direct indicators are lacking. The validation of condition maps based on pressure proxies is a key but challenging step. In this study, we tested a previously designed pressure-based cropland condition map for Hungary using bird census data. Besides validating the composite condition indicator, we also tested some key elements of the mapping process, such as the choice of variables and thresholds.Using multiple comparisons of means by Tukey’s contrast and Random Forest modelling, we examined the relationship of (1) the continuous pressure-based cropland condition variables, (2) their rescaled, ordinal version (called sub-indicators), and (3) the composite cropland condition indicator (sum of the sub-indicators) with a biodiversity measure, the standardised relative richness of characteristic farmland bird species (rRRCS). To get a picture of the spatial patterns of the examined relationships across Hungary, individual Random Forest models were constructed for all the spatial units of the bird census database, using focal analysis with a 30 km radius moving window.We found significant differences in the mean rRRCS for nearly all sub-indicator categories, signifying that the literature-derived thresholds were mostly sound. Categories with higher (better) condition scores had higher mean rRRCS; the differences are significant in the mid-range but not in the extreme categories, indicating a need for a meaningful simplification of the categories. The goodness-of-fit (R2) of the Random Forest models was found to be high, but it is spatially heterogeneous (ranged from 0.69 to 0.89, with a median value of 0.81), similarly to the variable importance. The proportion of semi-natural areas proved to be the most important condition variable. The proportion of maize and alfalfa were more important than parcel size. Our results show that condition maps based on pressure proxies can reflect patterns of biodiversity surprisingly well. They also highlight the spatial context dependence of the uncertainty of condition maps.

Subtypes of borderline personality features in adolescence: Insights from cross-lagged panel network analysis.

Borderline personality disorder (BPD) is a complex and severe psychiatric condition characterized by emotional, self-image, behavior, and relational instability. While adult BPD heterogeneity has been extensively studied, the phenomenological borderline personality features (BPFs) in adolescence remain uninvestigated. This study aimed to explore the potentially dynamic causal relationships between BPFs in adolescence and identify the subtypes through cross-lagged panel network (CLPN) analysis. Two independent Chinese adolescent samples were followed over 18 months (N₁ = 1,056, M1age = 15.37, SD1 = 1.86) and 6 months (N₂ = 723, M2age = 16.84, SD₂ = 0.48) to track BPFs. CLPN modeling was employed to investigate the stability, potential causal relations, and subtypes of adolescent BPFs. The results revealed a relatively stable overall adolescent BPF network structure with some subtle changes over time. Impulsivity emerged as the BPF with the highest out-expected influence, indicating its predictive role for other BPFs. A strong reciprocal causal relationship was observed between impulsivity and affective instability. Based on the CLPN estimation, two distinct BPFs subgroups were spontaneously clustered: externalized-dysregulation subtype (impulsivity, affective instability, and self-harm/suicide) and introjective-disturbance subtype (identity disturbance, chronic emptiness, and stress-related dissociation). The present study tentatively explores a potential typology for adolescent BPF based on these two clusters, which possibly have different pathological mechanisms, and moreover offer insights into the essential construct and clinical intervention of adolescent BPD. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Species interactions drive continuous assembly of freshwater communities in stochastic environments

Understanding the factors driving the maintenance of long-term biodiversity in changing environments is essential for improving restoration and sustainability strategies in the face of global environmental change. Biodiversity is shaped by both niche and stochastic processes, however the strength of deterministic processes in unpredictable environmental regimes is highly debated. Since communities continuously change over time and space—species persist, disappear or (re)appear—understanding the drivers of species gains and losses from communities should inform us about whether niche or stochastic processes dominate community dynamics. Applying a nonparametric causal discovery approach to a 30-year time series containing annual abundances of benthic invertebrates across 66 locations in New Zealand rivers, we found a strong negative causal relationship between species gains and losses directly driven by predation indicating that niche processes dominate community dynamics. Despite the unpredictable nature of these system, environmental noise was only indirectly related to species gains and losses through altering life history trait distribution. Using a stochastic birth-death framework, we demonstrate that the negative relationship between species gains and losses can not emerge without strong niche processes. Our results showed that even in systems that are dominated by unpredictable environmental variability, species interactions drive continuous community assembly.

A causal association between esophageal cancer and the oral microbiome: a Mendelian randomization study based on an Asian population.

Previous studies have suggested a crosstalk between the oral microbiome and esophageal cancer (EC), but the exact relationship is unclear. This study aimed to investigate the causal relationship between changes in the oral microbiome and EC by Mendelian randomization (MR). In the study, bidirectional MR analyses were conducted using genome-wide association study data from the oral microbiomes from the 4D-SZ cohort and EC data from the BioBank Japan cohort. Multiple sensitivity tests, including Cochrane's Q statistic, MR-Egger intercept, and MR-PRESSO, were used to assess and validate the relative stability of the resulting data at various levels. Among the 3,117 samples studied, 73 oral microbiomes were found to be statistically causally associated with EC, 38 of which were considered protective factors. According to species analyses, positive results were concentrated in three phyla: Firmicutes (29 species), Patescibacteria (18 species), and Actinobacteria (9 species). It was also determined that Parvimonas micra, Aggregatibacter, and Clostridia had a negative causal relationship, implying that EC caused a decrease in the counts. Following p-value correction, periodonticum_C, unclassified_mgs_3234, and unclassified_mgs_45 were identified as having a strong evidence-grade causal relationship with EC. There was no strong evidence in the results of the inverse MR analyses of EC to the oral microbiome. The sensitivity analysis confirmed the robustness of the findings. This study discovered a bidirectional causal relationship between the oral microbiome and EC, which may provide new insights into the future use of the microbiome for early screening and probiotic therapy.

Coffee consumption, cancer, and healthy aging: epidemiological evidence and underlying mechanisms.

This comprehensive review examines the role of coffee consumption in promoting healthy aging and its potential impact on cancer prevention. Previous research has shown that moderate coffee intake may contribute to extending healthspan and enhancing longevity through beneficial effects on cardiometabolic health and key biological processes involved in aging. However, the relationship between coffee consumption and cancer risk remains controversial. This review synthesizes longitudinal observational and interventional data on the effects of coffee consumption on overall and site-specific cancers, explores underlying biological mechanisms, and discusses clinical and public health implications. Additionally, the review highlights evidence from Mendelian randomization (MR) studies to assess potential causal relationships. Our findings suggest that coffee consumption is associated with a reduced risk of several cancers, including skin, liver, prostate, and endometrial cancers, and may also lower cancer recurrence rates, particularly in colorectal cancer. These protective associations appear consistent across different demographic groups, with the most significant benefits observed at consumption levels of three or more cups per day. However, evidence is inconclusive for many other cancers, and coffee consumption is consistently linked to an increased risk of lung cancer. MR studies generally do not support a strong causal relationship for most cancers, though some suggest potential protective effects for hepatocellular, colorectal, and possibly prostate cancers, with mixed results for ovarian cancer and an increased risk for esophageal cancer and multiple myeloma. The protective effect of coffee on liver and prostate cancer is supported by both observational and MR studies. The potential anti-cancer benefits of coffee are attributed to its bioactive compounds, such as caffeine, chlorogenic acids, and diterpenes, which possess antioxidant and anti-inflammatory properties. These compounds may reduce oxidative stress, inhibit cancer cell proliferation, induce apoptosis, and modulate hormone levels. The review emphasizes the need for further research to clarify dose-response relationships, causal associations, and the biological mechanisms underlying these associations. While coffee consumption appears to contribute to cancer prevention and healthy aging, caution is warranted due to the increased risk of certain cancers, highlighting the complexity of its health effects.

Causality of blood metabolites and metabolic pathways on peripheral arteriosclerosis: a Mendelian randomization study.

Peripheral arteriosclerosis is caused by any atherosclerosis outside the heart and brain. However, the underlying biological mechanisms are not fully understood. This study aims to explore the causal relationship between blood metabolites and peripheral arteriosclerosis. A Mendelian randomization (MR) analysis was implemented to estimate the causality of blood metabolites on peripheral arteriosclerosis. A genome-wide association study (GWAS) of 1,400 metabolites was used as the exposure, whereas two different GWAS datasets of peripheral arteriosclerosis were the outcomes. Inverse-variance weighted (IVW) was the main analysis of causal analysis. MR-Egger, the simple mode, weighted median and weighted mode were used to increase the stability and robustness of the results. Cochran Q test, MR-Egger intercept test, the funnel plot, and MR-Pleiotropy RESidual Sum and Outlier were used for sensitivity analyses. Furthermore, metabolic pathway enrichment analysis was performed using MetaboAnalyst5.0. In this MR study, eight blood metabolites have a strong causal relationship with peripheral arteriosclerosis, including 1-myristoyl-2-arachidonoyl-GPC (14:0/20:4), 1-palmitoyl-2-arachidonoyl-gpc (16:0/20:4n6), 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE, 1-palmitoyl-2-dihomo-linolenoyl-GPC, Gamma-glutamylleucine, Deoxycholic acid glucuronide and two named X- (X-24546, X-26111). In addition, five important metabolic pathways in peripheral arteriosclerosis were identified through metabolic pathway analysis. This study provides evidence for the causal relationship between blood metabolites and peripheral arteriosclerosis, and these eight blood metabolites provide new perspectives for screening and prevention of peripheral arteriosclerosis in the future.

Role of FGF21 in mediating the effect of phosphatidylcholine on GBM.

The causal relationship and mechanisms between lipids and glioblastoma (GBM) remain unclear. This study aims to investigate the independent causal relationship between liposomal phosphatidylcholine 16:0_22:6 (PC16) and GBM, and to identify the potential mediating role of the inflammatory factor-fibroblast growth factor 21(FGF21). Utilizing summary statistics from genome-wide association studies (GWAS) of lipids (179 types in 7174 Finnish individuals), GBM (243 cases and 287137 controls), and inflammatory factors (91 types in 14824 European individuals), a two-sample Mendelian Randomization (MR) approach was employed to establish the causal link between liposomal PC16 and GBM. Additionally, a two-step MR method was used to quantify the proportion of the causal effect of PC16 on GBM that is mediated by the inflammatory factor FGF21. MR analyses revealed a strong causal relationship between PC16 and GBM (OR=1.72, 95% CI: 1.11-2.68, P=0.016), but no reverse causality was observed from GBM to PC16 (OR=1.01, 95% CI: 0.99-1.02, P=0.38). Mediation analysis showed a strong causal relationship between PC16 and the FGF21 (OR = 0.94, 95% CI: 0.89-0.99, P=0.018) as well as between FGF21 and GBM (OR = 0.42, 95% CI: 0.25-0.71, P=0.001), with the mediation effect accounting for 9.78% of the total effect. This suggests that the causal relationship between PC16 and GBM is likely mediated by the intermediary factor FGF21. No evidence of pleiotropy was found in the sensitivity analysis of these positive results. In summary, the findings of this study suggest that liposomal PC16 may increase the risk of GBM occurrence, and FGF21 may play a significant mediating role in this causal relationship.

Causal relationship between depression and metabolic dysfunction-associated steatotic liver disease: a bidirectional Mendelian randomized study.

With the global rise in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common chronic liver disease. Concurrently, depression is a highly prevalent mental disorder. As the incidence of MASLD and depression continues to increase, a growing body of research indicates a potential association between the two conditions. However, the direction of causality between depression and MASLD remains uncertain. To address this gap, our study utilizes a two-sample Mendelian randomization (MR) approach to explore the bidirectional causal relationship between depression and MASLD. We extracted single nucleotide polymorphisms (SNPs) associated with depression and MASLD from pooled data of genome-wide association studies (GWAS). A comprehensive assessment of possible causality was also performed. Possible mediating effects of liver enzymes on MASLD were also assessed. A total of three GWAS pooled data on depression as well as GWAS data related to MASLD and GWAS data on four liver enzymes were used in this study. Our findings indicated a strong causal relationship between depression and MASLD (OR, 1.557; 95% CI, 1.097-2.211; P = 0.016). And we found a mediating effect of gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT 10% (95% CI: 7% - 13%, P< 0.0002). AST, 4.14% (95% CI: 2.34% - 5.94%, P < 0.05). GGT 0.19% (95% CI: 0.15% - 0.22%, P< 0.000000002). However, we did not find a mediating effect of alkaline phosphatase (ALP). Our inverse MR analysis did not reveal any causal relationship between MASLD and depression. The MR analysis revealed a positive causal relationship between depression and MASLD, while no reverse causal relationship was identified. Liver enzymes may mediate the role between depression and MASLD.

Association Between Rheumatoid Arthritis and Clonal Hematopoiesis: A Mendelian Randomization Study.

Immunity activation and inflammation are the main characteristics of rheumatoid arthritis and clonal hematopoiesis. However, it remains unclear whether rheumatoid arthritis increase the risk of clonal hematopoiesis. Here, a Mendelian randomization (MR) analysis was conduct to explore the causal effects of rheumatoid arthritis on clonal hematopoiesis. Summary statistics data of rheumatoid arthritis (13,838 cases and 33,742 controls) and clonal hematopoiesis (10,203 cases and 173,918 controls) derived from a genomewide association study were selected to analyze. We selected inverse-variance weighted, MR-Egger, weighted median, simple mode, and weighted mode to evaluate the causal effect of rheumatoid arthritis on clonal hematopoiesis. The two-sample MR analysis suggested a strong causal relationship between rheumatoid arthritis and clonal hematopoiesis by inverse-variance weighted (OR = 1.002311673, 95% CI [1.000110757, 1.004517433], p = .039706) and weighted median (OR = 1.002311673, 95% CI [1.000110757, 1.004517433], p = .039518447) methods. No significant pleiotropy or heterogeneity was found in the sensitivity analysis. These results supported a potentially causal relationship between rheumatoid arthritis and clonal hematopoiesis, and the exposure of rheumatoid arthritis increased the risks of clonal hematopoiesis. Our findings highlight the importance of how chronic inflammation and immune activation induced rheumatoid arthritis enhances the risks of clonal hematopoiesis, and that early intervention with rheumatoid arthritis patients might reduce the clonal hematopoiesis risks in rheumatoid arthritis patients. Moreover, our study provides clues for prediction of risk factors and potential mechanisms of clonal hematopoiesis.

Blood metabolites and chronic kidney disease: a Mendelian randomization study

BackgroundHuman blood metabolites have demonstrated close associations with chronic kidney disease (CKD) in observational studies. Nonetheless, the causal relationship between metabolites and CKD is still unclear. This study aimed to assess the associations between metabolites and CKD risk.MethodsWe applied a two-sample Mendelian randomization (MR) analysis to evaluate relationships between 1400 blood metabolites and eight phenotypes (outcomes) (CKD, estimated glomerular filtration rate(eGFR), urine albumin to creatinine ratio, rapid progress to CKD, rapid decline of eGFR, membranous nephropathy, immunoglobulin A nephropathy, and diabetic nephropathy). The inverse variance weighted (IVW), MR-Egger, and weighted median were used to investigate the causal relationship. Sensitivity analyses were performed with Cochran’s Q, MR-Egger intercept, MR-PRESSO Global test, and leave-one-out analysis. Bonferroni correction was used to test the strength of the causal relationship.ResultsThrough the MR analysis of 1400 metabolites and eight clinical phenotypes, a total of 48 metabolites were found to be associated with various outcomes. Among them, N-acetylleucine (OR = 0.923, 95%CI: 0.89–0.957, PIVW = 1.450 × 10–5) has a strong causal relationship with lower risk of CKD after the Bonferroni-corrected test, whereas Glycine to alanine ratio has a strong causal relationship with higher risk of CKD (OR = 1.106, 95%CI: 1.063–1.151, PIVW = 5.850 × 10–7). No horizontal pleiotropy and heterogeneity were detected.ConclusionOur study offers groundbreaking insights into the integration of metabolomics and genomics to reveal the pathogenesis of and therapeutic strategies for CKD. It underscores 48 metabolites as potential causal candidates, meriting further investigation.

Does Financial Derivative Hedging Reduce Firms’ Financial Constraints?

This study examines the relationship between the firms’ derivative risk management and its financial constraints. Firms face a wedge between their internal and external financing for their investments. I test whether this wedge reduces firms’ financial constraints when they hedge using interest rate, foreign currency, and commodity derivatives. Using an event study and a difference-in-differences framework around implementing Financial Accounting Standard (FAS) 123R, this study shows a strong causal relationship between derivative hedging and financial constraints. I find that net debt increases for the derivative hedging firms, on the other hand, cash holdings and net equity issuance decreases. When managers of non-financial corporations believe that their firm will face a liquidity shortage, they save more cash out of cash flow as a precautionary measure. Both cash flow-cash sensitivity and investment-cash flow sensitivity decrease. The analysis also shows that both the loan spread and the probability of covenant violation decrease after firms start derivative hedging. The main implication of the analysis is that risk management influences the asymmetric information between lenders and borrowers: the increase in risk management, the less the asymmetry.

Political Mobilization in Heterogeneous Societies Under a Consociational Political System: A Comparative Study of Identities and Demonstrations in Iraq, Lebanon and Iran

This article is a comparative study of the influences that consociational democracies have on political mobilization. By drawing on theories on collective action, social movements and ethnopolitics, it offers a novel explanation of how the consociational political system affects oppositional political mobilization. The nature of the political system has a strong causal relationship with the identity of the political mobilization. While some political systems generate national oppositional political mobilization, consociational democracies create a divisive environment that prevents cross-sectarian mobilization. Three case studies were examined to test the theory: Iraq, Lebanon and Iran. These countries share many similarities in terms of economic conditions, and social diversity but differ in political mobilization. While political mobilization in Iraq and Lebanon has mostly represented a particular sect within the society at different intervals, Iran, by contrast, witnessed more nationalistic political movements.

Genetically predicted causal effects of gut microbiota on spinal pain: a two-sample Mendelian randomization analysis.

Observational studies have hinted at a correlation between the gut microbiota and spinal pain (SP). However, the impact of the gut microbiota on SP remains inconclusive. In this study, we employed a two-sample Mendelian randomization (MR) analysis to explore the causal relationship between the gut microbiota and SP, encompassing neck pain (NP), thoracic spine pain (TSP), low back pain (LBP), and back pain (BP). The compiled gut microbiota data originated from a genome-wide association study (GWAS) conducted by the MiBioGen consortium (n = 18,340). Summary data for NP were sourced from the UK Biobank, TSP from the FinnGen Biobank, and LBP from both the UK Biobank and FinnGen Biobank. Summary data for BP were obtained from the UK Biobank. The primary analytical approach for assessing causal relationships was the Inverse Variance Weighted (IVW) method, supplemented by various sensitivity analyses to ensure result robustness. The IVW analysis unveiled 37 bacterial genera with a potential causal relationship to SP. After Benjamini-Hochberg corrected test, four bacterial genera emerged with a strong causal relationship to SP. Specifically, Oxalobacter (OR: 1.143, 95% CI 1.061-1.232, P = 0.0004) and Tyzzerella 3 (OR: 1.145, 95% CI 1.059-1.238, P = 0.0007) were identified as risk factors for LBP, while Ruminococcaceae UCG011 (OR: 0.859, 95% CI 0.791-0.932, P = 0.0003) was marked as a protective factor for LBP, and Olsenella (OR: 0.893, 95% CI 0.839-0.951, P = 0.0004) was recognized as a protective factor for low back pain or/and sciatica. No significant heterogeneity or horizontal pleiotropy was observed through alternative testing methods. This study establishes a causal relationship between the gut microbiota and SP, shedding light on the "gut-spine" axis. These findings offer novel perspectives for understanding the etiology of SP and provide a theoretical foundation for potential interventions targeting the gut microbiota to prevent and treat SP.

Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: a Mendelian randomization study.

Currently, there has been observed a significant alteration in the composition of the gut microbiome (GM) and serum metabolites in patients with psoriatic arthritis (PsA) compared to healthy individuals. However, previous observational studies have shown inconsistent results regarding the alteration of gut microbiota/metabolites. In order to shed light on this matter, we utilized Mendelian randomization to determine the causal effect of GM/metabolites on PsA. We retrieved summary-level data of GM taxa/metabolites and PsA from publicly available GWAS statistics. Causal relationships between GM/metabolites and PsA were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the robustness of our findings, we conducted sensitivity analyses, multivariable MR analysis (MVMR), and additional analysis including replication verification analysis, LDSC regression, and Steiger test analysis. Furthermore, we investigated reverse causality through a reverse MR analysis. Finally, we conducted an analysis of expression quantitative trait loci (eQTLs) involved in the metabolic pathway to explore potential molecular mechanisms of metabolism. Our findings reveal that eight GM taxa and twenty-three serum metabolites are causally related to PsA (P < 0.05). Notably, a higher relative abundance of Family Rikenellaceae (ORIVW: 0.622, 95% CI: 0.438-0.883, FDR = 0.045) and elevated serum levels of X-11538 (ORIVW: 0.442, 95% CI: 0.250-0.781, FDR = 0.046) maintain significant causal associations with a reduced risk of PsA, even after adjusting for multiple testing correction and conducting MVMR analysis. These findings suggest that Family Rikenellaceae and X-11538 may have protective effects against PsA. Our sensitivity analysis and additional analysis revealed no significant horizontal pleiotropy, reverse causality, or heterogeneity. The functional enrichment analysis revealed that the eQTLs examined were primarily associated with glycerolipid metabolism and the expression of key metabolic factors influenced by bacterial infections (Vibrio cholerae and Helicobacter pylori) as well as the mTOR signaling pathway. In conclusion, our study demonstrates that Family Rikenellaceae and X-11538 exhibit a strong and negative causal relationship with PsA. These particular GM taxa and metabolites have the potential to serve as innovative biomarkers, offering valuable insights into the treatment and prevention of PsA. Moreover, bacterial infections and mTOR-mediated activation of metabolic factors may play an important role in this process.