Causal Correlation Research Articles

The causality between CD8+NKT cells and CD16−CD56 on NK cells with hepatocellular carcinoma: a Mendelian randomization study

BackgroundHepatocellular carcinoma (HCC), which is featured with high morbidity and mortality worldwide, is a primary malignant tumor of the liver. Recently, there is a wealth of supporting evidence revealing that NK cell-related immune traits are strongly associated with the development of HCC, but the causality between them has not been proven.MethodsTwo-sample Mendelian randomization (MR) study was performed to probe the causal correlation between NK cell-related immune traits and HCC. Genetic variations in NK cell-related immune traits were extracted from recent genome-wide association studies (GWAS) of individuals with European blood lineage. HCC data were derived from the UK Biobank Consortium's GWAS summary count data, including a total of 372,184 female and male subjects, with 168 cases and 372,016 controls, all of whom are of European ancestry. Sensitivity analysis was mainly used for heterogeneity and pleiotropy testing.ResultsOur research indicated the causality between NK cell-related immune traits and HCC. Importantly, CD8+NKT cells had protective causal effects on HCC (OR = 0.9996;95%CI,0.9993–0.9999; P = 0.0489). CD16−CD56 caused similar effects on NK cells (OR = 0.9997;95%CI,0.9996–0.9999; P = 0.0117) as CD8+NKT cells. Intercepts from Egger showed no pleiotropy and confounding factors. Furthermore, insufficient evidence was found to support the existence of heterogeneity by Cochran's Q test.ConclusionMR analysis suggested that low CD8+NKT cells and CD16−CD56 expression on NK cells were linked with a higher risk of HCC.

Causal Relationships of Chronic Constipation and Irritable Bowel Syndrome with Digestive Tract Cancers: A Mendelian Randomization Study.

Chronic constipation and irritable bowel syndrome (IBS) manifest as prevalent gastrointestinal disorders, while digestive tract cancers (DTCs) present formidable challenges to global well-being. However, extant observational studies proffer uncertain insights into potential causal relationships of constipation and IBS with susceptibility to DTCs. We executed Mendelian randomization (MR) analysis to establish causal connections between these conditions and seven distinct categories of DTCs, including colorectal carcinoma (CRC), hepatocellular cancer (HCC), esophageal malignancy (ESCA), pancreatic adenocarcinoma (PAAD), biliary tract carcinoma (BTCs), gastric carcinoma (GC), and small intestine neoplasm (SIC). Leveraging instrumental variables (IVs) obtained from GWAS data of the FinnGen database, we employed a range of analytical methodologies, including inverse-variance weighting multiplicative random effects (IVW_MRE), inverse-variance weighting fixed effects (IVW_FE), maximum likelihood (ML), weighted median (WM), MR‒Egger regression, and the MR-PRESSO test. We observed a substantial linkage between genetically predicted constipation and increased vulnerability to PAAD (OR = 2.29, 95% CI: 1.422-3.69, P = 0.001) via the IVW method. Following the removal of outlier SNPs through MR-PRESSO, genetically predicted IBS was affiliated with an increased risk of CRC (OR = 1.17, 95% CI: 1-1.37, P = 0.05). Nonetheless, decisive causal correlations of constipation or IBS with other DTCs remain elusive. In summary, genetically predicted constipation was associated with an augmented PAAD risk, and IBS was associated with an increased CRC susceptibility within European cohorts, in agreement with some observational studies. Nevertheless, the causal associations of constipation and IBS with other DTCs remain inconclusive.

A Mendelian randomization study of the effect of serum 25-hydroxyvitamin D levels on autoimmune thyroid disease.

The influence of vitamin D on autoimmune thyroid disease (AITD) remains a subject of ongoing debate. This study employs Mendelian randomization (MR) to investigate the causal correlations of serum 25-hydroxyvitamin D (25[OH]D) levels with autoimmune thyroiditis (AIT), autoimmune hyperthyroidism (AIH), and Graves disease (GD). Data on single nucleotide polymorphisms related to serum 25(OH)D levels, AIT, AIH, and GD were sourced from UK Biobank and FinnGen. Inverse variance weighted, MR-Egger, and weighted median were employed to test the exposure-outcome causal relationship. Assessments of horizontal pleiotropy, heterogeneity, and stability were performed using the MR-Egger intercept, Cochran's Q test, and leave-one-out sensitivity analysis, respectively. The results of MR analysis showed increased serum 25(OH)D levels was associated with a reduced risk of AIT (OR 0.499, 95% CI 0.289 to 0.860, p = 0.012) but not causal associated with AIH (OR 0.935, 95% CI 0.695 to 1.256, p = 0.654) and GD (OR 0.813, 95% CI 0.635 to 1.040, p = 0.100). Intercept analysis showed no horizontal pleiotropy (p > 0.05), and Cochran's Q test showed no heterogeneity (p > 0.05). Sensitivity analysis suggested that these results were robust. An increased serum 25(OH)D level is associated with AIT risk reduction but unrelated to AIH and GD. This finding suggests that vitamin D supplementation can be valuable for preventing and treating AIT.

CAT Bridge: an efficient toolkit for gene-metabolite association mining from multiomics data.

With advancements in sequencing and mass spectrometry technologies, multiomics data can now be easily acquired for understanding complex biological systems. Nevertheless, substantial challenges remain in determining the association between gene-metabolite pairs due to the nonlinear and multifactorial interactions within cellular networks. The complexity arises from the interplay of multiple genes and metabolites, often involving feedback loops and time-dependent regulatory mechanisms that are not easily captured by traditional analysis methods. Here, we introduce Compounds And Transcripts Bridge (abbreviated as CAT Bridge, available at https://catbridge.work), a free user-friendly platform for longitudinal multiomics analysis to efficiently identify transcripts associated with metabolites using time-series omics data. To evaluate the association of gene-metabolite pairs, CAT Bridge is a pioneering work benchmarking a set of statistical methods spanning causality estimation and correlation coefficient calculation for multiomics analysis. Additionally, CAT Bridge features an artificial intelligence agent to assist users interpreting the association results. We applied CAT Bridge to experimentally obtained Capsicum chinense (chili pepper) and public human and Escherichia coli time-series transcriptome and metabolome datasets. CAT Bridge successfully identified genes involved in the biosynthesis of capsaicin in C. chinense. Furthermore, case study results showed that the convergent cross-mapping method outperforms traditional approaches in longitudinal multiomics analyses. CAT Bridge simplifies access to various established methods for longitudinal multiomics analysis and enables researchers to swiftly identify associated gene-metabolite pairs for further validation.

Causal associations of BAFF-R on IgD+ CD24- B cell immune cell trait with hepatocellular carcinoma and the mediating role of phenylacetylglutamate levels: a Mendelian randomization study.

We conducted a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between immune cell traits and hepatocellular carcinoma (HCC) and identified the mediating factor of metabolites. The exposure factors were immune cell traits, the mediators were metabolites, and the outcome variable was HCC. Inverse-variance weighted method (IVW) was the main method. Weighted median, MR-Egger regression, weighted mode, simple mode, and MR pleiotropy residual sum and outlier (MRPRESSO) methods were used as complementary methods. The results were tested by using the Bayesian weighted Mendelian randomization (BWMR) approach in our MR study. Subsequently, the potential mediating effect was investigated by conducting a two-step mediation analysis. We identified 26 traits with suggestive correlations between immune cell traits and HCC, with 4 immune cell traits among them having causal correlations with HCC. There were no causal correlations between HCC and immune cell traits in the reverse MR analysis. In the mediation analysis, we found a positive causal association between B cell-activating factor receptors (BAFF-R) on IgD+ CD24- B cell and HCC [IVW: odd ratio (OR), 0.845; 95% CI, 0.759-0.942; p = 0.002]. Phenylacetylglutamate (PAG) levels mediated 7.353% of the causal pathway from BAFF-R on IgD+ CD24- B cell and HCC. In conclusion, BAFF-R on IgD+ CD24- B cell lowers risk of HCC, with PAG levels playing a mediating role.

Pityriasis Rosea and Pityriasis Rosea-Like Eruption Following COVID-19 Vaccination: A Narrative Review.

COVID-19 pandemic completely changed every aspect of human life. Several measures were adopted to limit the spreading of the infection. Among these, vaccination was the main one. Globally, vaccination campaign was a success, showing to be efficient in controlling and preventing the SARS-Cov2 infection, reducing the risk of disease progression, hospitalization, and mortality. However, with the increasing number of vaccines administered, several cutaneous reactions were described, making dermatologists key players in their recognition and treatment. Among these, also viral reactivations have been described. In particular, cases of Pityriasis Rosea (PR) and PR-like reactivations have been collected. An early diagnosis is mandatory to avoid mistreatments. In this context, we conducted a review of the current literature investigating cases of PR following COVID-19 vaccination with the aim of understanding the possible pathogenetic mechanisms and causal correlation as well as to investigate the risk of this cutaneous eruption, to offer clinicians a wide perspective on the linkage between PR and COVID-19 vaccines.

The causality between gut microbiota and endometriosis: a bidirectional Mendelian randomization study.

Observational studies and animal experiments had suggested a potential relationship between gut microbiota abundance and pathogenesis of endometriosis (EMs), but the relevance of this relationship remains to be clarified. We perform a two-sample bidirectional Mendelian randomization (MR) analysis to explore whether there is a causal correlation between the abundance of the gut microbiota and EMs and the direction of causality. Genome-wide association study (GWAS) data ukb-d-N80, finn-b-N14-EM, and MiBinGen were selected. Inverse variance weighted (IVW), weighted median, and MR Egger are selected for causal inference. The Cochran Q test, Egger intercept test, and leave-one-out analysis are performed for sensitivity analyses. In the primary outcome, we find that a higher abundance of class Negativicutes, genus Dialister, genus Enterorhabdus, genus Eubacterium xylanophilum group, genus Methanobrevibacter and order Selenomonadales predict a higher risk of EMs, and a higher abundance of genus Coprococcus and genus Senegalimassilia predict a lower risk of EMs. During verifiable outcomes, we find that a higher abundance of phylum Cyanobacteria, genus Ruminococcaceae UCG002, and genus Coprococcus 3 predict a higher risk of EMs, and a higher abundance of genus Flavonifracto, genus Bifidobacterium, and genus Rikenellaceae RC9 predict a lower risk of EMs. In primary reverse MR analysis, we find that EMs predict a lower abundance of the genus Eubacterium fissicatena group, genus Prevotella7, genus Butyricicoccus, family Lactobacillaceae, and a higher abundance of genus Ruminococcaceae UCG009. In verifiable reverse MR analysis, we find that EMs predict a lower abundance of the genus Ruminococcaceae UCG004 and a higher abundance of the genus Howardella. Our study implies a mutual causality between gut microbiota abundance and the pathogenesis of EMs, which may provide a novel direction for EMs diagnosis, prevention, and treatment, may promote future functional or clinical analysis.

Genetic Insights into the Gut-Lung Axis: Mendelian Randomization Analysis on Gut Microbiota, Lung Function, and COPD.

Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with a complex etiology involving genetic and environmental factors. The dysbiosis of gut microbiota has been implicated in COPD. Mendelian Randomization (MR) provides a tool to investigate causal links using genetic variants as instrumental variables. This study aims to employ MR analysis to explore the causal relationship between gut microbiota, lung function, and COPD. We utilized genome-wide association study (GWAS) data from MiBioGen, UK Biobank and FinnGen, which were related to gut microbial taxa, lung function parameters including forced vital capacity in one second (FEV1), forced vital capacity (FVC), and percentage of predicted FEV1 (FEV1%pred), as well as GWAS data for COPD. MR analysis was conducted to assess the causal effects of gut microbiota on lung function and the risk of COPD. Sensitivity analysis was utilized to examine the stability of the causal relationships. Multiple testing and reverse analysis were employed to evaluate the robustness of these relationships. Using the IVW method, 64 causal correlations were identified. Through conducting sensitivity analysis, multiple testing, and reverse analysis, we identified 14 robust and stable causal relationships. The bacterial taxa that showed a positive association with lung function included Desulfovibrionaceae, Erysipelotrichales, Desulfovibrionales, Clostridiales, Clostridia, Deltaproteobacteria and Erysipelotrichia, while Selenomonadales and Negativicutes showed a negative association with lung function. The abundance of Holdemanella were positively correlated with the risk of COPD, while FamilyXIII exhibited a negative correlation with the risk of COPD. Several microbial taxa were discovered to have a positive causal correlation with lung function, offering potential insights into the development of probiotics. The presence of microbial taxa negatively correlated with lung function and positively correlated with COPD emphasized the potential impact of gut microbiota dysbiosis on respiratory health.

ПРАВО ПРАЦІВНИКА НА ПРОСУВАННЯ ПО РОБОТІ ВІДПОВІДНО ДО НАЦІОНАЛЬНОГО ЗАКОНОДАВСТВА ПРО ПРАЦЮ

Background. The relations that constitute the subject matter of labour law are distinguished by their rather broad scope. After all, along with the labour relationship itself, there are relations related to recruitment, collective bargaining, vocational training, labour disputes, etc. In this case, the implementation of relations related to job promotion is of particular interest. This category is actually at the intersection of legal regulation of pre-employment relations and employment relationship itself. Such ambiguity underlines the relevance of studying the issues of job promotion, which is important for both parties to employment relationship – an employee and an employer. The purpose of this research is to clarify the peculiarities of legal regulation of job promotion, its place in labour law, and its proper practical implementation. Methods. In the course of preparation of the article, the author applied dialectical, comparative legal, formal and logical and other methods of research. With the help of the dialectical method, in particular, the author identifies the specific features of legal regulation of job promotion. The comparative legal method allowed for a comparative legal study of the provisions of national and international legislation governing the issues of job promotion. The formal logical method was used to identify the shortcomings of legal regulation of job promotion and to correlate this category with the employer's right to make a free choice among candidates for a vacant position. Results. If there is a vacant position, the employer has the right to freely choose among candidates for the position, which is expressly provided for in Article 22 of the Labour Code of Ukraine. This can be either a person who is not employed by the employer or an employee who already holds a certain, usually lower, position. In labour law, an employer's choice of a candidate for a vacant position directly from the staff is associated with such a category as job promotion. Labour legislation does not define job promotion, focusing mainly on the employee's right to such promotion. The provision of Article 145 of the Labour Code of Ukraine should not be considered as an absolute obligation of the employer to provide an employee with a promotion if the latter successfully and conscientiously performs their job function. In this case, the employee's right to be promoted depends on the following factors: a) the employer has a vacant position; b) there is a causal correlation between the employee's successful and efficient performance of the job function and the requirements for the job duties of the vacant position; c) clear and transparent procedures for employee evaluation and promotion are in place. Conclusions. Fair, accessible and inclusive job promotion procedures will ensure the effective exercise of the employee's right to such promotion, as well as its harmonious correlation with the employer's right to make a free choice among candidates for a vacant position. In particular, the employer will have a fairly detailed idea of the existing potential of employees, and the latter will not feel distrustful of the employer's actions and disappointed in future professional activities. When developing promotion procedures, which may be established at the level of a collective agreement or a relevant special local regulatory act of the employer, it is important to: a) focus on the need to involve the primary trade union organisation, and in its absence – a representative freely chosen by employees, in the implementation of employee evaluation and promotion procedures; b) defining clear and transparent criteria for eligibility for promotion; c) moving away from one-person decision-making on job promotions towards the establishment of appropriate collegial bodies; d) properly informing employees about the existing procedures for evaluating their performance that affect their further promotion.

Correlation between impostor syndrome among doctoral students and supervisor empathy in Tunisia.

The prevalence of impostor syndrome among PhD students has increased rapidly in recent years, having very negative effects on their mental and psychological health as well as on their doctoral journey. This exploratory study aims to examine whether there is a causal correlation between impostor syndrome among PhD students and empathy among supervisors. This study encompasses 562 doctoral students (300 females, 262 males) and 152 Tunisian supervisors (68 females, 84 males). Employing ANOVA, significant influences on impostor syndrome emerge for gender, marital status, professional status, and the doctoral enrollment level (p < 0.001). Concurrently, supervisors' empathy is significantly affected by gender, marital status, and experience (p < 0.001). Linear regression establishes a noteworthy negative correlation (p = 0.045): a 1-unit increase in empathy correlates with a 0.122-unit decrease in impostor syndrome. These findings underscore the intricate relationship between socio-professional factors, empathy, and impostor syndrome within the academic milieu, offering crucial insights for interventions and psychological support. The study aligns with the broader context of understanding mental health challenges in academia, emphasizing the imperative for ongoing support initiatives.

Mediation effects of metabolites and sex hormones on the relationship between body mass index and breast cancer: Mendelian randomization analysis and mediation analysis.

Observational investigations have indicated a notable correlation between body mass index (BMI) and breast cancer (BC). Nevertheless, the precise biological pathways driving this correlation remain ambiguous. Consequently, we utilized Mendelian randomization (MR) techniques to explore the causative link between BMI and genetic predisposition to BC, as well as the potential intermediary influences. Utilizing extensive cohorts sourced from publicly accessible genome-wide association studies (GWAS) datasets of European populations, we conducted Mendelian randomization (MR) analysis. The primary method employed was the Inverse Variance Weighted (IVW) model. We evaluated both heterogeneity and horizontal pleiotropy. Our MR analysis unveiled several metabolites and sex hormones as mediators in the association between BMI and BC. The IVW model indicated significant negative causal correlations between BMI and BC, ER+BC, and ER-BC. Thirty-five metabolites, thirty-three metabolites and sex hormones, and fifteen metabolites respectively mediated the causal effects of BMI on BC, ER+BC, and ER-BC. Furthermore, our study found that BMI influences BC risk through different mediating factors; BMI increases ER+BC risk through the pathway of sex hormones (biologically available testosterone) and decreases the causal relationship of BC risk through multiple metabolite pathways. This study discovered that BMI increases ER+BC risk through the pathway of sex hormones (biologically available testosterone), and decreases BC risk through multiple metabolite pathways causally. These discoveries could offer insights into the development of preventive strategies and interventions for BC, while further investigations should delve into alternative feasible biological pathways.

Bidirectional Two‐Sample Mendelian Randomization Analysis Unveils a Causal Correlation of Mitochondrial Function‐Related Proteins with the Risk of Diabetic Nephropathy

Bidirectional Two‐Sample Mendelian Randomization Analysis Unveils a Causal Correlation of Mitochondrial Function‐Related Proteins with the Risk of Diabetic Nephropathy

Pengaruh Penerapan Prinsip Good Corporate Governance Terhadap Kinerja Keuangan Lembaga Perkreditan Desa di Kecamatan Kintamani

This test intends to prove the impact of transparency, accountability, responsibility, independence and fairness on the financial performance of LPDs in Kintamani District. This test uses a causal quantitative system to analyze causal correlations between the independent and dependent variables. The test population is 61 LPD along with 39 LPD as a sample. Two informants were taken from each LPD, namely the head of the LPD and the head of the LPD supervisory body, resulting in a total of 78 informants. Sample determination system using purposive sampling. The data analysis technique is multiple regression analysis. the test findings show (1) transparency, accountability, responsibility, independence and fairness have a substantial role in financial performance (2) transparency has a positive and substantial role in financial performance, (3) accountability has a positive and substantial role in financial performance, (4) responsibility has a positive role and substantially on financial performance, (5) independence has a positive and substantial role on financial performance, (6) fairness has a positive and substantial role on financial performance

Role of low-density lipoprotein in mediating the effect of air pollution on coronary heart disease: a two-step multivariate Mendelian randomization study.

Air pollution is affecting the health of millions of people all over the world. The causal correlations of PM2.5, PM10, and nitrogen dioxide (NOx), as the main fine particulate matter, and coronary heart disease (CHD) are yet to be explored. Low-density lipoprotein (LDL) has been a principal factor in the pathogenesis of CHD. It is an interesting issue to consider whether LDL mediates the effect of air pollutants in CHD pathogenesis. A genome-wide association study (GWAS) on the European population, followed up from 2010 to 2018, involving over 400,000 participants, was based on a land-use regression model. The annual mean concentrations of major air pollutant particles, PM2.5 (n=423,796), PM10 (n=423,796), and NOx (n=456,380), were recorded. The large GWAS database of CHD covered over ten million SNPs with independent single nucleotide polymorphisms (SNPs). LDL database collected major biochemical blood parameters from over 400,000 patients (n=440,546). Taken together, we conducted independent two-sample Mendelian randomization (MR) analyses for the causality between air pollutants (PM2.5, PM10, and NOx) and CHD. Multivariate MR analysis was conducted using causal relationships to determine the direct effects of exposure on outcome. The fixed-effect inverse variance weighted (IVW2) method was mainly employed to assess this relationship, with a confidence interval of 95% for the odds ratio (OR). Also, MR-Egger, weighted median, maximum likelihood ratio method, and random-effects inverse variance-weighted (IVW1) method were adopted as supplementary methods. Two-sample MR results based on the IVW2 method suggested positive correlations between PM2.5 and CHD [OR 1.875 (1.279-2.748), p=0.001], PM10 and CHD [OR 2.586 (1.479-4.523), p=0.001], and NOx and CHD [OR 2.991 (2.021-4.427), p=4.37E-08]. The direct effect and mediating proportion were calculated using multivariable Mendelian randomization (MVMR). Lastly, the mediating proportions of LDL in the regulatory roles of PM2.5, PM10, and NOx in CHD were 2.82%, 4.73%, and 9.54%, respectively. PM2.5, PM10, and NOx share direct causal associations with CHD, and LDL performs a mediating role in this pathogenic process. Early prevention against air pollution (such as increasing green areas and reducing large-scale industrial dust emissions) and early lipid-lowering treatment can effectively prevent the occurrence of CHD.

Mendelian randomization suggests causal correlations between inflammatory cytokines and immune cells with mastitis.

Previous studies have reported that immunoinflammatory responses have associations with mastitis. Here, we aimed to further figure out whether circulating inflammatory cytokines and immune cells causally impact mastitis liability. The two-sample Mendelian randomization made use of genetic variances of 91 inflammatory cytokines from a large publicly available genome-wide association study (GWAS) containing 14,824 participants, 731 immunophenotypes data from 3,757 individuals as exposures separately, and mastitis from a GWAS summary (1880 cases and 211699 controls of European ancestry) as outcome. The primary analysis applied the inverse-variance weighted (IVW) method to estimate causal influences, with MR-Egger, weighted median, weighted mode and simple mode as supplementary approaches. Heterogeneity and pleiotropy were evaluated by the Cochrane Q test, MR-Egger intercept test, and MR-PRESSO global test. The results indicated that CX3CL1 may be suggestively relevant to the risk of mastitis (odds ratio, OR = 1.434, 95% CI = 1.142~1.800, p = 0.002). Moreover, three immunophenotypes were identified as having a potential causal link to mastitis (p < 0.05). Significantly, CD28- CD8dim %CD8dim (OR = 1.058, 95% CI = 1.024 ~ 1.093, p = 0.0006) and CD45 on CD33br HLA DR+ (OR = 1.097, 95% CI = 1.039 ~ 1.157, p = 0.0008) were found to induce mastitis possibly. Conversely, CD39+ secreting Treg AC (OR = 0.929, 95% CI = 0.884~ 0.978, p = 0.005) pertained to protective factors of mastitis. Cochran's Q test and MR-Egger intercept test indicated no significant heterogeneity (p > 0.05) or pleiotropy (p > 0.05), supporting the robustness and reliability of our findings. Our study adds to current knowledge on the causal roles of inflammatory cytokines and immune cells on mastitis by genetic means, thus guiding future clinical research.

Counterfactual Causal-Effect Intervention for Interpretable Medical Visual Question Answering.

Medical Visual Question Answering (VQA-Med) is a challenging task that involves answering clinical questions related to medical images. However, most current VQA-Med methods ignore the causal correlation between specific lesion or abnormality features and answers, while also failing to provide accurate explanations for their decisions. To explore the interpretability of VQA-Med, this paper proposes a novel CCIS-MVQA model for VQA-Med based on a counterfactual causal-effect intervention strategy. This model consists of the modified ResNet for image feature extraction, a GloVe decoder for question feature extraction, a bilinear attention network for vision and language feature fusion, and an interpretability generator for producing the interpretability and prediction results. The proposed CCIS-MVQA introduces a layer-wise relevance propagation method to automatically generate counterfactual samples. Additionally, CCIS-MVQA applies counterfactual causal reasoning throughout the training phase to enhance interpretability and generalization. Extensive experiments on three benchmark datasets show that the proposed CCIS-MVQA model outperforms the state-of-the-art methods. Enough visualization results are produced to analyze the interpretability and performance of CCIS-MVQA.

Exploring causal correlations between plasma proteins and peripheral neuropathy: a Mendelian randomization.

Peripheral neuropathy (PN) is a common neurological disorder, and circulating plasma proteins with causal genetic evidence are a major source of therapeutic targets. This study identifies several potential plasma proteins that are causally related to PN risk, providing new insights into protein-mediated pathogenesis of PN and potential targets for novel therapies. To identify potential therapeutic targets for PN, we employed two-sample Mendelian randomization (MR) to identify plasma proteins associated with six common PN. First, we screened for proteins related to PN using genome-wide association studies (GWAS), obtaining genetic data on plasma proteomes from 35,559 Icelanders. Summary data for six common PN, including Carpal Tunnel Syndrome (CTS), Trigeminal Neuralgia (TN), Alcoholic Neuropathy (AIP), Drug-induced Neuropathy (DIP), Diabetic Neuropathy (DP), and Guillain-Barré syndrome (GBS), were obtained from the FinnGen database. Two-sample MR and colocalization analyses were then conducted to further identify protein-PN pairs with presumed causal relationships. Enrichment analysis of positive proteins revealed potential biological processes and pathways. Based on drug-gene interaction analysis, we ultimately identified causal proteins associated with PN that could serve as potential drug targets for treating PN. Through MR analysis, we identified eight proteins (UBC12, SEM4C, IL23R, Prothrombin, CBS, Microglobulin, MATN4, COLEC12) with causal relationships to PN. We found that UBC12 is a protective factor for DP and CTS, while the remaining proteins are risk factors. Further colocalization analysis showed a posterior probability of hypothesis 4 (PPH4) less than 0.75, indicating no positive colocalization results were found. From the pathway enrichment analysis, we discovered that the proteins were mainly concentrated in pathways related to defense response to bacterium, receptor signaling pathway via STAT, cell killing, negative regulation of cytokine production, and leukocyte mediated immunity. Finally, in Drug-Gene Interaction database (DGIdb), we identified three protein-coding genes (IL23R, F2, CBS) as potential drug targets for PN. Mendelian randomization studies confirm the causal relationship between genetically predicted PN-related risk and genetically predicted plasma protein abundance. Plasma proteins, as biomarkers associated with PN, can provide potential drug targets for etiological intervention research in PN.

Exploring causal correlations of inflammatory biomarkers in idiopathic normal-pressure hydrocephalus: insights from bidirectional Mendelian randomization analysis.

Neuroinflammatory processes have been identified as playing a crucial role in the pathophysiology of various neurodegenerative diseases, including idiopathic normal-pressure hydrocephalus (iNPH). iNPH, defined as a common disease of cognitive impairment in older adults, poses major challenges for therapeutic interventions owing to the stringent methodological requirements of relevant studies, clinical heterogeneity, unclear etiology, and uncertain diagnostic criteria. This study aims to assess the relationship between circulating inflammatory biomarkers and iNPH risk using bidirectional two-sample Mendelian randomization (MR) combined with meta-analysis. In our bidirectional MR study, genetic data from a genome-wide association study (GWAS) involving 1,456 iNPH cases and 409,726 controls of European ancestry were employed. Single-nucleotide polymorphisms (SNPs) associated with exposures served as instrumental variables for estimating the causal relationships between iNPH and 132 types of circulating inflammatory biomarkers from corresponding GWAS data. Causal associations were primarily examined using the inverse variance-weighted method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode analyses. In the results, heterogeneity was assessed using the Cochran Q test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test and the MR pleiotropy residual sum and outliers test. Sensitivity analysis was conducted through leave-one-out analysis. Reverse MR analyses were performed to mitigate bias from reverse causality. Meta-analyses of identical inflammatory biomarkers from both data sources strengthened the findings. Results indicated a genetically predicted association between Interleukin-16 (IL-16) [OR: 1.228, 95% CI: 1.049-1.439, p = 0.011], TNF-related apoptosis ligand (TRAIL) [OR: 1.111, 95% CI: 1.019-1.210, p = 0.017] and Urokinase-type plasminogen activator (uPA) [OR: 1.303, 95% CI: 1.025-1.658, p = 0.031] and the risk of iNPH. Additionally, changes in human Glial cell line-derived neurotrophic factor (hGDNF) [OR: 1.044, 95% CI: 1.006-1.084, p = 0.023], Matrix metalloproteinase-1 (MMP-1) [OR: 1.058, 95% CI: 1.020, 1.098, p = 0.003] and Interleukin-12p70 (IL-12p70) [OR: 0.897, 95% CI: 0.946-0.997, p = 0.037] levels were identified as possible consequences of iNPH. Our MR study of inflammatory biomarkers and iNPH, indicated that IL-16, TRAIL, and uPA contribute to iNPH pathogenesis. Furthermore, iNPH may influence the expression of hGDNF, MMP-1, and IL-12p70. Therefore, targeting specific inflammatory biomarkers could be promising strategy for future iNPH treatment and prevention.

Investigating the causal relationship between gut microbiota and gastroenteropancreatic neuroendocrine neoplasms: a bidirectional Mendelian randomization study.

The interaction between the intestinal flora and gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) remains poorly understood, despite the known effect of the gut microbiota on gastrointestinal adenocarcinomas. Hence, the present research aimed to determine the potential causal correlation between the intestinal flora and GEP-NENs by conducting a bidirectional Mendelian randomization (MR) analysis. Two-sample MR analysis was conducted using the summary statistics of the gut microbiota from the MiBioGen consortium and those of GEP-NENs from the FinnGen research project. The inverse-variance weighted approach was utilized as the primary analytical method. To enhance the robustness of our findings, multiple sensitivity tests were performed, including Cochran's Q test for evaluating heterogeneity, the MR-Egger intercept test to detect horizontal pleiotropy, and the MR-PRESSO test to identify outliers and assess pleiotropy bias. Additionally, a leave-one-out analysis was performed to validate the consistency of our findings. The MR-Steiger test was also utilized to determine the causal direction in the correlation between the gut microbiota and GEP-NENs. Finally, a reverse MR analysis was performed to assess reverse causality between the intestinal flora and GEP-NENs. We identified 42 taxa of the gut microbiota that were potentially causally associated with GEP-NENs; of these taxa, 7, 8, 11, and 16 taxa were causally associated with pancreatic NENs, colorectal NENs, small intestinal NENs, and gastric NENs, respectively. After adjusting for false discovery rate (FDR) correction, we found significant causal links of Euryarchaeota with small intestinal NENs and Family XIII UCG-001 with gastric NENs. The sensitivity analyses confirmed the stability of these correlations. In the reverse MR analysis, colorectal NENs and small intestinal NENs were found to be associated with variations in 8 and 6 different taxa of the gut microbiota, respectively. After adjusting for FDR correction, no significant causal links were detected between GEP-NENs and the intestinal flora. The present study reveals a potential causal association between certain taxa of the intestinal flora and GEP-NENs, thus providing new perspectives regarding the role of the intestinal flora in the development of these tumors. These insights could provide innovative approaches to screen and prevent these diseases.

Causal effects of post-traumatic stress disorder on autoimmune thyroid disease: insights from mendelian randomization.

The relationship between post-traumatic stress disorder (PTSD) and autoimmune thyroid disease (AITD) needs further evaluation. This study employs Mendelian randomization (MR) to investigate the causal correlations of PTSD with autoimmune thyroiditis (AIT) and Graves' disease (GD). Datasets for PTSD, AIT, and GD were obtained from FinnGen. The exposure-outcome causal relationship was assessed using inverse variance weighted, MR-Egger, and weighted median. Horizontal pleiotropy was evaluated through the MR-Egger intercept, heterogeneity was examined using Cochran's Q test, and robustness was assessed via leave-one-out sensitivity analysis. MR analysis indicated no significant causal relationship between PTSD and AIT (OR 0.920, 95% CI 0.832 to 1.017, p = 0.103), but a potential increase in the risk of GD associated with PTSD (OR 1.056, 95% CI 1.008 to 1.105, p = 0.021). MR-Egger intercept showed no horizontal pleiotropy (p > 0.05), and Cochran's Q showed no heterogeneity (p > 0.05). Sensitivity analysis suggested the MR results were robust. Evidence of an MR association between genetic liability to PTSD and an increased risk of GD were provided, but no evidence of association between PTSD and AIT. The findings indicate that individuals with PTSD may have an increased likelihood of developing GD, underscoring the importance of further research to comprehend the intricate interplay between PTSD and thyroid disorders.