Interactions Between the Genes of Vasodilatation Pathways

The search for genetic factors in the multigenic disease of hypertension has been hampered by inconsistent findings. Hypertension perpetuates several other diseases, adding to adult morbidity and mortality.1 Genetic studies include sin-gle-locus and genome-wide association studies.2–4 Lacking, however, are studies on gene–gene interactions that contrib-ute to susceptibility to hypertension5,6 and other common diseases. Hence, the complex mechanisms of multifactorial diseases may be missed if only a single gene and/or a single locus is investigated.7,8 Products of β-2 adrenergic receptor (ADRB2) and nitric oxide synthase (NOS3) genes are part of the sympathetic and parasympathetic nervous systems and are known to be involved in metabolic and cardiovascular remodeling.9 ADRB2 codes for a G protein–coupled receptor and, like NOS3, is expressed in vascular endothelial cells.10 Stimulation of ADRB2 activates adenylyl cyclase, which induces cyclic adenosine-3′, 5′-monophospate; the latter in turn increases arginine uptake and thereby triggers the nitric oxide system to activate vasodilatation.10 Thus, the interactions between the ADRB2 and NOS3 genetic variants may be relevant in the pathophysiology of hypertension.11–13 To test our hypothesis in a case–control design, we set forth 3 major objectives: (i) to determine systolic blood pressure (SBP), diastolic bloo