Cathepsin-mediated regulation of alpha-synuclein in Parkinson's disease: a Mendelian randomization study.

The observational association between cathepsin and Parkinson's disease (PD) has been partially explored in previous research. However, the causal relationship remains unclear. In this study, our objective is to investigate the causal link between cathepsin and PD using Mendelian randomization (MR) analysis and elucidate the underlying mechanisms governing their interaction. Utilizing bidirectional two-sample MR and multivariable MR, we systematically investigates the causal relationship between nine cathepsins and PD. The data pertaining to cathepsins were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project, while data related to PD were sourced from versions R9 and R10 of the FinnGen database. The primary analytical method utilized was the inverse variance weighted (IVW), with MR analysis initially conducted using PD data from R9, complemented by a series of sensitivity analyses. Subsequently, replication analysis was performed on the R10 dataset, and meta-analysis were employed to merge the findings from both datasets. To explore potential mechanisms by which Cathepsins may impact PD, MR analyses were performed on significant Cathepsins with alpha-synuclein. MR analysis and colocalization analysis were conducted on expression quantitative trait loci (eQTL) data of gene related to alpha-synuclein with PD data. Forward MR analyses revealed more cathepsin B (CTSB) associated with less PD risk (OR = 0.898, 95%CI: 0.834-0.966, p = 0.004), while more cathepsin H (CTSH) (OR = 1.076, 95%CI: 1.007-1.149, p = 0.029) and more cathepsin S (CTSS) (OR = 1.076, 95%CI: 1.007-1.150, p = 0.030) associated with increasing PD risk. Meta-analyses validated these associations. Multivariate MR Results were consistent with those before adjustment. No significant results were observed in bidirectional MR analysis. In the investigation of the underlying mechanism, our findings demonstrate that CTSB significantly reduces the levels of alpha-synuclein (OR = 0.909, 95%CI: 0.841-0.983, p = 0.017). Concurrently, a genetically determined positive correlation between alpha-synuclein and PD is illuminated by both eQTL MR and colocalization analysis. In conclusion, this MR study yields robust evidence suggesting an association between elevated levels of CTSB and reduced PD risk, mediated by the downregulation of alpha-synuclein levels. Conversely, higher levels of CTSH and CTSS are associated with an increased risk of PD. These findings offer novel insights into the pathophysiological mechanisms of PD and identify potential drug targets for disease prevention and treatment warranting further clinical investigations.

Lin L ，Wu Z ，Luo H ，Huang Y ... -  《Frontiers in Aging Neuroscience》

Cathepsins and Parkinson's disease: insights from Mendelian randomization analyses.

Parkinson's disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes participate in a range of physiological and pathological processes, including the degradation of harmful proteins. Prior research has pointed towards a potential link between cathepsins and PD; however, the precise causal relationship between the cathepsin family and PD remains unclear. This study employed univariate and multivariate Mendelian randomization (MR) analyses to explore the causal relationship between the nine cathepsins and Parkinson's disease (PD) risk. For the primary analysis, genome-wide association study (GWAS) summary statistics for the plasma levels of the nine cathepsins and PD was obtained from the INTERVAL study and the International Parkinson's Disease Genomics Consortium. GWAS for PD replication analysis were obtained from the FinnGen consortium, and a meta-analysis was performed for the primary and replication analyses to evaluate the association between genetically predicted cathepsin plasma levels and PD risk. After identifying significant MR estimates, genetic co-localization analyses were conducted to determine whether shared or distinct causal variants influenced both cathepsins and PD. Elevated cathepsin B levels were associated with a decreased risk of PD in univariate MR analysis (odds ratio [OR] = 0.890, 95% confidence interval [CI]: 0.831-0.954, pFDR = 0.009). However, there was no indication that PD affected cathepsin B levels (OR = 0.965, 95% CI: 0.858-1.087, p = 0.852). In addition, after adjusting for the remaining cathepsins, cathepsin B levels independently and significantly contributed to the reduced risk of PD in multivariate MR analysis (OR = 0.887, 95% CI: 0.823-0.957, p = 0.002). The results of the replication MR analysis with the FinnGen GWAS for PD (OR = 0.921, 95% CI: 0.860-0.987, p = 0.020) and meta-analysis (OR = 0.905, 95% CI: 0.862-0.951, p < 0.001) were consistent with those of the primary analysis. Colocalization analysis did not provide any evidence of a shared causal variant between cathepsins and PD (PP.H4.abf = 0.005). This genetic investigation supports the hypothesis that cathepsin B exerts a protective effect against PD. The quantification of cathepsin B levels could potentially serve as a predictive biomarker for susceptibility to PD, providing new insights into the pathomechanisms of the disease and possible interventions.

Yusufujiang A ，Zeng S ，Li H 《Frontiers in Aging Neuroscience》

The association between immune cells and breast cancer: insights from Mendelian randomization and meta-analysis.

Breast cancer (BC) is the most common cancer among women worldwide, with 2.3 million new cases and 685 000 deaths annually. It has the highest incidence in North America, Europe, and Australia and lower rates in parts of Asia and Africa. Risk factors include age, family history, hormone replacement therapy, obesity, alcohol consumption, and lack of physical activity. BRCA1 and BRCA2 gene mutations significantly increase the risk. The 5-year survival rate is over 90% in developed countries but lower in developing ones. Early screening and diagnosis, using mammography and MRI, are crucial for reducing mortality. In recent years, significant progress has been made in studying BC immunophenotyping, particularly in multicolor flow cytometry, molecular imaging techniques, and tumor microenvironment analysis. These technologies improve diagnosis, classification, and detection of minimal residual disease. Novel immunotherapies targeting the tumor microenvironment, like CAR-T cell therapy, show high efficiency and fewer side effects. High levels of tumor-infiltrating lymphocytes correlate with better prognosis, while immune checkpoint molecules (PD-1, PD-L1) help cancer cells evade the immune system. Tumor-associated macrophages promote invasion and metastasis. Blocking molecules like CTLA-4, LAG-3, and TIM-3 enhance antitumor responses, and cytokines like IL-10 and TGF-β aid tumor growth and immune evasion. Mendelian randomization (MR) studies use genetic variants to reduce confounding bias and avoid reverse causation, providing robust causal inferences about immune cell phenotypes and BC. This approach supports the development of precision medicine and personalized treatment strategies for BC. This study aims to conduct MR analysis on 731 immune cell phenotypes with BC in the BCAC and Finngen R10 datasets, followed by a meta-analysis of the primary results using the inverse-variance weighted (IVW) method and multiple corrections for the significance P -values from the meta-analysis. Specifically, the study is divided into three parts: First, data on 731 immune cell phenotypes and BC are obtained and preprocessed from the GWAS Catalog and Open GWAS (BCAC) and the Finngen R10 databases. Second, MR analysis is performed on the 731 immune cell phenotypes with BC data from the BCAC and Finngen R10 databases, followed by a meta-analysis of the primary results using the IVW method, with multiple corrections for the significance P -values from the meta-analysis. Finally, the positively identified immune cell phenotypes are used as outcome variables, and BC as the exposure variable for reverse MR validation. The study found that two immune phenotypes exhibited strong significant associations in MR analysis combined with meta-analysis and multiple corrections. For the immune phenotype CD3 on CD28+ CD4-CD8- T cells, the results were as follows: in the BCAC dataset, the IVW result was odds ratio (OR) = 0.942 (95% CI: 0.915-0.970, P =6.76×10 -5 ), β =-0.059; MR Egger result was β =-0.095; and the weighted median result was β =-0.060. In the Finngen R10 dataset, the IVW result was OR=0.956 (95% CI: 0.907-1.01, P =0.092), β =-0.045; MR Egger result was β =-0.070; and weighted median result was β =-0.035. The β values were consistent in direction across all three MR methods in both datasets. The meta-analysis of the IVW results from both datasets showed OR=0.945 (95% CI: 0.922-0.970, P =1.70×10 -5 ). After Bonferroni correction, the significant P- value was P =0.01, confirming the immune phenotype as a protective factor against BC. For the immune phenotype HLA DR on CD33- HLA DR+, the results were as follows: in the BCAC dataset, the IVW result was OR=0.977 (95% CI: 0.964-0.990, P =7.64×10 -4 ), β =-0.023; MR Egger result was β =-0.016; and the weighted median result was β =-0.019. In the Finngen R10 dataset, the IVW result was OR=0.960 (95% CI: 0.938-0.983, P =6.51×10 -4 ), β =-0.041; MR Egger result was β =-0.064; and weighted median result was β =-0.058. The β values were consistent in direction across all three MR methods in both datasets. The meta-analysis of the IVW results from both datasets showed OR=0.973 (95% CI: 0.961-0.984, P =3.80×10 -6 ). After Bonferroni correction, the significant P -value was P =0.003, confirming this immune phenotype as a protective factor against BC. When the immune cell phenotypes CD3 on CD28+ CD4-CD8- T cells and HLA DR on CD33- HLA DR+ were used as outcomes and BC was used as exposure, the data processing and analysis procedures were the same. The MR analysis results are as follows: data from the FinnGen database regarding the effect of positive immune phenotypes on malignant neoplasm of the breast indicated a β coefficient of -0.011, OR = 0.99 (95% CI: -0.117-0.096, P =0.846); data from the BCAC database regarding favorable immune phenotypes for BC demonstrated a β coefficient of -0.052, OR=0.095 (95% CI: -0.144-0.040, P =0.266). The results suggest insufficient evidence in both databases to indicate that BC inversely affects these two immune cell phenotypes. Evidence suggests that the immune cell phenotypes CD3 on CD28+ CD4-CD8- T cells and HLA DR on CD33- HLA DR+ protect against BC. This protective effect may be achieved through various mechanisms, including enhancing immune surveillance to recognize and eliminate tumor cells; secreting cytokines to inhibit tumor cell proliferation and growth directly; triggering apoptotic pathways in tumor cells to reduce their number; modulating the tumor microenvironment to make it unfavorable for tumor growth and spread; activating other immune cells to boost the overall immune response; and inhibiting angiogenesis to reduce the tumor's nutrient supply. These mechanisms work together to help protect BC patients and slow disease progression. Both immune cell phenotypes are protective factors for BC patients and can be targeted to enhance their function and related pathways for BC treatment.

Xu W ，Zhang T ，Zhu Z ，Yang Y ... -  《-》

Cathepsins and cancer risk: a Mendelian randomization study.

Previous observational epidemiological studies reported an association between cathepsins and cancer, however, a causal relationship is uncertain. This study evaluated the causal relationship between cathepsins and cancer using Mendelian randomization (MR) analysis. We used publicly available genome-wide association study (GWAS) data for bidirectional MR analysis. Inverse variance weighting (IVW) was used as the primary MR method of MR analysis. After correction for the False Discovery Rate (FDR), two cathepsins were found to be significantly associated with cancer risk: cathepsin H (CTSH) levels increased the risk of lung cancer (OR = 1.070, 95% CI = 1.027-1.114, P = 0.001, PFDR = 0.009), and CTSH levels decreased the risk of basal cell carcinoma (OR = 0.947, 95% CI = 0.919-0.975, P = 0.0002, P FDR = 0.002). In addition, there was no statistically significant effect of the 20 cancers on the nine cathepsins. Some unadjusted low P-value phenotypes are worth mentioning, including a positive correlation between cathepsin O (CTSO) and breast cancer (OR = 1.012, 95% CI = 1.001-1.025, P = 0.041), cathepsin S (CTSS) and pharyngeal cancer (OR = 1.017, 95% CI = 1.001-1.034, P = 0.043), and CTSS and endometrial cancer (OR = 1.055, 95% CI = 1.012-1.101, P = 0.012); and there was a negative correlation between cathepsin Z and ovarian cancer (CTSZ) (OR = 0.970, 95% CI = 0.949-0.991, P = 0.006), CTSS and prostate cancer (OR = 0.947, 95% CI = 0.902-0.944, P = 0.028), and cathepsin E (CTSE) and pancreatic cancer (OR = 0.963, 95% CI = 0.938-0.990, P = 0.006). Our MR analyses showed a causal relationship between cathepsins and cancers and may help provide new insights for further mechanistic and clinical studies of cathepsin-mediated cancer.

Deng T ，Lu X ，Jia X ，Du J ，Wang L ，Cao B ，Yang M ，Yin Y ，Liu F ... -  《Frontiers in Endocrinology》

Association between cathepsins and benign prostate diseases: a bidirectional two-sample Mendelian randomization study.

The relationship between cathepsins and prostate cancer (PCa) has been reported. However, there is a lack of research on cathepsins and benign prostate diseases (BPDs). This study investigated the potential genetic link between cathepsins and BPDs through the utilization of Mendelian randomization (MR) analysis to determine if a causal relationship exists. Publicly accessible summary statistics on BPDs were obtained from FinnGen Biobank. The data comprised 149,363 individuals, with 30,066 cases and 119,297 controls for BPH, and 123,057 individuals, with 3,760 cases and 119,297 controls for prostatitis. The IEU OpenGWAS provided the Genome-wide association data on ten cathepsins. To evaluate the causal relationship between BPDs and cathepsins, five distinct MR analyses were employed, with the primary method being the inverse variance weighted (IVW) approach. Additionally, sensitivity analyses were conducted to examine the horizontal pleiotropy and heterogeneity of the findings. The examination of IVW MR findings showed that cathepsin O had a beneficial effect on BPH (IVW OR=0.94, 95% CI 0.89-0.98, P=0.0055), while cathepsin X posed a threat to prostatitis (IVW OR=1.08, 95% CI 1.00-1.16, P=0.047). Through reverse MR analysis, it was revealed that prostatitis had an adverse impact on cathepsin V (IVW OR=0.89, 95% CI 0.80-0.99, P=0.035), while no favorable association was observed between BPH and cathepsins. The results obtained from MR-Egger, weighted median, simple mode, and weighted mode methods were consistent with the findings of the IVW approach. Based on sensitivity analyses, heterogeneity, and horizontal pleiotropy are unlikely to distort the results. This study offers the initial evidence of a genetic causal link between cathepsins and BPDs. Our findings revealed that cathepsin O was beneficial in preventing BPH, whereas cathepsin X posed a potential threat to prostatitis. Additionally, prostatitis negatively affected cathepsin V level. These three cathepsins could be targets of diagnosis and treatment for BPDs, which need further research.

Cao H ，Liu B ，Gong K ，Wu H ，Wang Y ，Zhang H ，Shi C ，Wang P ，Du H ，Zhou H ，Wang S ... -  《Frontiers in Endocrinology》