Mendelian randomization analysis identifies association of CACNA1C expression with thoracic aortic disease

Background Thoracic aortic aneurysms and dissections (TAA/D) are life-threatening conditions without established pharmacological therapies to prevent disease onset or progression. Hypertension is a major risk factor, and antihypertensive medication is often prescribed to patients to reduce aortic wall stress. Calcium channel blockers (CCBs) inhibit L-type calcium channels that regulate vascular smooth muscle cell (VSMC) contraction, potentially affecting aortic wall integrity. Experimental and observational data suggest an association between CCB use and increased TAA/D risk. The α1C subunit of the L-type calcium channel is encoded by CACNA1C, linking CCB therapy to this pathway. Whether genetically determined variation in CACNA1C expression influences TAA/D risk remains unknown. Purpose To investigate the effect of genetically predicted CACNA1C expression on TAA/D risk and ascending aortic diameter, accounting for potential mediation by blood pressure traits. Methods We performed two-sample Mendelian randomization (MR) using cis-eQTLs for CACNA1C in aortic tissue as instrumental variables. Instruments were selected through linkage disequilibrium clumping and LASSO regression, yielding two instrument sets. Outcomes included TAA/D, ascending aortic diameter, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP). To evaluate mediation, we performed MR of blood pressure traits on aortic outcomes. We then applied a two-step MR framework to quantify mediation by blood pressure on the association between CACNA1C expression and aortic outcomes. Results Genetically predicted higher CACNA1C expression was associated with decreased TAA/D risk (β = -0.18, P = 0.004) and smaller ascending aortic diameter (β = -0.08, P = 0.011). In contrast, higher CACNA1C expression was associated with increased SBP, DBP and PP (β = 0.84; 0.27; 0.64, P = 3.9 × 10-4; 0.020; 5.7 × 10-5, respectively). MR analyses demonstrated that higher SBP and DBP were associated with increased TAA/D risk and aortic diameter, whereas PP was associated with lower TAA/D risk (all P < 5 × 10-7). In two-step MR analyses, adjustment for blood pressure did not attenuate the associations between CACNA1C expression and aortic outcomes. Higher CACNA1C expression remained associated with lower TAA/D risk and smaller aortic dimension (e.g. SBP-adjusted β = -0.19; -0.09, P = 0.002; 0.004, respectively). Conclusion Higher genetically predicted CACNA1C expression is associated with lower TAA/D risk and smaller ascending aortic diameter, despite being associated with higher blood pressure. These associations persisted after accounting for blood pressure traits. As CCBs target L-type calcium channels, our findings are directionally consistent with prior observational studies linking CCB use to increased TAA/D risk. These results support the need for careful evaluation of CCB therapy in patients at risk for thoracic aortic disease.