BACKGROUND: Conventional epidemiological studies have reported inconsistent results regarding the potential adverse effects of long-term use of antihypertensive drugs on cancer risk. Nevertheless, evidence of their impact on pancreatic cancer risk is limited and deserves further elucidation. METHODS: We selected genetic variants from the genes encoding the target proteins (angiotensin-converting enzyme, beta-1 adrenergic receptor, and solute carrier family 12 member 3) of the examined antihypertensive drugs as instruments based on expression quantitative trait loci (eQTL) studies. Genetic summary statistics of blood pressure and pancreatic cancer were obtained from genome-wide association studies (GWASs) in Europeans and East Asians. Inverse-variance weight and MR-Egger methods were employed to estimate the effect of genetic variations in the drug targets on pancreatic cancer risk, and meta-analysis was used to combine the results from 3 independent datasets. Positive control analysis was conducted by using Wald ratio test to justify the genetic instruments of the drug by demonstrating the expected effect on the blood pressure which has an established causal relationship with the drug of interest. RESULTS: Genetically proxied ACEIs were associated with lower pancreatic risk (OR = 0.506, 95% CI: 0.284-0.901, P = 0.021
OR = 0.265, 95% CI: 0.094-0.751, P = 0.012
OR = 0.236, 95% CI:0.078-0.712, P = 0.010, respectively) in 3 independent datasets and the combined results were validated in a meta-analysis using a random effects model (OR = 0.37, 95% CI: 0.22-0.64, P <
0.01) or fixed effects model (OR = 0.39, 95% CI: 0.25-0.62, P <
0.01). Other drug targets did not show consistent significant associations with pancreatic cancer risk in all 3 independent datasets. CONCLUSIONS: Our study indicated that genetically proxied therapeutic inhibition of ACE was associated with a lower risk of pancreatic cancer, which may have translational potential in clinical practice. However, further long-term randomized controlled trials and observational studies are needed to clarify the effect of ACEIs on the pancreatic cancer risk.