Causal associations of plasma proteins with lung squamous cell carcinoma risk: a proteome-wide Mendelian randomization and colocalization analysis

Abstract Background Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer with a high mortality rate. Identifying causal plasma proteins associated with LUSC could provide new insights into the pathophysiology of the disease and potential therapeutic targets. This study aimed to identify plasma proteins causally linked to LUSC risk using proteome-wide Mendelian randomization (MR) and colocalization analyses. Methods Proteome-wide MR analysis was conducted using data from the UK Biobank Pharma Proteomics Project and deCODE genetics. Summary-level data for LUSC were obtained from the ILCCO Consortium, the FinnGen study, and a separate GWAS study. A total of 1,046 shared protein quantitative trait loci (pQTLs) were analyzed. Sensitivity analyses included the HEIDI test for horizontal pleiotropy and colocalization analysis to validate the causal associations. Results MR analysis identified six plasma proteins associated with LUSC risk: HSPA1L, PCSK7, POLI, SPINK2, TCL1A, and VARS. HSPA1L (OR = 0.47; 95% CI: 0.34–0.65; P = 4.89 × 10 –6 ), SPINK2 (OR = 0.68; 95% CI: 0.58–0.80; P = 3.17 × 10 –6 ), and VARS (OR = 0.44; 95% CI: 0.31–0.63; P = 5.94 × 10 –6 ) were associated with a decreased risk of LUSC. Conversely, PCSK7 (OR = 1.37; 95% CI: 1.21–1.56; P = 1.40 × 10 –6 ), POLI (OR = 4.50; 95% CI: 2.25–9.00; P = 2.13 × 10 –5 ), and TCL1A (OR = 1.72; 95% CI: 1.34–2.21; P = 1.89 × 10 –5 ) were associated with an increased risk. The SMR analysis and HEIDI test confirmed the robustness of these associations. HSPA1L, SPINK2, and VARS showed significant inverse associations, with strong colocalization evidence for TCL1A (PPH4 = 0.817). Conclusions This study identified six plasma proteins potentially causal for LUSC risk. HSPA1L, SPINK2, and VARS are associated with decreased risk, while PCSK7, POLI, and TCL1A are linked to increased risk. These findings provide new insights into LUSC pathogenesis and highlight potential targets for therapeutic intervention.