Circulating white blood cell traits, chemokines and small cell lung cancer risk: a Mendelian randomization study

Small cell lung cancer (SCLC) commonly originates in the context of persistent inflammation. The impact of white blood cell (WBC) counts and the presence of infiltrating inflammatory cytokines in relation to tumor initiation, progression, and treatment response in SCLC remains uncertain. To elucidate the potential relationships of circulating WBCs and chemokines with SCLC, we conducted a univariable (UVMR) and multivariable Mendelian randomization (MVMR) study.

We conducted a two-sample Mendelian randomization (MR) investigation to evaluate the causal impact of circulating WBCs and chemokines on the risk of SCLC. The genetic data for SCLC were derived from a genome-wide association study (GWAS) involving 24,108 participants, including 2,664 cases and 21,444 controls of European ancestry. The genetic variances of circulating WBCs and chemokines were also from GWAS. In the analysis of UVMR, the primary method employed was the inverse variance weighted (IVW) method. To infer causality, robust adjusted profile scores, weighted median (WM), and MR Egger were employed as supplementary methods. To ensure the robustness of the MR results, sensitivity analyses, including the Cochran Q test, Egger intercept test, and leave-one-out analysis, were conducted. Furthermore, MVMR was carried out to assess the direct causal effects of WBCs and chemokines on the risk of SCLC.

Using two-sample MR, we found that genetic predisposition to CD45RA⁺ CD8⁺ T cell, CD39⁺ CD4⁺ T cell, chemokine (C-X-C motif) ligand 16 (CXCL16) was associated with an increased risk of SCLC. There were suggestive inverse associations of genetically predicted dendritic cell, CD14^- CD16⁺ monocyte, P-selectin glycoprotein ligand 1 (PSGL-1) and C-C motif chemokine ligand 3 (CCL3) with SCLC risk. MVMR further confirmed that CXCL16 exerted a direct effect on SCLC, while CD14^- CD16⁺ monocyte and PSGL-1 indicated that they are protective in SCLC.

Using two-sample MR, we found that genetic predisposition to CD45RA⁺ CD8⁺ T cell, CD39⁺ CD4⁺ T cell, CXCL16 was associated with an increased risk of SCLC. There were suggestive inverse associations of genetically predicted dendritic cell, CD14^- CD16⁺ monocyte, PSGL-1 and CCL3 with SCLC risk. MVMR further confirmed that CXCL16 exerted a direct effect on SCLC, while CD14^- CD16⁺ monocyte and PSGL-1 indicated that they are protective in SCLC.