Reevaluating the Role of ACE Inhibitors in Skin Fibrosis Risk: Evidence from Mendelian Randomization

Abstract: Background: Skin fibrosis, characterized by excessive extracellular matrix deposition, leads to hypertrophic scars and keloids, which are both common and often detrimental conditions. Angiotensin-converting enzyme (ACE) inhibitors have shown promise in animal studies and limited clinical trials for reducing scar formation. However, the causal relationship between ACE inhibition and skin fibrosis remains unclear. Methods: This study employed two-sample Mendelian randomization (MR) analysis to investigate the causal effect of ACE inhibition on skin fibrotic diseases. We utilized genetic variants associated with serum ACE levels, ACE inhibition, and effect of decreasing blood pressure by ACE inhibition as instrumental variables. We analyzed the association between these exposures and the incidence of skin fibrosis, hypertrophic scars, and keloids using various MR methods. Results: We found no significant causal relationship between genetically proxied serum ACE levels, or local skin tissue ACE expression and the risk of skin fibrosis, hypertrophic scars, or keloids. Additionally, there was no direct causal relationship between the effect of ACE inhibitors on blood pressure reduction and the risk of skin fibrotic diseases. However, we observed a significant negative association between systolic blood pressure (SBP) and the risk of hypertrophic scars. Conversely, we found a positive association between β-blockers and the risk of skin fibrosis. Conclusion: Our findings suggest that ACE inhibitors do not have a direct causal effect on the risk of skin fibrotic diseases, including hypertrophic scars and keloids. This challenges the potential of ACE inhibitors as a therapeutic option for preventing or treating these conditions.