The renin-angiotensin-aldosterone system (RAAS) is a proteolytic cascade that regulates and maintains blood pressure (BP). This study aimed to explore the interactive and integrative effects of multiple RAAS polymorphisms on BP at rest and during behavioral stress in a normotensive population. A total of 920 young white and black twins (age: 12 to 30 years; 45% blacks) was subjected to three 10-minute stress tasks. Thirteen potential functional polymorphisms from 4 major RAAS genes were

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... d. We performed multilocus prediction allowing for genetic modification effects (gene-gene, gene-gender, gene-ethnicity, and gene-body mass index) using Multivariate Adaptive Regression Splines and generalized estimating equations. Single polymorphism analyses showed modest effects of M235T (angiotensinogen) and A-239T (angiotensin I-converting enzyme; P value range: 0.005 to 0.036), accounting for Ϸ1% of the total variance of systolic BP at rest and during stress. Compared with this, the best multilocus models revealed multiple independent genetic modification effects (gene-gene, gene-gender, and gene-body mass index; P value range: 0.003 to 0.009), accounting for 2.5% and 7.3% of the total variance for systolic BP levels at rest and during stress, respectively. Our data support the hypothesis that multiple RAAS genetic modifications account for BP variation. We conclude that the RAAS genetic modifications may contribute more to the dynamic BP regulation in response to behavioral stress compared with the static BP value. In addition, we reported a gene-gene interaction between M235T (angiotensinogen) and A1159G (angiotensin I-converting enzyme) on stress systolic BP levels. We proposed a viable approach to test for the multiple genetic contributions to BP and hypertension. (Hypertension. 2007;49:107-112.)