Elevated risk for stroke in genetically predisposed bicuspid aortic valve disease: evidences from a mendelian randomization study

Abstract Background Patients with bicuspid aortic valve (BAV) have been recognized to have an elevated risk for stroke. However, the exact causal association between BAV and stroke remains elusive due to stroke-related comorbidities, residual confounding bias and sample size limitations of observational studies. Purpose To identify the causal relationship between genetically predisposed BAV and 15 cardiovascular diseases (CVDs), and whether calcific aortic valve stenosis (CAVS) or atrial fibrillation (AF) could serve as the mediator on the pathway from BAV to stroke by mendelian randomization (MR) approach. Methods Uncorrelated (r² < 0.001) and genome-wide significant (P < 5×10^-8) single nucleotide polymorphisms were extracted from the largest genome-wide association study statistics (2,236 patients and 11,604 controls) of BAV by Gehlen et al. Summary-level statistics for 15 CVDs were obtained from the UK Biobank study, FinnGen study, HERMES consortium, CARDIoGRAMplusC4D consortium and GIGASTROKE consortium. We used 2-sample MR to estimate the causal association between BAV and 15 CVDs, evaluated 12 potential mediators and mediated proportions within 2-step MR framework. Inverse variance weighted was utilized as primary MR analyses method. Results for each outcome from different sources were pooled using the random effect meta-analysis. False discovery rate (FDR) was calculated by Benjamini-Hochberg method to account for multiple comparisons. Results Genetically predicted per log-odds liability increase of BAV was significantly associated with aortic aneurysm (OR, 1.26; 95% CI, 1.13-1.40; FDR-adjusted P = 3.54 × 10^-4), any stroke (OR, 1.06; 95% CI, 1.02-1.09; FDR-adjusted P = 0.004), ischemic stroke (IS) (OR, 1.17; 95% CI, 1.03-1.11; FDR-adjusted P = 0.001) and cardioembolic stroke (CES) (OR, 1.15; 95% CI, 1.06-1.25; FDR-adjusted P = 0.004). No significant association were observed between BAV and another 11 CVD outcomes. Instead of CAVS, genetic liability to AF mediated the total effect of BAV on any stroke (proportion mediated = 13.2% [95% CI, 3.1% - 23.2%]), IS (proportion mediated = 10.8% [95% CI, 2.5% - 19.1%]) and CES (proportion mediated = 21.5% [95% CI, 5.3% - 37.7%]). Conclusions Genetically predisposed BAV is associated with a higher risk of any stroke, IS and CES, which could be mediated by AF. This study implies the pathophysiological processes from BAV towards stroke and highlights the clinical significance of AF intervention in reducing the incidence of stroke for BAV patients.Causal association between BAV and CVDs