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》

Genetic insights into the role of cathepsins in cardiovascular diseases: a Mendelian randomization study.

This study aimed to explore the causal relationships between cathepsins and cardiovascular diseases (CVDs) by Mendelian randomization (MR) analysis. Single nucleotide polymorphisms (SNPs) associated with nine cathepsin types (cathepsins B, E, F, G, H, O, S, L2, and Z) were obtained from the INTERVAL study (3301 individuals). CVDs data were acquired from the UK Biobank (coronary atherosclerosis: 14 334 cases, 346 860 controls) and a genome-wide association study (GWAS) (myocardial infarction: 20 917 cases, 440 906 controls; myocarditis: 633 cases, 427 278 controls; chronic heart failure: 14 262 cases, 471 898 controls; angina pectoris: 30 025 cases, 440 906 controls; stable angina pectoris: 17 894 cases, 325 132 controls; unstable angina pectoris: 9481 cases, 446 987 controls; pericarditis: 1795 cases, 453 370 controls). Inverse variance weighted (IVW), MR-Egger, weighted median methods were adopted to conduct univariable MR (UVMR), reverse MR, multivariable MR (MVMR) analyses to estimate causality. The UVMR analyses demonstrated significant causal relationships between higher cathepsin E levels and increased risk of coronary atherosclerosis [IVW: P = 0.0051, odds ratio (OR) = 1.0033, 95% confidence interval (CI) = 1.0010-1.0056] and myocardial infarction (IVW: P = 0.0097, OR = 1.0553, 95% CI = 1.0131-1.0993), while elevated cathepsin L2 levels were causally related to reduced risk of myocarditis (IVW: P = 0.0120, OR = 0.6895, 95% CI = 0.5158-0.9216) and chronic heart failure (IVW: P = 0.0134, OR = 0.9316, 95% CI = 0.8807-0.9854). Reverse MR analyses revealed that myocardial infarction increased cathepsin O levels (IVW: P = 0.0400, OR = 1.0708, 95% CI = 1.0031-1.1431). MVMR analyses treating nine cathepsins together revealed that the positive causality between cathepsin E levels and coronary atherosclerosis risk (IVW: P = 0.0390, OR = 1.0030, 95% CI = 1.0000-1.0060), and the protective effect of cathepsin L2 levels on myocarditis (IVW: P = 0.0030, OR = 0.6610, 95% CI = 0.5031-0.8676) and chronic heart failure (IVW: P = 0.0090, OR = 0.9259, 95% CI = 0.8737-0.9812) remained, as higher cathepsin O levels were found to be causally related to increased risks of myocarditis (IVW: P = 0.0030, OR = 1.6145, 95% CI = 1.1829-2.2034) and chronic heart failure (IVW: P = 0.0300, OR = 1.0779, 95% CI = 1.0070-1.1537). The study highlights the causalities of cathepsin E, L2, and O on CVDs, offering insights into their roles in cardiovascular biomarkers and therapeutic targets development. Further research is required to apply these genetic findings clinically.

Zeng R ，Zhou Z ，Liao W ，Guo B ... -  《ESC Heart Failure》

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》

Association between cathepsins and skin cancers: A bidirectional two-sample Mendelian randomization study.

Several cathepsins have been identified as being involved in the development of cancer. Nevertheless, the connection between cathepsins and skin cancers remained highly elusive. A bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal association between cathepsins and skin malignancies. The genome-wide association studies (GWAS) data for cathepsins, malignant melanoma (MM), and basal cell carcinoma (BCC) were obtained from European research. The primary method employed was inverse variance weighted. In addition, MR-Egger, weighted median, weighted mode, and simple mode were also executed. Sensitivity analysis was performed using Cochran's Q test, MR-Egger, and MR-PRESSO. From univariable MR (UVMR), cathepsin H, and S were determined to have a causal relationship with BCC. Additionally, cathepsin H was identified as associated with MM. Multivariable MR (MVMR) showed that after correcting for risk factors of skin carcinoma, cathepsin H was detected to be protective against BCC, whereas cathepsin S has been observed as a risk factor for BCC. No substantial pleiotropy and heterogeneity were identified in the sensitivity analysis. This study was the first to establish a direct link between cathepsins and skin malignancies. Cathepsin H and S have the potential to serve as new biomarkers for BCC, offering valuable assistance in the prompt identification, treatment, and prevention of the disease. Nevertheless, additional clinical trials are required to validate our findings.

Ma X ，Zhuang H ，Xu M ，Hou F ，Xue C ... -  《-》

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》