Center for Research,
Prevention and Treatment of Atherosclerosis
Tel: (02)6778599
Head:
Eran Leitersdorf, M.D., Professor of Medicine,
Dorothy &
Maurice Bucksbaum Chair in Molecular
Genetics
Faculty:
Yechezkiel Stein, M.D., Professor of Medicine
Gideon Friedman, M.D., Associate Professor of Medicine
Arie Ben Yehuda, M.D., Associate Professor of Medicine
Vardiella Meiner, M.D. Lecturer in Medicine and Human Genetics
The Center for Research, Prevention and Treatment of Atherosclerosis
is part of the Division of Medicine at Hadassah University
Hospital in Jerusalem. It is responsible for all clinical
and research activities related to prevention of cardiovascular
disease and implementation of national and international guidelines.
Our main clinical activities
include:
1)
Treatment of patients with lipid disorders, atherosclerosis
or its complications and initiation of clinical preventive
programs.
2)
Clinical, biochemical and molecular diagnosis of dyslipidemias,
Cardiomyopathies, and rare metabolic disorders.
3)
Implementation
of current knowledge, national and international guidelines
for the prevention and treatment of atherosclerosis.
4)
Development of new diagnostic tools and treatment modalities
based on the results of basic and clinical research.
The lipid clinic is a referral center
for patients with lipid disorders. The patients are referred
for consultation by their treating physicians. The latter
include general practitioners and specialists in family medicine,
internists, cardiologists and others. Each consultation includes
determination of plasma lipid and lipoprotein levels by a
CDC-controlled laboratory, medical examination and a dietary
consultation. The following specialized tests are performed
upon specific requests:
Quantification of plasma lipoprotein concentrations by ultracentrifugation,
genotyping of apolipoprotein genes and analysis of specific
disease-causing mutations.
Research
Activity:
The main research interests are in molecular genetics of dyslipidemias,
atherosclerosis, and other causes of sudden death. Genetic epidemiology
of arteriosclerotic cardiovascular disease and drugs affecting
lipid metabolism.
The main research projects are:
Basic Research:
A. Molecular genetics of
familial hypercholesterolemia (FH). We have shown that in Israel,
FH is associated with at least fourteen different LDL receptor
gene mutations. Four unique mutations are responsible for a
large number of the known cases. The proliferation of these
four different LDL receptor mutations is related to founder
mechanisms. DNA samples from hundreds of FH families are currently
available in our DNA bank. We have also developed specific assays
in order to directly detect these mutations in DNA samples obtained
from FH patients.
B. Molecular genetics of cerebro-tendinous
xanthomatosis (CTX). CTX is an autosomal recessive lipid storage
disease caused by mutations in the sterol 27-hydroxylase (CYP27)
gene. The clinical hallmarks of the disease include tendon xanthomas,
premature atherosclerosis, juvenile cataracts and progressive
neurological dysfunction. CYP27 was cloned in our laboratory.
Following the characterization of CYP27, three distinct mutations
have been identified in Jews of North African origin.
The phenotypic expression of mutations in CYP27 vary between
families and even within families. Collaborative studies with
other investigators from England, France, South Africa, the
USA, Australia and Hong Kong revealed the extensive molecular
heterogeneity of CTX in the world. So far 20 novel CYP27 mutations
were identified in our laboratory.
C. Establishment of a CYP27 knockout
mouse model. We have cloned the mouse CYP27 gene anddesigned
a targeting plasmid. The construct designed to disrupt CYP27
by inserting via homologous recombination a selectable marker
into one of its exons. Our targeting plasmid was introduced
into mouse embryonic stem cells (ES cells.). ES cells having
a modified CYP27 gene were reintroduced into host blastocysts
and germline transmission of the mutant gene has been achieved.
The phenotypes of the animals harboring the mutant gene were
studied through the analysis of the resulting metabolic abnormalities
and pathological changes. These animals are currently used in
several international collaborative projects with our laboratory.
D. Identification of a cholesterol
lowering gene (CLG). We have recently studied a family with
familial hypercholesterolemia (FH) which had FH members with
lower than expected LDL-C levels. The existence of CLG was proven
by linkage analysis, which identified a locus at 13q. We found
strong evidence for linkage at this locus with LDL, HDL, total
cholesterol, and body mass index. These data provide support
for the existence of a novel gene influencing lipid concentrations
in man. Currently, CLG is mapped to a region of approximately
10 centimorgan. Further mapping is underway. We use three main
strategies: 1. Identification of additional haplotypes associated
with low LDL-C levels through the study of other populations,
and 2. Use of Single nucleotide polymorphism (SNP) analysis
in order to identify gene or point mutations associated with
low LDL level phenotype, and 3. Identification of specific tissues
with highest expression of CLG by< using metabolic turnover
studies in order to confirm the identified gene expression product
activity with the particular members of the family carrying
the particular phenotype.
Clinical Research:
A. MED PED (Make Early Diagnosis
Prevent Early Death) FH (familial hypercholesterolemia) program.
FH is an autosomal dominant disease manifested by extremely
high plasma cholesterol levels leading to premature morbidity
and mortality from cardiovascular diseases. The main purpose
of the MED PED program is to identify and study patients and
families with FH. These families are registered in a specific
database, which is maintained in our center. Clinical diagnosis
of FH is supported by the analysis of the specific LDL receptor
gene mutations. Therapy is carried out through the outpatient
lipid clinic. The patients are also involved in clinical trials
testing new drugs for hypercholesterolemia.
B. Treatment of familial hypercholesterolemia
with HMG CoA reductase inhibitors. The efficacy, tolerability
and safety of lipid lowering drugs either alone or in combination
with other lipid lowering drugs is tested in our center on high
risk patients with FH. We have conducted several consecutive
studies using HMG CoA reductase inhibitors in patients with
FH. These studies, phase II-IV, include a dose finding pharmacogenetic
single-blind study, several high dose, double blind studies
and drug combinations. We were the first to use molecular genetic
characterization of FH patients on a drug trial and document
that constitutional, genetic and familial determinants, control
the response of plasma lipids and lipoproteins to statins.
C. Establishment of a shared database
for patients and families with Cardiomyopathies affiliated with
The European Working Group on Myocardial Diseases. These primary
heart muscle diseases represent an important cause of cardiac
morbidity and mortality in developed countries. Specific mutations
responsible for the disease had been so far identified only
in hypertrophic cardiomyopathy (HCM). Genetic typing is expected
to solve major preclinical diagnostic, prognostic, preventive,
behavioral and family counseling questions which can not be
solved by clinical research. Israeli researchers from all major
medical centers are members of this concerted action, which
coordinates Israeli clinical and molecular research of the epidemiological,
clinical and genetic aspects of CM. The research includes creation
of a standardized database of patients with CM (Dilated, Hypertrophic,
Restrictive, Right Ventricular Arrhythmogenic and Unclassified)
and a DNA bank for patients with the familial form of CM as
well as analysis of gene markers (microsatellites) as well as
known mutations in four candidate genes.
