UNASSIGNED: Studies on the relationships between diseases of the urinary system and human plasma proteomes have identified several potential biomarkers. However, none of these studies have elucidated the causal relationships between plasma proteins and urolithiasis.
UNASSIGNED: The objective of the study was to investigate the potential risks of plasma metabolites in urolithiasis using a two-sample Mendelian randomization (MR) study.
UNASSIGNED: A total of 1,400 metabolites were identified in the most comprehensive genome-wide association study (GWAS) of plasma metabolomics in a European population to date, and single-nucleotide polymorphisms (SNPs) were used as the instrumental variables for the plasma metabolites. The European GWAS data for urinary calculi included 482,123 case samples and 6,223 control samples (ebi-a-GCST90018935). The associations between the plasma metabolites and risk of urolithiasis were evaluated by inverse variance weighting (IVW) and supplemented by sensitivity analyses of the MR-Egger and MR-PRESSO tests.
UNASSIGNED: For the first time, we found a causal relationship between two plasma metabolites (p < 1.03 × 10-4) and urolithiasis (p < 0.05). The chemical 4-hydroxychlorothalonil, which is an intermediate product of the pesticide hydroxychlorothalonil, could promote urolithiasis (odds ratio (OR) = 1.12) as a risk factor. Moreover, 1-stearoyl-2-arachidonoyl-GPC, which is an important component of phospholipid metabolism in the human body, can inhibit urolithiasis (OR = 0.94).
UNASSIGNED: Our results suggest that blood metabolites can be used as blood markers and drug targets in the prevention, diagnosis, and treatment of urolithiasis; furthermore, our results can provide a basis for policy makers to formulate prevention and treatment policies for urolithiasis.

UNASSIGNED: Clinical observations indicate a correlation between the gut microbiota and overactive bladder (OAB) symptoms. Nevertheless, the causal relationship and mechanisms between gut microbiota and OAB symptoms remain elusive.
UNASSIGNED: Two-sample Mendelian randomization (MR) analyses were performed to assess the association between gut microbiota and OAB symptoms, including urinary incontinence (UI). Data were obtained from the MiBioGen International Consortium genome-wide association studies (GWAS) dataset and the IEU GWAS database. The inverse variance weighted method was used as the primary approach in the MR analysis, with the weighted median, MR-Egger, and weighted mode methods as supplementary approaches. Sensitivity analyses were employed to assess potential violations of the MR assumptions.
UNASSIGNED: Our analysis identified seven gut bacterial taxa with a causal relationship to OAB and nine gut bacterial taxa associated with UI. Genera Eubacteriumfissicatenumgroup, LachnospiraceaeNK4A136group, and Romboutsia were identified as protective factors against OAB, while genera Barnesiella, FamilyXIIIAD3011group, Odoribacter, and RuminococcaceaeUCG005 were associated with an increased risk of OAB. A higher abundance of the genus Coprococcus3, order Burkholderiales, and phylum Verrucomicrobia predicted a lower risk of UI. Conversely, the class Mollicutes, genus Ruminococcus gauvreauii group, order Mollicutes RF9, and phylum Firmicutes and Tenericutes were positively correlated with UI risk. The sensitivity analysis excluded the influence of potential heterogeneity and horizontal pleiotropy.
UNASSIGNED: This study revealed a causal relationship between gut microbiota and OAB symptoms, providing new insights and a theoretical foundation to identify biomarkers and therapeutic targets for patients with OAB symptoms.

UNASSIGNED: Observational studies suggest associations between gut microbiota and polymyositis (PM) and dermatomyositis (DM), but causal relationships are unclear. We investigate the causal effects of gut microbiota on PM and DM, providing insights hoping to provide insights for future treatment and prevention.
UNASSIGNED: Summary statistics of gut microbiota were obtained from a multi-ethnic Genome Wide Association Studies (GWAS) meta-analysis, including 119 taxa from 18,340 Europeans. PM/DM statistics were extracted from GWAS analyses. Mendelian randomization (MR) with IVW, MR-Egger, and weighted median methods was performed. Sensitivity analyses addressed heterogeneity and pleiotropy. Of the 119 bacterial genera studied, six showed causal links.
UNASSIGNED: Alloprevotella (OR: 3.075, 95% CI: 1.127-8.386, p = 0.028), Ruminococcaceae UCG003 (OR: 4.219, 95% CI: 1.227-14.511, p = 0.022), Dialister (OR: 0.273, 95% CI: 0.077-0.974, p = 0.045) were associated with PM. Anaerotruncus (OR: 0.314, 95% CI: 0.112-0.882, p = 0.028), Ruminococcaceae UCG002 (OR: 2.439, 95% CI: 1.173-5.071, p = 0.017), Sutterella (OR: 3.392, 95% CI: 1.302-8.839, p = 0.012) were related to DM. Sensitivity analyses validated these associations.
UNASSIGNED: We establish causal relationships between Ruminococcaceae, Sutterella, Anaerotruncus with DM, Alloprevotella, Ruminococcaceae UCG003, and Dialister with PM. Common microbiota, like Ruminococcaceae, have significant clinical implications. These findings open up greater possibilities for the gut microbiota to contribute to the development of PM/DM and for future monitoring of the gut microbiota in patients with PM/DM.

BACKGROUND: Several observational or retrospective studies have previously been conducted to explore the possible association between lung cancer and human papillomavirus (HPV) infection. However, there may be inconsistencies in the data and conclusions due to differences in study design and HPV testing methods. There are currently no studies that provide conclusive evidence to support the involvement of HPV in the occurrence and development of lung cancer. Therefore, the relationship between HPV and lung cancer remains controversial and uncertain. This study aimed to explore whether HPV infection is causally related to lung cancer risk by systematically performing a two-way Two-Sample Mendelian Randomization (TSMR) analysis.
METHODS: In the International Lung Cancer Consortium (ILCCO) genome-wide association study dataset, we included 11,348 lung cancer (LUCA) cases, including 3275 squamous cell carcinoma (LUSC) cases, 3442 adenocarcinoma (LUAD) cases, and 15,861 cases of control. Using genetic variants associated with the HPV E7 protein as instrumental variables, we summarized statistics associated with HPV infection in the MRC IEU OpenGWAS database, which included the HPV-16 E7 protein and the HPV-18 E7 protein. Two-sample Mendelian randomization (MR) results are expressed as odds ratios (OR) and 95% confidence intervals (CI).
RESULTS: Based on a comprehensive analysis of genome-wide association study (GWAS) data from public databases, we mainly used inverse-variance weighted (IVW) to estimate causal relationships, while using MR-Egger, weighted median, simple mode, and weighted mode, and other four methods as supplements. Two-sample MR Analysis revealed no causal relationship between exposure factors (HPV-16 E7 protein and HPV-18 E7 protein) and outcome factors (lung cancer (LUCA) and its subtypes squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD)) in forward MR Analysis using the IVW approach.HPV-16 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 1.002; 95% [CI]: 0.961 - 1.045; p = 0.920; [OR] = 1.023; 95% [CI]: 0.966 - 1.084; p = 0.438; [OR] = 0.994; 95% [CI]: 0.927 - 1.066; p = 0.872); HPV-18 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 0.965; 95% [CI]: 0.914 - 1.019; p = 0.197; [OR] = 0.933; 95% [CI]: 0.834 - 1.043; p = 0.222; [OR] = 1.028; 95% [CI]: 0.945 - 1.118; p = 0.524. It was observed through reverse MR that LUCA and its subtypes LUSC and LUAD were used as exposure factors, and HPV infection (HPV-16 E7 protein and HPV-18 E7 protein) was used as the outcome factors, the results of the IVW method are also invalid.LUCA and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.036; 95% [CI]: 0.761 - 1.411; p = 0.82; [OR] = 1.318; 95% [CI]: 0.949 - 1.830; p = 0.099; LUSC and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.123; 95% [CI]0.847 - 1.489; p = 0.421; [OR] = 0.931; 95% [CI]: 0.660 - 1.313; p = 0.682; LUAD and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.182; 95% [CI] 0.983 - 1.421; p = 0.075; [OR] = 1.017; 95% [CI]: 0.817 - 1.267; p = 0.877.Our results indicate that there is no causal relationship between genetically predicted HPV infection and LUCA and its subtypes LUSC and LUAD. In addition, in the reverse MR analysis, we did not observe a significant causal relationship between LUCA and its subtypes LUSC and LUAD on HPV infection.
CONCLUSIONS: Our findings do not support a genetic association between HPV infection and lung cancer.

UNASSIGNED: Previous studies have shown a connection between physical activity and migraines, but they don\'t prove a cause-and-effect relationship due to potential biases in observational methods.
UNASSIGNED: Utilizing accelerometer-measured physical activity data from a cohort of 377,234 participants in the UK Biobank and information from 599,356 European migraine patients (including 48,975 cases and 550,381 controls) obtained from 24 cohorts, we performed a bidirectional Mendelian randomization analysis to investigate the genetic bidirectional causal relationship between accelerometer-measured physical activity and migraines.
UNASSIGNED: Research findings indicated a slight negative genetic correlation between \"average acceleration\" physical activity (rg  = -0.091, p = 0.011), overall physical activity (rg  = -0.081, p = 0.017), and migraine. Nevertheless, no shared genetic components were observed between migraine and \"fraction of accelerations > 425 mg\" of physical activity (rg  = -0.124, p = 0.076). The study results also demonstrated a lack of genetic bidirectional causality between accelerometer-measured physical activity and migraine (\"average acceleration\", OR = 1.002, 95% CI 0.975-1.031, p = 0.855, \"fraction of accelerations > 425 mg\", OR = 1.127, 95% CI 0.802-1.583, p = 0.488, overall physical activity, OR = 0.961, 95% CI 0.713-1.296, p = 0.799), and vice versa. Additionally, this lack of causal association persists even after adjusting for obesity (OR = 1.005, p = 0.578), education (OR = 1.019, p = 0.143), and depression (OR = 1.005, p = 0.847), either separately or simultaneously.
UNASSIGNED: The Mendelian randomization results based on genetic data do not provide support for a causal association between physical activity and migraine.

UNASSIGNED: The relationship between peripheral immune cells and immunoglobulin A nephropathy (IgAN) is widely known; however, causal evidence of this link is lacking. Here, we aimed to determine the causal effect of peripheral immune cells, specifically total white blood cells, lymphocytes, monocytes, basophils, eosinophils, and neutrophils, as well as lymphocyte subset traits, on the IgAN risk using a Mendelian randomization (MR) analysis.
UNASSIGNED: The inverse-variance weighted (IVW) method was used for the primary analysis. We applied three complementary methods, including the weighted median, MR-Egger regression, and MR-PRESSO, to detect and correct for the effect of horizontal pleiotropy. Additionally, we performed a multivariable MR (MVMR) analysis, adjusting for the effects of C-reactive protein (CRP) levels. The roles of specific lymphocyte subtypes and their significance have garnered interest. Bidirectional two-sample MR analysis was performed to test the potential causal relationships between immune traits, including median fluorescence intensities (MFIs) and the relative cell count (AC), and IgAN.
UNASSIGNED: The IVW-MR analysis suggested a potential causal relationship between lymphocyte counts and IgAN in Europe (OR per 1-SD increase: 1.43, 95% CI: 1.08-1.88, P = 0.0123). The risk effect of lymphocytes remained even after adjusting for CRP levels using the MVMR method (OR per 1-SD increase: 1.44, 95% CI: 1.05-1.96, P = 0.0210). The other sensitivity analyses showed a consistent trend. The largest GWAS published to date was used for peripheral blood immunophenotyping to explore the potential causal relationship between peripheral immune cell subsets and IgAN. Six AC-IgAN and 14 MFI-IgAN pairs that reached statistical significance (P < 0.05) were detected. Notably, CD3, expressed in eight subsets of T cells, consistently showed a positive correlation with IgAN. The bidirectional MR analysis did not reveal any evidence of reverse causality. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates.
UNASSIGNED: Genetically determined high lymphocyte counts were associated with IgAN, supporting that high lymphocyte counts is causal risk factor for IgAN.

BACKGROUND: Previous research has highlighted correlations between blood cell counts and chronic liver disease. Nonetheless, the causal relationships remain unknown.
OBJECTIVE: To evaluate the causal effect of blood cell traits on liver enzymes and nonalcoholic fatty liver disease (NAFLD) risk.
METHODS: Independent genetic variants strongly associated with blood cell traits were extracted from a genome-wide association study (GWAS) conducted by the Blood Cell Consortium. Summary-level data for liver enzymes were obtained from the United Kingdom Biobank. NAFLD data were obtained from a GWAS meta-analysis (8434 cases and 770180 controls, discovery dataset) and the Fingen GWAS (2275 cases and 372727 controls, replication dataset). This analysis was conducted using the inverse-variance weighted method, followed by various sensitivity analyses.
RESULTS: One SD increase in the genetically predicted haemoglobin concentration (HGB) was associated with a β of 0.0078 (95%CI: 0.0059-0.0096), 0.0108 (95%CI: 0.0080-0.0136), 0.0361 (95%CI: 0.0156-0.0567), and 0.0083 (95%CI: 00046-0.0121) for alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase, and gamma-glutamyl transferase, respectively. Genetically predicted haematocrit was associated with ALP (β = 0.0078, 95%CI: 0.0052-0.0104) and ALT (β = 0.0057, 95%CI: 0.0039-0.0075). Genetically determined HGB and the reticulocyte fraction of red blood cells increased the risk of NAFLD [odds ratio (OR) = 1.199, 95%CI: 1.087-1.322] and (OR = 1.157, 95%CI: 1.071-1.250). The results of the sensitivity analyses remained significant.
CONCLUSIONS: Novel causal blood cell traits related to liver enzymes and NAFLD development were revealed through Mendelian randomization analysis, which may facilitate the diagnosis and prevention of NAFLD.

UNASSIGNED: The existing observational research on the relationship between physical activity (PA) and skin cancer (SC) is contentious, which points to the intricate nature of their association and underscores the imperative for more nuanced research to untangle the causal dynamics at play. The aim of this article is to delve deeper into this complex relationship, seeking to clarify whether PA serves as a protective factor against SC, or contributes to its risk.
UNASSIGNED: We utilized data from the genome-wide association study (GWAS) of PA from GWAS Catalog (include self-reported moderate to vigorous PA (MVPA), self-reported vigorous PA (VPA), and accelerometer-based average-accelerated PA). The data of SC is from FinnGen. All of the participants are of European ancestry. We used two-sample Mendelian Randomization (TSMR) to analyze the causal relationship between PA and SC.The research was conducted using inverse variance weighted (IVW) method as the primary approach, and MR Egger regression as supplementary analytical method. To ensure the robustness of the results, Cochran\'s Q-test and MR pleiotropy residual sum and outlier (MR-PRESSO) global tests were used to measure sensitivity.
UNASSIGNED: Our analysis indicated that average-accelerated PA was associated with an increased risk of SC (ORIVW = 0.94, 95% CI 0.93-0.96, P < 0.001). While neither MVPA (ORIVW = 0.99, 95% CI 0.67-1.47, P = 0.962) nor VPA (ORIVW = 0.80, 95% CI 0.29-2.18, P = 0.656) shows causal relationship on risk of SC.
UNASSIGNED: Our research suggests that PA is associated with a decrease in SC, provides a new perspective for future SC prevention. Our research findings bolster the hypothesis that increased levels of PA, characterized by average acceleration, are associated with a reduced risk of developing skin cancer. This has filled the gap of research on the causal relationship between PA and SC, and could pave the way for novel preventive strategies against skin cancer.

UNASSIGNED: Although descriptive studies have found an association between thyroid dysfunction (TD) and alopecia areata (AA), however, the causal relationship between TD and AA remains unclear. The purpose of this study is to investigate the causal relationship between the two and the specific directions.
UNASSIGNED: We performed large-scale, two-sample Mendelian randomization (MR) analyses to examine whether there was an association between TD (such as Graves\' disease (GD), Hashimoto\'s thyroiditis (HT), thyroid cancer (TC), thyroid stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), etc.) and AA. Genome-wide association study (GWAS) summary statistics for TD and AA were from the IEU OpenGwas project. The inverse variance-weighted (IVW) method was used as the primary analysis method to evaluate the causality between TD and AA, supplemented by the weighted median, MR-Egger, simple mode and weighted mode. In addition, sensitivity analyses were performed to assess the reliability of the study results.
UNASSIGNED: Our study found that single nucleotide polymorphisms (SNPs) in HT (IVW OR = 1.396, 95% CI 1.030-1.892, P=0.031) and hypothyroidism (IVW OR = 1.431, 95% CI 1.138-1.799, P=0.002) significantly increased the risk of AA. Reverse MR analysis indicated that genetic susceptibility to AA (β=-0.029, 95%CI=-0.051 to -0.007, P=0.009) may be a risk for TRH. Positive MR analysis observed no statistically significant causal relationship between other TD and AA (IVW P>0.05). Reverse MR analysis also showed no statistically significant association between AA and other TD (IVW P>0.05) other than TRH. Furthermore, additional sensitivity analyses were performed, including a leave-one-out test, a heterogeneity test, and a pleiotropy test to assess the robustness of the results.
UNASSIGNED: This study provides a very comprehensive analysis of the causal relationship between TD and AA, providing convincing genetic evidence to support the causal relationship between TD and alopecia areata. It reveals some causes of AA patients, which is of great significance for the management and treatment of AA patients.

UNASSIGNED: Recent epidemiological studies have indicated a correlation between platelet indices and pulmonary arterial hypertension (PAH), yet the causality between them remains unclear. To explore the causal relationship between four platelet indices and PAH, with the aim of providing a theoretical basis for clinical prevention and treatment.
UNASSIGNED: Single-nucleotide polymorphisms (SNPs) associated with platelet-related traits were selected as exposure factors from published genome-wide association studies (GWAS), including: platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW). Summary-level data for PAH were obtained from the FinnGen study (248 cases and 289,117 controls). Two-sample and multivariable Mendelian randomization (MR) analyses were conducted to assess the causal relationship between exposure factors and the risk of outcomes. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach, supplemented by weighted median, mode-based estimation, MR-Egger regression, and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test to detect and adjust for pleiotropy, ensuring the reliability of the results through sensitivity analysis.
UNASSIGNED: (1) The IVW results from the two-sample MR analysis showed a positive causal association between PLT and the risk of developing PAH [(OR = 1.649, 95%CI: 1.206-2.256, P = 0.0017)], with the sensitivity analysis confirming the robustness of the causal relationship. The MR-Egger intercept analysis did not detect potential pleiotropy (P = 0.879). (2) The MVMR results showed no statistically significant causal relationship between these four markers and the risk of developing PAH. After adjusting for collinearity, a direct positive causal association was observed between PLT and the risk of developing PAH (OR = 1.525, 95%CI: 1.063-2.189, P = 0.022).
UNASSIGNED: The positive correlation between PLT and the risk of PAH suggests that correcting elevated platelet levels may reduce the risk of developing PAH.