Systematic Mendelian randomization using the human plasma proteome to identify therapeutic targets for lung adenocarcinoma

Abstract

Abstract Background Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer and the leading cause of cancer-related deaths. Identifying novel drug targets for LUAD is essential, with the proteome serving as a major source of therapeutic targets. We performed proteomo-wide Mendelian randomization (MR) and colocalization analyses to identify potential targets for LUAD. Methods Data summarizing 1394 plasma proteins were extracted from an extensive study on protein quantitative trait loci, including 4907 individuals. Genetic associations with LUAD were sourced from the Transdisciplinary Research in Cancer of the Lung, involving 11245 cases and 54619 controls. MR analysis was conducted to assess the associations between proteins and LUAD risk. Bayesian colocalization anslysis was used to ascertain shared causal variants between the identified proteins and LUAD. Furthermore, we employed a two-step MR to quantify the proportion of the effect of risk factors mediated by proteins on LUAD. Finally, a protein-protein interaction (PPI) analysis was employed to unveil potential links between proteins and current LUAD medications. Results Mendelian randomization analysis identified nine plasma proteins. MDGA2 (OR, 1.13; 95% CI, 1.08–1.19), NTM (OR, 1.12; 95% CI, 1.09–1.16) , PMM2 (OR, 1.35; 95% CI, 1.18–1.53), RNASET2 (OR, 1.15; 95% CI, 1.08–1.21), and TFPI (OR, 4.58; 95% CI, 3.02–6.94) increased the risk of LUAD, while ALAD (OR, 0.79; 95% CI, 0.72–0.87), FLT1 (OR, 0.39; 95% CI, 0.28–0.55) , ICAM5 (OR, 0.91; 95% CI, 0.88–0.95), and VWC2 (OR, 0.85; 95% CI, 0.79–0.92) decreased the risk. Bayesian colocalization indicated that RNASET2, TFPI, and VWC2 shared the same variant with LUAD. NTM and FLT1 interacted with target proteins of current LUAD medications. Furthermore, two therapeutics are presently under evaluation, three are druggable and four are future breakthrough points. Conclusions Our proteome-wide MR analysis revealed nine proteins associated with the risk of LUAD. RNASET2, TFPI, VWC2, NTM, and FLT1 might be promising drug targets for LUAD and deserve further clinical investigation.