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

Research Interests:

Molecular genetics of common human diseases.

Honors:

* National Academy of Sciences
* The Basic Science Prize, American Heart Association
* Homer Smith Award, American Society of Nephrology
* MSD International Award, International Society of Hypertension

The common human diseases that account for the vast majority of morbidity and mortality in our society are known to have underlying inherited components. Rapid advances in molecular genetics have led to a stage where identification of genetic variants contributing to these common but complex traits is feasible. Such identification promises to revolutionize the diagnostic and therapeutic approaches to these disorders.

Current Research:

Cardiovascular disease is the leading cause of death world-wide. Epidemiologic studies have identified hypertension, high cholesterol, diabetes and smoking as major risk factors. By investigation of rare families recruited from around the world that segregate single genes with large effect, we have identified genes that contribute to these traits, putting a molecular face on their pathogenesis. For example, we have identified mutations in 8 genes that cause high blood pressure (hypertension) and another 8 that cause low blood pressure. These mutations all converge on a final common pathway, the regulation of net salt reabsorption in the kidney. These findings have established the key role of variation in renal salt handling in blood pressure variation, and have led to changes in the approach to treatment of this disease in the general population. They have also identified new therapeutic targets that are predicted to have greater efficacy with reduced side effects. Finally, they have identified new signaling pathways involved in the regulation of blood pressure homeostasis. We have taken similar approaches to another common disease, osteoporosis, with the identification of gain of function mutations in LRP5, a component of the Wnt signaling pathway, in development of high bone density. This finding has led to intensive efforts to identify small molecules that impact this pathway to protect against and/or reverse osteoporosis in the general population. Ongoing studies use both emerging and novel approaches to identification of genes that contribute to disease burden in the population, and to understanding the pathways that link genes to disease.

Mutations that affect blood pressure in humans. A diagram of a nephron, the filtering unit of the kidney, is shown. The molecular pathways mediating NaCl reabsorption in individual renal cells along the nephron are shown, along with the pathway of the renin-angiotensin system, a major regulator of renal salt reabsorption. Inherited diseases affecting these pathways are indicated, with hypertensive disorders in red and hypotensive disorders in blue. From Lifton, Gharavi, and Geller. Cell, 104:545-556, 2001.