Collectively these studies provide convincing evidence for an ACE genotype–sex interaction effect on hypertension and possibly on blood pressure, although the mechanisms for these effects are still unknown. Moreover, these studies demonstrate that even in the absence of a genotype–sex interaction in quantitative trait variation (in this example, ACE protein levels66), a genotype–sex interaction can still occur with respect to an associated physiological trait (e.g., blood pressure)50,52 and a disease phenotype (e.g., hypertension)49-51. Lastly, these studies further provide an example in which the genetic model underlying the interaction can differ between the physiological trait and the disease: in males, the effect of the D allele of ACE is additive on blood pressure, but recessive on hypertension (models B and E, respectively, in Figure 2), suggesting a quantitative (blood pressure) threshold effect for expression, or penetrance, of a common disease (hypertension) that is sex-specific.
