AUTHOR=Deng Tingting , Lu Xixue , Jia Xuemin , Du Jinxin , Wang Lijuan , Cao Baorui , Yang Meina , Yin Ying , Liu Fanjie 

TITLE=Cathepsins and cancer risk: a Mendelian randomization study

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1428433

DOI=10.3389/fendo.2024.1428433

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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, <italic>P</italic> = 0.001, <italic>P<sub>FDR</sub></italic>= 0.009), and CTSH levels decreased the risk of basal cell carcinoma (OR = 0.947, 95% CI = 0.919–0.975, <italic>P</italic> = 0.0002, P<italic><sub>FDR</sub></italic>= 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, <italic>P</italic> = 0.041), cathepsin S (CTSS) and pharyngeal cancer (OR = 1.017, 95% CI = 1.001–1.034, <italic>P</italic> = 0.043), and CTSS and endometrial cancer (OR = 1.055, 95% CI = 1.012–1.101, <italic>P</italic> = 0.012); and there was a negative correlation between cathepsin Z and ovarian cancer (CTSZ) (OR = 0.970, 95% CI = 0.949–0.991, <italic>P</italic> = 0.006), CTSS and prostate cancer (OR = 0.947, 95% CI = 0.902–0.944, <italic>P</italic> = 0.028), and cathepsin E (CTSE) and pancreatic cancer (OR = 0.963, 95% CI = 0.938–0.990, <italic>P</italic> = 0.006).</p></sec><sec><title>Conclusion</title><p>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.</p></sec>