Studies in a rat model suggested genotype–sex interactions67. Both male and female rats heterozygous for an inactivating mutation in Ace had lower Ace protein levels compared to wild type animals (23% reduction in males and 35% reduction in females). However, only heterozygous males had a reduced blood pressure compared to the wild type males; heterozygous females had blood pressures similar to wild type females. Therefore, low Ace levels due to an inactivating mutation in the Ace gene did not affect blood pressure in female rats but protected against hypertension in male rats. The authors suggested that interactions with sex should be evaluated in genetic studies of the human ACE gene. Indeed, subsequent studies in humans have replicated this interaction49-51 (Table 1).
