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Researchers Uncover New Gene for Heart Failure in Caucasians(2)

January 18, 2011 By University of Pennsylvania

Nearly five million Americans live with heart failure, with as
many as 700,000 new cases diagnosed each year. In addition to
lifestyle factors, scientists have shown that heart failure has a
strong heritable component, but identifying the responsible genes
has been a major challenge. Now, new research has identified a
common genetic risk factor for heart failure in Caucasians that is
also linked to kidney function. The study, a collaboration between
the University of Pennsylvania School
of Medicine
, Washington University School of Medicine,
and other institutions, was published online this week in The
Proceedings of the National Academy of Sciences
.


  • New Research Shows Certain Genetic Profiles Increase Risk of
    Coronary Artery Disease, While Others Increase Risk of Heart
    Attack
  • Penn Heart and
    Vascular
  • University of Pennsylvania School
    of Medicine
  • University of Pennsylvania
    Health System

“The big surprise is that our results point to a kidney
gene, and not a heart gene,” says
Thomas P. Cappola, MD, ScM
, assistant professor of
Medicine at Penn and a lead author on the study.  “It
does make a lot of sense, however. When physicians treat heart
failure, kidney function is a major concern, and many heart failure
drugs affect the kidney directly.  Our findings show that the
heart and kidney should also be considered together in exploring
genetic predisposition to heart failure.”

Heart failure is very complex and this has often stymied
research using traditional approaches.  “Our study is a
successful example of a newer model of biomedical research in which
several laboratories and institutions combine numerous scientific
approaches to tackle difficult research problems,” said
Cappola.   For example, the research leveraged unique
genotyping platforms (the IBC gene array) and study populations
(the Penn Heart Failure Study and the Human Heart Tissue Bank) at
the University of Pennsylvania.  These resources were coupled
with advanced sequencing approaches and laboratory models at
Washington University.

“The results of this study highlight the advantage of
performing unbiased studies to find DNA sequence variants
associated with disease,” said Gerald W. Dorn II, MD,
professor of Medicine at Washington University School of Medicine
and also a lead author on the study.  “Nobody had
previously considered that kidney-specific gene defects might
predispose a person to heart failure.”

The gene variant is common in Caucasians and changes the
amino-acid sequence of CLCNKA, a kidney protein that controls
chloride secretion in the urine.  The change in CLCNKA
substantially impairs its function.  Similar but rare
mutations in CLCNKA can cause striking elevation in renin and
aldosterone, hormones which have been shown to increase heart
failure risk.

The researchers say approximately one half of Caucasians have
one copy of the variant CLCNKA gene, with an estimated 27
percent  increase in heart failure risk, and one quarter carry
two copies, with a 54 percent increase in risk.  But they also
caution the carrying the variant is not a definitive indicator of
developing heart failure.   Cappola says, “The more
likely scenario is that heart failure risk associated with gene
will only express itself if you have other cardiac problems. 
For example, if you have high blood pressure or a heart attack, the
chance of developing heart failure is more likely if you have also
inherited the CLCNKA risk variant.”

Cappola and Dorn plan on continuing their long-standing
collaboration by studying what CLCNKA might mean in clinical
practice.  They have designed a heart failure prevention trial
using readily available drugs that oppose the hormone aldosterone
in CLCNKA carriers to be performed at University of Pennsylvania
and at Washington University.  If successful, these findings
could open the door to tailored individual preventative therapy
based on personal genotype, or “personalized
medicine.”

Editor’s Note: The research was supported by the National
Heart, Lung, and Blood Institute, including a Cardiac Translational
Implementation Program Grant through the NIH Grand Opportunity
component of the American Recovery and Reinvestment Act of
2009.

SOURCE

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