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Gene variants linked to inherited forms of hypertension
  

 

An eighteen-year search for genes involved in hypertension has yielded a risk factor for the disease. The gene, called GRK4, comes in at least four forms. Researchers have found that three variants of one form of GRK4—by themselves or through their interaction with other genes—are risk factors for hypertension, the most common form of high blood pressure. They are developing a gene test that will identify carriers of the three variants, or polymorphisms.


Schematic of the action of dopamine on the proximal tubule. View full

The research was led by Robin A. Felder, of The University of Virginia Health Sciences Center in Charlottesville, and Pedro A. Jose, of Georgetown University Medical Center in Washington, D.C. Based on studies of the human GRK4 (G protein-coupled receptor kinase) gene in human kidney cells and rodents, the researchers believe they have identified a likely culprit for inherited, or unexplained, forms of hypertension.

When one of these gene variants was introduced into mice, the animals developed high blood pressure. “This is the first demonstration that a polymorphism of a gene linked to hypertension can actually cause hypertension when introduced into an experimental animal,” says Felder.

Hypertension involves a breakdown in the body’s ability to get rid of excess salt. The three GRK4 variants appear to cause the GRK4 protein to be hyperactive in the kidney. This disrupts the function of dopamine receptors, which interact with GRK4 proteins.

Dopamine is perhaps best known as the brain chemical involved in regulating mood. But in the kidney, dopamine helps maintain the balance of salt and water in the blood. The receptor proteins do not function normally, however, when the GRK4 protein is hyperactive. The result is too much salt in the blood stream, and water is retained (to prevent the blood from getting too salty).

Using rats born with inherited forms of hypertension (spontaneously hypertensive rats), the researchers corrected the genetic defect by slowing down the production of GRK4. This suggests that similar interventions may one day be possible in humans.

The gene test will identify at-risk individuals who might benefit from reducing the salt in their diet. For some children at risk, a low-salt diet could reduce the degree of hypertension they experience when they become teenagers, which is when hypertension commonly appears. Early detection can prevent blindness, kidney disease, heart attacks, and stroke.

The gene test will be available by the end of the summer if all goes according to plan.

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Felder, R.A. et al. G protein-coupled receptor kinase 4 gene variants in human essential hypertension. Proc Natl Acad Sci USA 99, 3872-3877 (March 19, 2002).
 

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