The angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism influences ACE activity, cardiovascular risk, blood pressure, and possibly the risk of developing Alzheimer's dementia. We explored the association of the insertion/deletion polymorphism with sleep-disordered breathing (SDB) and hypertension in 1,100 subjects of the Wisconsin Sleep Cohort. The polymorphism did not influence body mass index or the occurrence of SDB, but was dose-dependently associated with blood pressure. Interestingly, SDB and the insertion/deletion polymorphism interacted significantly to modulate blood pressure independently of age, sex, ethnicity, and body mass index. Most specifically, the association of the deletion allele with hypertension was most pronounced in subjects with mild to moderate degrees of sleep apnea (5 < or = apnea-hypopnea index < or = 30). We hypothesize that in the absence of SDB the effect of the deletion allele alone may not be sufficient to increase blood pressure. At severe levels of SDB, the effect of sleep apnea on blood pressure overwhelms any association of the deletion allele with hypertension and occurs independent of any ACE gene genotype.