Genetic determinants of coronary vasomotor tone in humans.

APART FROM AND IN ADDITION to all established mechanisms and mediators in the regulation of coronary blood flow under normal and pathological circumstances (1), there remains substantial interindividual variability in coronary vasomotor responses, both in the experimental animal and in humans. Such interindividual variability has, among other factors such as age, diet, and environmental factors, a genetic background. The human genome contains about 1.4 million (12) to 2.1 million (32) single nucleotide polymorphisms that may or may not encode proteins with a function that is more or less different from that encoded by the wild-type genome. There is currently a large number of association studies that link a certain polymorphism with a certain clinical disease; notably there are also a number of such association studies that link the respective polymorphism with coronary artery disease, e.g., an angiotensin-converting enyzme gene insertion/deletion polymorphism (6), and polymorphisms in the angiotensinogen gene (35) that may both affect circulating angiotensin II levels or an insertion/deletion polymorphism in the a2B-adrenoceptor gene (29). There exists an extensive list of other polymorphisms potentially associated with coronary artery disease (for review, see Ref. 30). However, what is lacking in most studies is the analysis of a functional phenotype that links the observed polymorphism causally with the observed clinical entity. In this medical editorial we focus on two typical examples where such a functional phenotype is established: one with exaggerated coronary vasoconstriction and one with attenuated coronary vasodilation. Better insight in such genetic background will in the future have considerable impact, because identification of such polymorphisms will help identify individuals at increased risk for coronary events already in childhood and, eventually, enable a targeted therapy that eliminates the functional phenotype that causally links the polymorphism with the coronary event.