Yale School of Medicine researchers have
identified a rare defect in a single gene that poses
a substantial risk for metabolic syndrome and early
heart disease, the leading cause of death worldwide.
The international study, led by Arya Mani, M.D., assistant
professor of cardiology, and Richard Lifton, M.D., chair
of genetics at Yale, identifies a new pathway implicated
in heart disease. Even though the genetic mutation is
very rare, these findings point to new approaches for
improving this aspect of health.
“These findings indicate that altered activity
of a well-known signaling pathway, Wnt, has large effects
on multiple metabolic pathways that contribute to cardiovascular
disease,” said Mani.
Coronary artery disease (CAD) is commonly caused by
metabolic syndrome, which includes a constellation of
risk factors such as high low-density lipoprotein (LDL)
cholesterol, high triglycerides, low high-density lipoprotein
(HDL) cholesterol, hypertension and diabetes.
This study was based on a large family of Iranian ancestry
that had an extraordinary prevalence of early CAD. Among
58 blood relatives, 28 were diagnosed with early CAD
at or before age 50 for the men, and 55 for the women.
Twenty-three of the 28 died from CAD at young ages.
In contrast, relatives without early CAD died at an
average age of 81. The relatives with CAD had high LDL,
high triglycerides, hypertension, and diabetes, while
their unaffected relatives did not. The relatives with
CAD also were predisposed to osteoporosis, which is
particularly interesting given recent evidence of association
of osteoporosis with CAD.
By comparing the inheritance of CAD to the inheritance
of each chromosome segment in the pedigree, the team
narrowed the location of the disease-causing gene to
a short segment of chromosome 12. In this region, they
found a single mutation in a gene called LRP6, which
acts in the Wnt signaling pathway and which was previously
known to be involved in development and in certain forms
of cancer. The mutation changed one amino acid in the
protein, which the team showed altered the activity
of the protein encoded by LRP6.
“The reason for the observed association of multiple
risk factors with one another has been a mystery,”
Lifton said. “Our findings have implicated the
Wnt signaling pathway in the development of many risk
factors and early CAD. We expect that studies of the
Wnt signaling pathway in patients with early CAD, and
metabolic syndrome, will provide new insight into the
basic biology of disease causation and allow new approaches
to disease prevention.”
Reference: Science March 2, 2007
