GENETICS OF HYPERTENSION AND ITS INTERMEDIATE PHENOTYPES

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DESCRIPTION (Verbatim from Applicant's Abstract): Hypertension, an exceedingly common trait in most developed countries, imparts an increased risk of cardiovascular, cerebrovascular and renal diseases. Nevertheless, the primary determinants of elevated blood pressure in most patients are unknown. Recognizing that a sizable portion of variation in blood pressure is genetically determined, one line of research has focused on identifying genetic variants that contribute to the pathogenesis of hypertension. However, standard genetic linkage analysis using "hypertension" as a phenotype may lack power due to the multifactorial nature of the disorder. A way to overcome this challenge is to subdivide hypertensive subjects into more homogenous subgroups. We propose stratification on the basis of five intermediate phenotypes: 1) non-modulation of adrenal and renal vascular responses to angiotensin II with changes in sodium intake; 2) altered urinary kallikrein excretion; 3) low plasma renin activity response to volume depletion; 4) increased free cortisol excretion; and 5) insulin resistance. Each of these traits shows an increased prevalence in hypertensive subjects, can be plausibly linked to the pathophysiology of hypertension and, most importantly, shows evidence of heritability. Our overall goal, to define the underlying genetics of hypertension in an Asian population by studying intermediate phenotypes, can be divided into three parts. First, our rural Chinese population will be characterized by the collection of intermediate phenotype data on 600 unrelated individuals with high diastolic blood pressure and on 100 normotensive controls. Second, candidate genes will be chosen according to the underlying physiology of the intermediate phenotypes, and variations in the coding sequences of these potentially relevant genes will be identified. Finally, polymorphisms identified in the candidate genes will be tested through case-control analyses defined by the intermediate phenotypes. In pursuing this strategy, our intention is to reduce the heterogeneity that has surely impacted previous genetic studies of hypertension. Indeed, the proposed intermediate phenotypes have already been used successfully in studies of Western populations to implicate causative genetic variants. Our proposal is intended to expand this research by taking advantage of characteristics of rural Anqing, China. In contrast to urban areas of China, drug therapy is not readily available in rural Anqing, so measurements are not prone to treatment bias. Further, due to lack of readily available transportation, Anqing has remained isolated and relatively homogeneous. Thus, the genetic factors contributing to hypertension in this population may be less heterogeneous and more readily detected.