Angiotensin-converting enzyme inhibitors for aortic stenosis: a drug-target mendelian randomisation study

Introduction Large observational and Mendelian randomisation (MR) studies have demonstrated a strong association between hypertension and risk of aortic stenosis (AS). Amongst the antihypertensive drugs, angiotensin converting enzyme (ACE) inhibitors are hypothesised to be most likely to demonstrate benefit for AS due to their antihypertensive and antifibrotic effects. Methods We collected summary statistics for systolic blood pressure (SBP) and AS from genome-wide association studies including 1,028,980 and 956,682 European participants, respectively. We first performed conventional MR analyses to investigate a causal relationship between SBP and AS risk. Then drug-target MR was performed using distal and proximal effects approaches. In the distal effect drug-target MR analysis, we identified the genetic instrument for ACE inhibitors as single nucleotide polymorphisms within 200kb of the target ACE gene which were also significantly associated with SBP at p<5x10-8 and clumped using r2<0.01. In the proximal effect analysis we identified the genetic instrument for ACE inhibition as the lead SNP from expression quantitative trait locus analysis, then performed summary-data based Mendelian randomisation and heterogeneity in dependent instruments analysis (HEIDI). Results Genetically predicted SBP was significantly associated with increased risk of AS (OR 1.03 per mmHg increase in SBP, 95% CI 1.02-1.04, p<0.0001). On distal effect drug-target MR, genetically predicted ACE inhibition was significantly associated with reduced risk of AS (OR 0.92 per mmHg lower SBP, 95% CI 0.85-0.99, p=0.027). The validation analysis using the proximal effect drug-target MR approach demonstrated concordant results, with genetically predicted ACE inhibition significantly associated with reduced risk of AS (OR 0.69 per standard deviation decrease in gene expression, 95% 0.49-0.98, p=0.041) and the HEIDI analysis (p=0.57) was consistent with the presence of a shared causal variant. A positive control for the effect of ACE inhibition on risk of coronary artery disease demonstrated expected results (OR 0.90 per mmHg lower SBP, 95% CI 0.85-0.96, p=0.0004). Conclusions This study provides genetic evidence supporting a potential therapeutic role for ACE inhibitors in reducing the risk of AS. The concordance between both proximal (gene expression) and distal (blood pressure) genetic approaches strengthens the validity of the findings, and provides a strong rationale for randomised controlled trials of ACE inhibitors for AS.