Exploration of plasma genetic markers mediating lung cancer-induced cardiovascular disorders based on genome wide association studies.

Abstract

Lung cancer is strongly associated with increased cardiovascular disease (CVD) risk, yet the molecular mechanisms remain poorly understood. Batched two-sample Mendelian randomization (MR) analysis was performed to investigate cancer types and CVDs with significant associations. Local genetic correlation analyses were performed to identify meaningful genetic regions. Genomic Structural Equation Modeling (gSEM) was applied to identify latent factors shared between selected cancer types and CVDs. A transcriptome-wide association study (TWAS) was performed to identify relevant genetic markers. A two-stage MR analysis was performed to investigate potential mediators. Colocalization analysis was performed to assess the sensitivity of the results. Seventeen cancer types were positively associated with CVD risk, with lung cancer exhibiting the strongest link. Using LAVA and ρ-HESS, we identified local genetic correlations between lung cancer and specific CVDs, including coronary artery disease (CAD), heart failure (HF), abdominal aortic aneurysm (AAA), and atrial fibrillation (AF). Weighted median MR analysis identified a negative effect for IREB2 (OR = 0.9; 95% CI 0.84-0.95; P < 0.05), and positive effects for both KRTCAP2 (OR = 1.1; 95% CI 1.02-1.21; P < 0.05) and MTX1P1 (OR = 1.1; 95% CI 1.02-1.21; P < 0.05), on lung cancer-induced AAA. ZBTB7B exhibited a positive mediating effect in the association between lung cancer and HF risk (OR = 1.04; 95% CI 1.01-1.07; P < 0.05). This study highlights IREB2, KRTCAP2, MTX1P1, and ZBTB7B as potential therapeutic targets for cancer-related CVD risk, emphasizing the importance of considering genetic factors in understanding and managing cardiovascular complications associated with lung cancer.