Causal relationship between cathepsins and major salivary gland neoplasms: a bidirectional Mendelian randomization study

Background: Observational studies have suggested a potential link between cathepsins and major salivary gland neoplasms (MSGNs), but the causality of this relationship remains uncertain. Mendelian randomization (MR) is a significant genetic method that employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs). This approach reduces confounding effects, enabling the analysis of causal relationships between exposure traits and outcome diseases. This study aimed to explore the causal links between cathepsins and MSGNs by utilizing MR analysis. Methods: In this research, we collected IVs associated with 11 different types of cathepsins (including cathepsins D, L1, B, E, F, G, H, O, S, L2, and Z) from the Medical Research Council (MRC) integrative epidemiology unit (IEU) open genome-wide association studies (GWAS) database. Data for cathepsins D and L1 were sourced from the SCALLOP consortium, which included 21,758 Europeans identified via the Olink proximity extension assay (PEA). Cathepsins B, E, F, G, H, O, S, L2, and Z were obtained from the INTERVAL study involving 3,301 European participants using the SOMAscan assay. We also collected data on benign major salivary gland neoplasms (BMSGNs) from the FinnGen database, consisting of 3,353 cases and 450,380 controls, and information on major salivary gland carcinomas (MSGCs) from the UK Biobank, which included 105 cases and 456,243 controls. Diagnostic criteria for both BMSGNs and MSGCs followed the international statistical classification of diseases and related health problems 10th revision (ICD-10) classification. A comprehensive bidirectional MR study was executed employing diverse methodologies, including inverse variance weighted (IVW), MR-Egger regression, weighted median, and weighted mode. Additionally, sensitivity analyses were conducted to emphasize the solidity of the study. Results: Increased levels of cathepsin F (CTSF), cathepsin O (CTSO), and cathepsin L2 (CTSL2) were associated with a higher risk of BMSGNs (CTSF: IVW: P=0.01, odds ratio (OR) =1.12, CTSO: IVW: P=0.02, OR =1.14; CTSL2: IVW: P=0.01, OR =1.17). Additionally, no causal association was found between cathepsins and MSGCs. Reverse MR analyses did not establish a causal relationship between BMSGNs and various cathepsins. However, it did reveal that a higher risk of MSGCs was associated with lower levels of CTSL2 (IVW: P=0.01, beta =-0.046). Conclusions: The study presents compelling evidence of a correlation between elevated CTSF, CTSO, and CTSL2 levels and an increased risk of BMSGNs. Elevated CTSF, CTSO, and CTSL2 levels may serve as significant biomarkers for diagnosing BMSGNs definitively. Conversely, reduced levels of CTSL2 provide a novel foundation for diagnosing MSGCs and differentiating them from BMSGNs. Moreover, CTSF, CTSO, and CTSL2 represent potential new targets for therapeutic intervention in BMSGNs and MSGCs.