Genetic Mutation Found in Peripheral Artery Disease
DURHAM, N.C. – A tiny handful of genes appears to hold
important clues to understanding why some patients with
peripheral artery disease (PAD) face high rates of amputation
and early death while others are spared those consequences, say
researchers at Duke University Medical Center.
The finding, appearing online in the journal Circulation, is
the first to document a genetic mutation linked to PAD.
Although the work was done in mice, researchers say it is
likely to give them new insight into how PAD develops and
progresses in humans.
Dr. Brian Annex, professor of medicine and director of
vascular medicine at Duke, says the study stemmed directly from
his clinical experience. "Over and over, I'd see two patients
show up at the same time. They would be the same sex, same age,
have identical risk factors and have similar blockages in their
arteries. One of them would experience very slow progression of
the disease, while the other would face limb loss or death
within six months. I just knew there just had to be a genetic
basis for it."
Peripheral arterial disease occurs when major arteries in
the legs become clogged with plaque, a fatty build-up that's
similar to the deposits in coronary arteries that can lead to a
heart attack. Symptoms range from leg pain brought on by
walking that goes away with rest – that's the more benign form
of the disease – to a more serious form, marked by continuous
pain and sores and ulcers on the legs that often lead to
Annex says the mild form rarely progresses into the more
severe form. "In reality, we may be looking at two types of
diseases, although we've always thought of PAD as one."
Annex had the perfect participants for the study right at
his fingertips: two strains of mice with surgically-induced
blocked blood flow that mimicked human response to PAD. One
strain recovered well, showing restored blood flow and little
tissue death; the other had greater tissue loss and poor
recovery of normal blood flow.
In collaboration with Dr. Douglas Marchuk, a professor of
molecular genetics and microbiology at Duke, researchers
crossbred the two strains and eventually isolated a mouse that
enabled them to identify a relatively small region on
chromosome 7 that appears to protect the mice from the
consequences of the surgically-induced, PAD-like injury.
"Essentially, we now have a field of about 20 genes that we
think may be involved in shaping the way peripheral artery
disease develops," says Annex. "At this point, we are not
certain which ones are playing an active role, however. Still,
we feel strongly that our discovery opens a new wave of
investigation that may one day yield novel prevention
strategies or treatments."
The study was funded by the National Institutes of
Colleagues from Duke who contributed to the study include
co-lead authors Ayotunde Dokun, from the division of
endocrinology; Sehoon Keum, from the division of molecular
genetics and microbiology; Surovi Hazarika, Yongjun Li, and
co-senior author Douglas Marchuk, also from the department of
molecular genetics and microbiology.
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