Prior research has proposed a potential association between lung cancer and inflammatory cytokines, yet the specific causal relationship remains unclear, especially across various lung cancer pathologies. This study utilized bidirectional Mendelian randomization (MR) to explore these causal connections, unveiling novel insights. Our research revealed distinctive inflammatory cytokine profiles for each subtype of lung cancer and identified potential biomarkers that could refine diagnostic and therapeutic approaches. We applied two-sample Mendelian randomization, leveraging genetic variance data from three extensive genome-wide association studies (GWAS) focusing on different lung cancer types (lung adenocarcinoma: 1590 cases and 314,193 controls of healthy individuals of European descent; lung squamous cell carcinoma: 1510 cases and 314,193 controls of European ancestry; small cell lung cancer: 717 cases and 314,193 controls of European ancestry). A separate GWAS summary on inflammatory cytokines from 8,293 healthy participants was also included. The inverse variance weighting method was utilized to examine causal relationships, with robustness confirmed through multiple sensitivity analyses, including MR-Egger, weighted median, and MR-PRESSO. Our analysis revealed that elevated levels of IL_1RA were associated with an increased risk of lung adenocarcinoma (OR: 1.29, 95% CI: 1.02-1.64, p = 0.031), while higher MCP_1_MCAF levels correlated with a decreased risk of lung squamous cell carcinoma (OR: 0.77, 95% CI: 0.61-0.98, p = 0.031). Furthermore, IL_10, IL_13, and TRAIL levels were positively associated with lung squamous cell carcinoma risk (IL_10: OR: 1.27, 95% CI: 1.06-1.53, p = 0.012; IL_13: OR: 1.15, 95% CI: 1.06-1.53, p = 0.036; TRAIL: OR: 1.15, 95% CI: 1.06-1.53, p = 0.043). No association was found between inflammatory cytokine levels and small cell lung cancer development, whereas SDF_1A and B-NGF were linked to an increased risk of this cancer type (SDF_1A: OR: 1.13, 95% CI: 1.05-1.21, p = 0.001; B-NGF: OR: 1.13, 95% CI: 1.01-1.27, p = 0.029). No significant relationship was observed between the 41 circulating inflammatory cytokines and lung adenocarcinoma or squamous cell carcinoma development. Our findings indicate distinct associations between specific inflammatory cytokines and different types of lung cancer. Elevated IL_1RA levels are a risk marker for lung adenocarcinoma, whereas higher MCP_1_MCAF levels appear protective against lung squamous cell carcinoma. Conversely, elevated levels of IL_10, IL_13, and TRAIL are linked with an increased risk of lung squamous cell carcinoma. The relationships of SDF_1A and B-NGF with small-cell lung cancer highlight the complexity of inflammatory markers in cancer development. This study provides a nuanced understanding of the role of inflammatory cytokines in lung cancer, underscoring their potential in refining diagnosis and treatment strategies.

UNASSIGNED: Previous epidemiological studies have reported an association between Sjögren\'s syndrome (SS) and Parkinson\'s disease (PD); however, the causality and direction of this relationship remain unclear. In this study, we aimed to investigate the causal relationship between genetically determined SS and the risk of PD using bidirectional Mendelian randomization (MR).
UNASSIGNED: Summary statistics for Sjögren\'s syndrome used as exposure were obtained from the FinnGen database, comprising 1,290 cases and 213,145 controls. The outcome dataset for PD was derived from the United Kingdom Biobank database, including 6,998 cases and 415,466 controls. Various MR methods, such as inverse variance weighted (IVW), Mendelian randomization Egger regression (MR-Egger), weighted median (WM), simple mode, weighted mode, MR-pleiotropy residual sum and outlier (MR-PRESSO), and robust adjusted profile score (RAPS), were employed to investigate the causal effects of SS on PD. Instrumental variable strength evaluation and sensitivity analyses were conducted to ensure the reliability of the results. In addition, reverse MR analysis was performed to examine the causal effects of PD on SS.
UNASSIGNED: The WM, IVW, RAPS and MR-PRESSO methods demonstrated a significant association between genetically predicted SS and reduced risk of PD (odds ratio ORWM = 0.9988, ORIVW = 0.9987, ORRAPS = 0.9987, ORMR-PRESSO = 0.9987, respectively, P < 0.05). None of the MR analyses showed evidence of horizontal pleiotropy (P > 0.05) based on the MR-Egger and MR-PRESSO tests, and there was no statistical heterogeneity in the test results of the MR-Egger and IVW methods. The leave-one-out sensitivity analysis confirmed the robustness of the causal relationship between SS and PD. Furthermore, reverse MR analysis did not support any causal effects of PD on SS.
UNASSIGNED: Our MR study supports a potential causal association between SS and a reduced risk of PD. Further extensive clinical investigations and comprehensive fundamental research are warranted to elucidate the underlying mechanisms linking SS and PD.

Structural equation models (SEMs) involving feedback loops may offer advantages over standard instrumental variables estimators in terms of modelling causal effects in the presence of bidirectional relationships. In the following note, we show that in the case of a single \"exposure\" and \"outcome\" variable, modelling relationships using a SEM with a simple bidirectional linear feedback loop offers no advantage over traditional instrumental variables estimators in terms of consistency (i.e. both approaches yield consistent estimates of the causal effect, provided that causal estimates are obtained in both directions). In the case of finite samples, traditional IV estimators and SEM exhibited similar power across many of the conditions we examined, although which method performed best depended on the residual correlation between variables and the strength of the instruments. In particular, the power of SEM was insensitive to the residual correlation between variables, whereas the power of the Wald estimator/2SLS improved (deteriorated) relative to SEM as the magnitude of the residual correlation increased (decreased) assuming a positive causal effect of the exposure on the outcome. The power of SEM improved relative to the Wald estimator/2SLS as the instruments explained more residual variance in the \"outcome\" variable.

Prostatitis represents a common disease of the male genitourinary system, significantly impacting the physical and mental health of male patients. While numerous studies have suggested a potential link between immune cell activity and prostatitis, the exact causal role of immune cells in prostatitis remains uncertain. This study aims to explore the causal relationship between immune cell characteristics and prostatitis using a bidirectional Mendelian randomization approach. This study utilizes data from the public GWAS database and employs bidirectional Mendelian randomization analysis to investigate the causal relationship between immune cells and prostatitis. The causal relationship between 731 immune cell features and prostatitis was primarily investigated through inverse variance weighting (IVW), complemented by MR-Egger regression, a simple model, the weighted median method, and a weighted model. Ultimately, the results underwent sensitivity analysis to assess the heterogeneity, horizontal pleiotropy, and stability of Single Nucleotide Polymorphisms (SNPs) in immune cells and prostatitis. MR analysis revealed 17 immune cells exhibiting significant causal effects on prostatitis. In contrast, findings from reverse MR indicated a significant causal relationship between prostatitis and 13 immune cells. Our study utilizes bidirectional Mendelian Randomization to establish causal relationships between specific immune cell phenotypes and prostatitis, highlighting the reciprocal influence between immune system behavior and the disease. Our findings suggest targeted therapeutic approaches and the importance of including diverse populations for broader validation and personalized treatment strategies.

UNASSIGNED: Inflammatory cytokines (ICs) play an important role in erectile dysfunction (ED). Previous studies have demonstrated that most ED patients have high levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). The causality between 41 ICs and ED is investigated using the Mendelian randomization (MR) approach.
UNASSIGNED: Single nucleotide polymorphisms (SNPs) exposure data of 41 ICs came from a genome-wide association study (GWAS) of 8293 subjects. At the same time, the FINNGEN R9 database provided the ED outcome data containing 2205 ED patients and 164104 controls. MR-Egger (ME), inverse variance weighting (IVW), and weighted median (WM) were applied to conduct the MR study and IVW was taken as the main criterion.
UNASSIGNED: From a genetic perspective, the increase of interferon-inducible protein-10 (IP-10) level significantly increased the risk of ED (P=0.043, odds ratio (OR)=1.269, 95% confidence interval (95%CI): 1.007-1.600), while the increase of interleukin-1 receptor antagonist (IL-1RA) markedly decreased the risk of ED (P=0.037, OR=0.768, 95%CI: 0.600-0.984). Meanwhile, IP-10 (p=0.099) and IL-1RA (p=0.135) failed to demonstrate causality in reverse MR analysis.
UNASSIGNED: Changes in ICs levels will significantly affect the risk of ED, especially IP-10 as a risk component for ED and IL-1RA as a protective component for ED. In the future, we can achieve targeted treatment and prevention of ED by intervening with specific inflammatory factors.

UNASSIGNED: Ankylosing spondylitis (AS) is an autoimmune disease that affects millions of individuals. Immune cells have been recognized as having a crucial role in the pathogenesis of AS. However, their relationship has not been fully explored.
UNASSIGNED: We chose to employ Mendelian randomization (MR) to investigate the potential correlation between immune cells and AS. We sourced the data on immune cells from the latest genome-wide association studies (GWASs). We obtained data on AS from the FinnGen consortium. Our comprehensive univariable MR analysis covered 731 immune cells to explore its potential causal relationship with AS. The primary analysis method was inverse-variance weighted (IVW). Additionally, we used Cochran\'s Q test and the MR-Egger intercept test to assess the presence of pleiotropy and heterogeneity. We examined whether our results could be influenced by individual single-nucleotide polymorphisms (SNPs) using the leave-one-out test. We conducted a bidirectional MR to investigate the reverse relationship. We also applied multivariable MR to decrease the potential influence between the immune cells.
UNASSIGNED: Overall, our univariable MR analysis revealed eight immune cells associated with AS. Among these, four immune cells contributed to an increased risk of AS, while four immune cells were identified as protective factors for AS. However, the Bonferroni test confirmed only one risk factor and one protective factor with a significance level of p < 6.84E-05. CD8 on effector memory CD8+ T cell could increase the risk of AS (p: 1.2302E-05, OR: 2.9871, 95%CI: 1.8289-4.8786). HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 1.2301E-06, OR: 0.5446, 95%CI: 0.4260-0.6962). We also identified a bidirectional relationship between CD4 on CD39+ activated CD4 regulatory T cells and AS utilizing the bidirectional MR. To address potential confounding among immune cells, we employed multivariable MR analysis, which revealed that only one immune cell had an independent effect on AS. HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 2.113E-06, OR: 0.0.5423, 95%CI: 0.4210-0.6983). Our findings were consistently stable and reliable.
UNASSIGNED: Our findings indicated a potential link between immune cells and AS, which could provide a new idea for future research. Nevertheless, the specific underlying mechanisms require further exploration.

Aortic valve stenosis (AVS) is the most prevalent cardiac valve lesion in developed countries, and pathogenesis is closely related to aging. DNA methylation-based epigenetic clock is now recognized as highly accurate predictor of the aging process and associated health outcomes. This study aimed to explore the causal relationship between epigenetic clock and AVS by conducting a bidirectional Mendelian randomization (MR) analysis.
Summary genome-wide association study statistics of epigenetic clocks (HannumAge, HorvathAge, PhenoAge, and GrimAge) and AVS were obtained and assessed for significant instrumental variables from Edinburgh DataShare (n = 34,710) and FinnGen biobank (cases = 9870 and controls = 402,311). The causal association between epigenetic clock and AVS was evaluated using inverse variance weighted (IVW), weighted median (WM), and MR-Egger methods. Multiple analyses (heterogeneity analysis, pleiotropy analysis, and sensitivity analysis) were performed for quality control assessment.
The MR analysis showed that the epigenetic age acceleration of HorvathAge and PhenoAge was associated with an increased risk of AVS (HorvathAge: OR = 1.043, P = 0.016 by IVW, OR = 1.058, P = 0.018 by WM; PhenoAge: OR = 1.058, P = 0.005 by IVW, OR = 1.053, P = 0.039 by WM). Quality control assessment proved our findings were reliable and robust. However, there was a lack of evidence supporting a causal link from AVS to epigenetic aging.
The present MR analysis unveiled a causal association between epigenetic clocks, especially HorvathAge and PhenoAge, with AVS. Further research is required to elucidate the underlying mechanisms and develop strategies for potential interventions.

OBJECTIVE: Currently, there is a variety of evidence linking the gut microbiota to changes in sex hormones. In contrast, the causal relationship between SHBG, a carrier of sex hormones, and the gut microbiota is unclear.
METHODS: Bidirectional two-sample Mendelian randomization (MR) analysis was used to detect the causal effect between SHBG and the gut microbiome. Summary statistics of genome-wide association studies (GWASs) for the gut microbiome and SHBG were obtained from public datasets. Inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger and simple mode methods were used to operate the MR analysis. F-statistics and sensitivity analyses performed to evaluate bias and reliability.
RESULTS: When we set gut microbiome as exposure and SHBG as outcome, we identified nine causal relationships. In males, Coprobacter (PIVW = 2.01 × 10-6 ), Ruminococcus2 (PIVW = 3.40 × 10-5 ), Barnesiella (PIVW = 2.79 × 10-2 ), Actinobacteria (PIVW = 3.25 × 10-2 ) and Eubacterium fissicatena groups (PIVW = 3.64 × 10-2 ) were associated with lower SHBG levels; Alphaproteobacteria (PIVW = 1.61 × 10-2 ) is associated with higher SHBG levels. In females, Lachnoclostridium (PIVW = 9.75 × 10-3 ) and Defluviitaleaceae UCG011 (PIVW = 3.67 × 10-2 ) were associated with higher SHBG levels; Victivallaceae (PIVW = 2.23 × 10-2 ) was associated with lower SHBG levels. According to the results of reverse MR analysis, three significant causal effect of SHBG was found on gut microbiota. In males, Dorea (PIVW = 4.17 × 10-2 ) and Clostridiales (PIVW = 4.36 × 10-2 ) were associated with higher SHBG levels. In females, Lachnoclostridium (PIVW = 7.44 × 10-4 ) was associated with higherr SHBG levels. No signifcant heterogeneity of instrumental variables or horizontal pleiotropy was found in bidirectional two-sample MR analysis.
CONCLUSIONS: This study may provide new insights into the causal relationship between the gut microbiome and sex hormone-binding protein levels, as well as new treatment and prevention strategies for diseases such as abnormal changes in sex hormones.

Epidemiological and experimental evidence has linked chronic inflammation to the etiology of myeloproliferative neoplasm (MPN). However, it remains unclear whether genetic associations with specific inflammatory biomarkers are causal or due to bias. This study aimed to assess the effect of C-reactive protein (CRP) and systemic inflammatory regulators on MPN within a bidirectional Mendelian randomization design. Genetic associations with MPN were derived from a publicly available genome-wide association study (GWAS) comprising 1,086 cases and 407,155 controls of European ancestry. Additionally, data on inflammation were extracted from two GWASs focusing on CRP and cytokines. The causal relationships between exposure and outcome were explored using the inverse variance weighted (IVW) method. To confirm the final results, multiple sensitivity analyses, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were simultaneously employed. Our results suggest that lower levels of macrophage-migration inhibitory factor (IVW estimate odds ratio [OR IVW] per SD genetic cytokines change: 0.641; 95% confidence interval [CI]: 0.427-0.964; p  = 0.032) and higher levels of interleukin-2 receptor α (lL2Rα, 1.377, 95% CI: 1.006-1.883; p  = 0.046) are associated with an increased risk of MPN. Genetically predicted MPN is related to increased levels of RANTES (IVW estimate β: 0.043, 95% CI: 0.002-0.084; p  = 0.039) and interleukin-10 (IVW estimate β: 0.030, 95% CI: 0.001-0.060; p  = 0.041). This study provides evidence for a causal relationship between CRP, systemic inflammatory regulators, and MPN, and new insights into the etiology, prevention, and prognosis of MPN.

Observational studies have indicated associations between type 2 diabetes mellitus (T2DM) and both colorectal cancer (CRC) and inflammatory bowel disease (IBD). However, the underlying causality and biological mechanisms between these associations remains unclear.
We conducted a bidirectional Mendelian randomization (MR) analysis employing summary statistics from genome-wide association studies involving European individuals. The inverse variance weighting (IVW) method was the primary method used to assess causality. Additionally, we applied MR Egger, Weighted median, Simple mode, and Weighted mode to evaluate the robustness of the results. Outliers were identified and eliminated using the MR-PRESSO, while the MR-Egger intercept was used to assess the horizontal pleiotropic effects of single nucleotide polymorphisms (SNPs). The heterogeneity was evaluated using the Cochrane Q test, and sensitivity analysis was performed using leave-one-out method. The F statistic was calculated to evaluate weak instrumental variable bias. Finally, a pilot bioinformatics analysis was conducted to explore the underlying biological mechanisms between T2DM and IBD/UC.
The IVW results demonstrated that T2DM significantly reduced risks of IBD (OR=0.885, 95% CI: 0.818-0.958, P=0.002) and ulcerative colitis (UC) (OR=0.887, 95% CI: 0.812-0.968, P=0.007). Although the 95% CIs of MR Egger, Weighted median, Simple mode, and Weighted mode were broad, the majority of their estimates were consistent with the direction of IVW. Despite significant heterogeneity among SNPs, no horizontal pleiotropy was observed. The leave-one-out analysis showed that the causality remained consistent after each SNP was removed, underscoring the reliability of the results. Reverse MR analysis indicated that genetic susceptibility to both CRC and IBD had no significant effect on the relative risk of T2DM. Ten hub genes were identified, which mainly enriched in pathways including maturity onset diabetes of the young, thyroid cancer, gastric acid secretion, longevity regulating pathway, melanogenesis, and pancreatic secretion.
The presence of T2DM does not increase the risk of CRC or IBD. Moreover, T2DM might reduce risk of IBD, including UC. Conversely, the occurrence of CRC or IBD does not influence the risk of T2DM. The association between T2DM and IBD/UC may be related to the changes in multiple metabolic pathways and CTLA-4-mediated immune response.