The Center for Research, Prevention and Treatment of Atherosclerosis
Head: Eran Leitersdorf, M.D
Professor of Medicine
Dorothy & Maurice Bucksbaum Chair in
Molecular Genetics
Tel: (02)6778599
Fax: 972-2-641-1136.
E-mail: eranl@hadassah.org.il
Faculty:
Yechezkiel Stein, M.D., Professor of Medicine
Gideon Friedman, MD, Professor of Medicine
Vardiella Meiner, M.D. Lecturer in Medicine and Human Genetics
Daniel Schurr, MD
The Center for Research, Prevention and Treatment of Atherosclerosis is part of the Department 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. |