Expression and immune infiltration studies of IL-33-ST2-NF-κB signaling pathway in prostate cancer.

BACKGROUND: To analyze the expression of interleukin-33 (IL-33), growth-stimulated expression gene 2 (ST2), nuclear factor-kappaB (NF-κB) and immune cell infiltration in prostate cancer, this study aims to provide an experimental basis for the clinical prevention and treatment of prostate cancer. METHODS: The expression of IL-33 in PCa tissues was analyzed using TCGA, TIMER and HPA databases. Using the UALCAN database, the systematic exploration of the relationship between IL-33 and various clinicopathological parameters was conducted. The correlation between IL-33 expression and immune cell infiltration was investigated using TIMER, CIBERSORT and GEPIA databases. To verify these analyses, 22 cases of normal prostate (NP), 76 cases of benign prostatic hyperplasia (BPH), and 100 cases of PCa were recruited. Immunohistochemical staining was performed to examine the expression of IL-33, ST2, NF-κB, and the infiltration of immune cells. Correlations between these factors were then determined. RESULTS: The expression of IL-33, ST2 and NF-κB was significantly lower in PCa tissues compared with NP (p < 0.05). IL-33 was not associated with age in PCa but showed associations with race, molecular characteristics, lymph node metastatic status, TP53 mutation and tumor grade. Furthermore, IL-33 was associated with immune cell infiltration. Positive correlations were observed between IL-33 and ST2 expressions, as well as between IL-33 and CD68+ macrophages in BPH and PCa. CONCLUSIONS: IL-33, ST2 and NF-κB are lowly expressed in PCa tissues, their expression decreases with the increasing malignancy of cancer. IL-33, ST2 and NF-κB are factors associated with PCa immune infiltration. IL-33 has an inhibitory effect on prostate cancer through the IL-33/ST2/NF-κB signalling pathway.

Peripheral immune cell traits and Parkinson's disease: A Mendelian randomization study.

BACKGROUND: The peripheral immune system is altered in Parkinson's disease (PD), but the causal relationship between the two remains controversial. In this study, we aimed to estimate the causal relationship between peripheral immune features and PD using a two-sample Mendelian randomization (MR) approach. METHODS: Genome-wide association study (GWAS) data of peripheral blood immune signatures from European populations were used for exposure and PD summary statistics were used as results. We conducted a two-sample MR study using the inverse-variance weighted (IVW), MR-Egger, and weighted median methods to evaluate the causal association between these factors. MR-Egger and MR-PRESSO were used for sensitivity analysis to test and correct horizontal pleiotropy. RESULTS: A total of 731 immune traits were analyzed for association with PD using three MR methods. After adjustment for FDR, we observed four peripheral immunological features associated with PD using the IVW method, including expression of CX3CR1 on monocytes [OR: 0.85, 95% CI: (0.81, 0.91), P = 6.56E-07] and CX3CR1 on CD14+CD16+ monocytes [OR: 0.87, 95% CI: (0.82, 0.93), P = 9.95E-06]. CONCLUSIONS: Our study further revealed the important role of monocytes in PD and indicated that CX3CR1 expression on monocytes is associated with a reduced risk of PD.

The potential protective role of peripheral immunophenotypes in Alzheimer's disease: a Mendelian randomization study.

Introduction: Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a paramount role in AD, but whether there is a protective causal relationship between peripheral immunophenotypes and AD risk remains ambiguous. Methods: Two-sample Mendelian randomization (MR) was performed using large genome-wide association study (GWAS) genetic data to assess causal effects between peripheral immunophenotypes and AD risk. Utilizing the genetic associations of 731 immune cell traits as exposures. We adopted the inverse variance weighted method as the primary approach. The Weighted median and MR-Egger regression methods were employed as supplements. Various sensitivity analyses were performed to assess the robustness of the outcomes. Results: Based on the IVW method, we identified 14 immune cell traits that significantly reduced the risk of AD, of which six demonstrated statistical significance in both IVW and Weighted median methods. Among the seven immune traits, four were related to regulatory T (Treg) cells : (1) CD25++ CD45RA- CD4 not regulatory T cell % T cell (odds ratio (OR) [95% confidence interval (CI)] = 0.96 [0.95, 0.98], adjusted P = 1.17E-02), (2) CD25++ CD45RA- CD4 not regulatory T cell % CD4+ T cell (OR [95% CI] = 0.97 [0.96, 0.99], adjusted P = 3.77E-02), (3) Secreting CD4 regulatory T cell % CD4 regulatory T cell (OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03), (4) Activated & secreting CD4 regulatory T cell % CD4 regulatory T cell(OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03). In addition, HLA DR++ monocyte % monocyte (OR [95% CI] = 0.93 [0.89, 0.98], adjusted P = 4.87E-02) was associated with monocytes, and HLA DR on myeloid Dendritic Cell (OR [95% CI] = 0.93 [0.89, 0.97], adjusted P = 1.17E-02) was related to dendritic cells (DCs). Conclusion: These findings enhance the comprehension of the protective role of peripheral immunity in AD and provide further support for Treg and monocyte as potential targets for immunotherapy in AD.

Air pollution, greenspace exposure and risk of Parkinson's disease: a prospective study of 441,462 participants.

BACKGROUND: The current understandings of the relationship between air pollution (AP), greenspace exposure and Parkinson's Disease (PD) remain inconclusive. METHODS: We engaged 441,462 participants from the UK Biobank who were not diagnosed with PD. Utilizing Cox proportional hazard regression model, relationships between AP [nitrogen dioxide (NO2), and nitrogen oxides (NOX), particulate matter < 2.5 µm in aerodynamic diameter(PM2.5), coarse particulate matter between 2.5 µm and 10 µm in aerodynamic diameter(PM2.5-10), particulate matter < 10 µm in aerodynamic diameter(PM10)], greenspace exposure, and PD risk were determined independently. Our analyses comprised three models, adjusted for covariates, and affirmed through six sensitivity analyses to bolster the robustness of our findings. Moreover, mediation analysis was deployed to discern the mediating effect of AP between greenspaces and PD. RESULTS: During a median follow-up of 12.23 years (5,574,293 person-years), there were 3,293 PD events. Each interquartile (IQR) increment in NO2 and PM10 concentrations were associated with 10% and 8% increase in PD onset risk, while the increases in NOX, PM2.5 and PM2.5-10 were not associated with PD risk. Additionally, greenspace may safeguard by reducing NO2 and PM10 levels, with the effect mediated by NO2 and PM10 in greenspace-PD relationship. CONCLUSION: Our findings indicate that an IQR increase in ambient NO2 and PM10 concentrations was associated with risk of PD development, while other pollutants (NOX, PM2.5 and PM2.5-10) were not associated with PD risk. Firstly, we find that augmented exposure to greenspace was associated with the lower PD risk by reducing NO2 and PM10 levels.

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes (CD38, GPNMB, RAB29, TMEM175, TTC19) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

Association between irritable bowel syndrome and Parkinson's disease by Cohort study and Mendelian randomization analysis.

This study aimed to investigate the association between irritable bowel syndrome (IBS) and Parkinson's disease (PD) utilizing prospective cohort study and Mendelian randomization. The dataset contained a substantial cohort of 426,911 participants from the UK Biobank, discussing the association between IBS and PD with Cox proportional hazards models and case-control analysis while adjusting for covariates such as age, gender, ethnicity and education level. In univariate Cox regression model, the risk of PD was reduced in IBS patients (HR: 0.774, 95%CI: 0.625-0.956, P = 0.017), but the statistical significance diminished in the three models after adjusting for other variables. In a few subgroup analyses, IBS patients are less likely to develop into PD, and patients diagnosed with IBS after 2000 also had a lower risk (HR: 0.633, 95%CI: 0.403-0.994, P = 0.047) of subsequently developing PD. In addition, we matched five healthy control participants based on gender and age at the end of the study for each IBS patient diagnosed during the follow-up period, and logistic regression results (OR:1.239, 95%CI: 0.896-1.680, P = 0.181) showed that IBS was not associated with the risk of PD. Mendelian randomization did not find significant evidence of the causal relationship between IBS and Parkinson's disease (OR: 0.801, 95%CI: 0.570-1.278, P = 0.204). Overall, we suggest that IBS status is not associated with the risk of developing PD, and that these findings provide valuable insights into the clinical management and resource allocation of patients with IBS.

Association between inflammatory bowel disease and Parkinson's disease: a prospective cohort study of 468,556 UK biobank participants.

Introduction: Inflammatory Bowel Disease (IBD) and Parkinson's disease (PD) are both chronic, progressive disorders. As such, given the inconclusive results of extensive research on the association between IBD and PD, our study intends to examine this relationship further using the UK Biobank database. Methods: We conducted a prospective cohort study using the Cox proportional hazards model, analyzing data from the UK Biobank to investigate the relationship between IBD and PD, following subjects until PD diagnosis, loss to follow up, death or study termination on 30 June, 2023. Results: The results show that IBD had no effect on the risk of PD (HR: 1.356, 95% CI: 0.941-1.955, p = 0.103), and the effect remained consistent in specific Crohn's disease, ulcerative colitis or unclassified IBD populations. In addition, after sensitivity analysis using propensity matching scores and excluding patients diagnosed with PD 5 or 10 years after baseline, IBD had no effect on the risk of PD. However, in the subgroup analysis, we found that in females (HR: 1.989, 95% CI: 1.032-3.835, p = 0.040), the polygenic risk score was highest (HR: 2.476, 95% CI: 1.401-4.374, p = 0.002), and having ulcerative colitis without hypertension (HR: 2.042, 95% CI: 1.128-3.697, p = 0.018) was associated with an increased risk of PD. Conclusion: In conclusion, over an average follow-up period of 13.93 years, we found no significant association between IBD and PD.