Cathepsins effect on diffuse large B cell lymphoma risk: A Mendelian randomization study

Recently, the relationship between cathepsins and a variety of diseases has gained increasing attention, especially various solid tumors and hematologic malignancies. However, there is no consensus on the causality between cathepsins and malignant lymphomas. The cathepsin genome-wide association studies (GWAS) dataset for this study was derived from THE INTERVAL STUDY and was freely downloaded via the OPENGWAS website. GWAS summary statistics for lymphomas were obtained from the FinnGen database. Single nucleotide polymorphisms satisfying the genome-wide association significance (P < 5 × 10-6) and linkage disequilibrium parameters (r2 = 0.001 and clumping distance = 10,000 kb) were screened for the subsequent 2-sample Mendelian randomization (MR) analysis. Sensitivity analyses were utilized to assess the stability and robustness of the MR conclusions. Genetically predicted Cathepsin S (CTSS) level was positively associated with the increased risk of diffuse large B cell lymphoma (DLBCL). Patients with elevated levels of CTSS are more susceptible to DLBCL, which corresponds to a 20.6% increased hazard (odds ratio inverse variance weighted [ORIVW] = 1.206, 95% confidence interval [CI] 1.054-1.380, P = .006). The causal role of the remaining cathepsins in DLBCL and other types of lymphoma was not established. No reverse causality between DLBCL and CTSS was observed after the backward MR analysis (ORIVW = 1.076, 95% CI 0.984-1.177, P = .109). The multivariate MR results supported that CTSS was causally responsible for DLBCL (ORIVW = 1.204, 95% CI 1.042-1.392, P = .012, ORMR-Egger = 1.200, 95% CI 1.038-1.387, P = .014). This study demonstrated a causal effect of CTSS on DLBCL based on the MR algorithm. Follow-up studies are needed to elucidate the underlying mechanisms between them and explore promising new therapeutic options for DLBCL patients.