Abstract WP191: Genetic Analyses Support A Causal Role Of Lung Cancer In Ischemic Stroke

Introduction: Lung cancer has been linked to increased risk of thromboembolic events, including stroke. However, a causal relationship between lung cancer and ischemic stroke (IS) has yet to be established. Methods: We conducted a two-stage study using observational and genetic data from the UK Biobank, a large cohort study that enrolled over 500,000 Britons aged 40-69. We included participants of European descent. In Stage I, we used logistic regression to test the association between self-reported / ICD-defined lung cancer and risk of IS. In Stage II, we constructed a polygenic risk score (PRS) using 31 independent genetic variants known to associate with lung cancer, fitted logistic regression to assess the relationship between this PRS and risk of IS, and implemented the inverse variance weighted method of Mendelian randomization (MR). We tested for horizontal pleiotropy using the MR-Egger and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) approaches. Results: Out of 409,629 participants of European descent enrolled in the UK Biobank, there were 5,060 IS cases (mean age, 61.6 [standard deviation 6.5]; female sex, 1813 [35.8%]). The prevalence of lung cancer was 1.9% (n=94) and 0.5% (n=1,961) among persons with and without IS, respectively (unadjusted p<0.001). In multivariable analyses, self-reported / ICD-defined lung cancer was associated with a 54% increase in risk of IS (adjusted OR, 1.54; 95% CI, 1.30-1.81; p<0.001). Genetic analyses supported a causal link between lung cancer and IS. In PRS analysis, each additional standard deviation of the lung cancer-related PRS was associated with a 3% increase in risk of IS (adjusted OR, 1.03; 95% CI, 1.01-1.06; p=0.018). In MR analysis, genetically determined lung cancer was associated with a 5% increase in risk of IS (OR, 1.05; 95% CI, 1.01-1.09; p=0.022). There was no significant horizontal pleiotropy (MR-Egger intercept p=0.663; MR-PRESSO global test p=0.993). Conclusions: Genetically determined lung cancer is associated with increased risk of ischemic stroke. These findings provide evidence for a causal link between lung cancer and ischemic stroke. Further studies are needed to identify the biological pathways that mediate this link.