Renin-angiotensin system gene polymorphisms: Potential mechanisms for their association with cardiovascular diseases

Since the first description of the angiotensin-converting enzyme insertion/deletion polymorphism more than a decade ago, many hundreds of investigations have reported associations between this polymorphism and cardiovascular diseases. Subsequently, similar studies were performed in relationship with several other renin-angiotensin system gene polymorphisms, most notably the angiotensinogen M235T polymorphism and the angiotensin AT₁ receptor A1166C polymorphism. Surprisingly however, especially in view of the many contradictory results that have been obtained, very little attention has been paid to the mechanism(s) that may link these genetic variants and respective diseases. Here, we review the limited evidence that is currently available on the functional consequences (including compensatory mechanisms) of the above three renin-angiotensin system gene polymorphisms, in order to provide an explanation for the reported associations (or lack thereof) between these polymorphisms and cardiovascular diseases.