The ACE I/D Polymorphism in US Adults: Limited Evidence of Association With Hypertension-Related Traits and Sex-Specific Effects by Race/Ethnicity

BACKGROUND: The insertion/deletion (I/D) variant (rs4646994) of the angiotensin I-converting enzyme (ACE) gene is one of the most studied polymorphisms in relation to blood pressure and essential hypertension in humans. The evidence to date, however, on an association of this variant with blood pressure-related outcomes has been inconclusive. METHODS: We examined 5,561 participants of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States, who were ≥20 years of age and who self-identified as non-Hispanic white, non-Hispanic black, or Mexican American. Within each race/ethnicity, we assessed genetic associations of the I/D variant with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension, as well as genotype-sex interactions, in four genetic models (additive, dominant, recessive, and codominant). RESULTS: The frequency of the I/D variant differed significantly by race/ethnicity (P = 0.001). Among non-Hispanic blacks, the D allele was significantly associated (P < 0.05) with increased SBP in additive and dominant covariate-adjusted models and was also associated with increased DBP in dominant models when participants taking ACE inhibitors were excluded from the analyses. No other significant associations were observed in any race/ethnic group. Significant genotype-sex interactions were detected among Mexican Americans, for whom positive associations with SBP and hypertension were seen among females, but not males. CONCLUSIONS: This study gives limited support for association of the ACE I/D variant with blood pressure and for sex-specific effects among particular race/ethnic groups, though we cannot rule out the role of genetic or environmental interactions.