Kidney Gene Implicated in Increased Heart Failure Risk

The risky gene controls kidney func-
tions – but can also damage the heart;
© panthermedia.net/vishnukumar Sivara-
man

The variant, a change in a single letter of the DNA sequence, impairs channels that control kidney function.

"It's not a heart gene," says Doctor Gerald W. Dorn II, the Philip and Sima K. Needleman Professor of Medicine at Washington University School of Medicine. "It's a kidney gene. This protein is not even expressed in the heart. Nobody has previously considered that kidney-specific gene defects might predispose you to heart failure."

Heart failure is diagnosed when the heart can no longer provide sufficient blood to the body. It can have a number of causes, including high blood pressure, cancer therapy, viral infections of the heart or heart attack.

"It's a syndrome," Dorn says. "You've had sufficient damage to your heart that it doesn't work very well. You collect fluid in your lungs, you swell up, and you have trouble breathing."

The unexpected results highlight the advantage of performing genome-wide studies to find DNA sequence variants associated with disease.

"I was surprised by the finding," says Doctor Thomas P. Cappola, assistant professor of medicine at the University of Pennsylvania School of Medicine. "This is a good example of how taking unbiased approaches to study human disease can lead you to unexpected targets."

In previous work, Dorn and colleagues used a partial genome-wide search technique to define the region of DNA in which sequence changes were associated with heart failure. But most of these sequence changes did not code for a change in protein and appeared not to have actually caused the increased risk. Instead, they served as markers, providing clues that this portion of the genome was worth a closer look. "We said we've got the right ZIP code, but we're not on the right block," Dorn says.

Studying three groups of Caucasian patients with heart failure, they found one DNA sequence variant that was common in all the groups and was actively involved in making an important protein for the body. A single change in the DNA sequence of a gene called CLCNKA leads to a change from arginine to glycine in the 83rd amino acid of the protein. This protein makes up part of a kidney channel responsible for controlling the secretion of chloride ions into the urine, an important process in maintaining the proper balance of salt and water in the body.

That single amino acid change reduced the channel's ability to shuttle chloride ions across the cell membrane by about half. Dorn hypothesizes that a result of this reduction could be elevated levels of a hormone called renin in the blood. Renin is produced in the kidney and is the first signal in a cascade that can damage the heart.


MEDICA.de; Source: Washington University School of Medicine