Mathematical modeling of the influence of ACE I/D polymorphism on blood pressure and antihypertensive therapy

Abstract

The angiotensin converting enzyme (ACE) gene (ACE) insertion/deletion (I/D) polymorphism has attracted much attention in recent years, as it raises the hope of personalizing ACE inhibitor therapy to optimize its efficiency and reduce side effects for genetically distinct subgroups. However, the extent of its influence among these subgroups remains inconclusive. Therefore, we extended our computational model of blood pressure regulation to investigate the effect of the ACE I/D polymorphism on hemodynamic parameters in humans and antihypertensive therapy. The model showed that the dependence of blood pressure on serum ACE activity is a function of saturation. Hence, a possible reason for the lack of association between ACE I/D and blood pressure levels could be a fairly high ACE activity in populations. Additionally, in an extended model simulating the effects of different classes of antihypertensive drugs, we explored the relationship between ACE I/D and the efficacy of inhibitors of the renin-angiotensin-aldosterone system. The model predicted that the response of cardiovascular and renal parameters to treatment directly depends on ACE activity. However, significant differences in parameter changes were observed only between groups with high and low ACE levels, while ACE I/D genotypes within the same group had similar changes in absolute values. We conclude that a single genetic variant is responsible for only a small fraction of heredity in treatment success, so its predictive value is limited.