Abstract: Series 100, Lecture 3

The Harvey Lectures Series 100 (2004—2005)

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Lecture #3: Thursday, January 20, 2005 — Time and Location

Hypertension: Unraveling a Complex Disease with Human Genetics

Richard P Lifton, MD, PhD

Chairman, Department of Genetics
Sterling Professor of Genetics, Internal Medicine and Molecular Biophysics and Biochemistry
Investigator, Howard Hughes Medical Institute

Howard Hughes Medical Institute, Yale University School of Medicine

New Haven, Connecticut

The common diseases are multifactorial in origin with contributions from genetic and environmental factors. In the setting of complex systems biology, genetic approaches have the capacity to identify key elements in the system by identifying genes that when mutated impart large effects on the trait. We have used this approach to investigate the pathogenesis of hypertension, or elevated blood pressure. Hypertension is the most common disease of the industrialized world, affecting a billion people world-wide and more than 50 million in the U.S. It is a major risk factor for heart attack, stroke, congestive heart failure and renal failure; pharmacologic lowering of blood pressure reduces the incidence of these outcomes. A major limitation in the treatment of hypertension is the poorly understood pathogenesis of this trait, with the consequence that treatment is empiric, with more than 70 drugs on the market, and treatment commonly fails to return blood pressure to normal. Because of the exceeding complexity of blood pressure regulation, hypertension has been variously proposed to be a primary disease of the brain, heart, kidney, adrenal, or vasculature; physiologic analysis has failed to settle the location of primary abnormalities. We have recruited rare families from around the world in which single genes impart large effects to either raise or lower blood pressure. To date we have identified mutations in six genes that cause marked elevations in blood pressure and eight genes drive blood pressure to low levels. Intriguingly, these genes all converge on a single pathway: the renal handling of salt. All the mutations that raise blood pressure increase net renal salt reabsorption while mutations that lower blood pressure decrease net salt reabsorption. These findings identify new elements and rate-determining steps required for normal long-term salt homeostasis, and they identify key environmental contributions as well. Moreover, they predict that medications targeting the salt homeostasis pathway should be of high efficacy in treating hypertension in the general population, predictions which are being confirmed by large randomized trials. Finally, they identify new targets whose modulation may prove of particular efficacy in the treatment of hypertension.