EU and Restless Legs. Proposal.
1. Titel
Epidemiology and genetics of the restless legs syndrome EUGENE RLS
2. Project type:
Network of Excellence
3. Key Words
Restless legs syndrome, epidemiology, dopaminergic therapy,
pharmacogenetics, linkage analysis, prevalence
.
1.1.1. Genomics and biotechnology for health
The project will focus on one of the most common neurological disorders with
high impact on sleep, the restless legs syndrome (RLS), and will investigate the
prevalence and genetic susceptibility factors and gene/environment interaction
in different European populations. The project aims at identifying genes
involved in sleep/wake regulation and will provide an understanding of general
molecular mechanisms of sleep disorders and their relation to the dopaminergic
system. This will provide a prerequesite for pharmaco-genomic treatment
options in the future.
Combating major diseases
Data from selected populations in Germany and the US point to an age
dependent prevalence of up to 10 % in the population and attribute RLS as one
of the most common sleep disorders. Its unawareness has so far resulted in the
useless prescription of sleeping pills resulting in enormous cost in health
systems in various countries. RLS has a significant impact on quality of life and
mental health and is associated with conditions as pregnancy, iron deficiency
and renal failure.
This project will establish a population derived European network for restless
legs syndrome in respect to genetic classifications of the disease and further
approaches to better treatment strategies. Next to the dopaminergic function
opioidergic and gabaergic systems will be studied with pharmacogenomics. We
will focus on the genetic susceptibility in relation to treatment responses and
associated disorders in different European populations.
5. Scientific and technical goals
The scientific goal of the project is to elucidate the prevalences of RLS in
different populations, characterize their pharmacological response and identify
families with hereditary forms of RLS. DNA of large families appropriate for
linkage analysis will be collected as well as DNA and clinical data from smaller
families for SIB-pair analysis and pharmacogenomic investigations. The search
for single major genes for RLS and further genetic susceptibility is the final goal
of the project and the basis for specifically designed treatments.
1. Populations based randomized samples will compare prevalences of RLS
within European countries and evaluate the impact of RLS on quality of
life. Sleep centers with experts of RLS mostly members of the
International Restless Legs Syndrome Study Group (IRLSSG), will assign
identified cases and perform the clinical classifications and follow cohorts
of patients to test treatment responses.
2. Tools for diagnosis in RLS, recently established for the clinical diagnosis,
will be evaluated and expanded to specific tools in genetic research.
3. Genetic studies with linkage to chromosomal loci will performed in
different populations and compared to previous findings of a locus on
chromosome 12, that has been attributed to the RLS in one French
Canadian family.
4. The identification of a major single gene and other susceptibility genes
involved will be aimed using linkage analysis followed by the use of SNIPgenotyping.
6. Work programme
Central sites specialized in RLS in each participating country will be established
and those will be coordinated from a German clinical and genetic center. For
epidemiological methods and study design the center of Epidemiology and
Social Medicine in Münster will be responsible. This center has already
performed the Study of Health in Pomerania (SHIP) Study, a population based
survey in the most northeastern part of Germany on the Baltic Sea. The study
area comprises three cities and 29 communities in West Pomerania.
1. Comparable epidemiological surveys with mailing questionnaires will be conducted
in the regions of centers with RLS experts. Diagnostic questionnaires recently
developed from the International RLS Study Group and currently under validation will
be applied. Prevalences of RLS, associated diseases and cultural differences and the
impact on quality of life and mental health will be determined.About 2.000
questionnaires will be sent in each country to identify cases of RLS.
2. Cases will be classified by face-to-face interviews with a diagnostic questionnaire.
This population will be enlarged by familial cases of RLS from centers of RLS experts
and DNA of all cases will be collected.
3. Special cohorts for a 3-year long-term observation will be selected and continuously
observed and treated by the expert centers. Standardized treatment strategies will be
applied using recently developed scales (severity scale, augmentation scale) to
determine short term and long term treatment responses.
4. Families with hereditary RLS will be identified by epidemiological studies, patient
populations and cohorts. Standardized clinical data with categorized classifications
from all European centers will be transfered to the genetic centers and a close
collaboration with genetic centers will be established
5. In informative large families a whole genom screen using polymorphic DNA
markers will be performed, the previously identified susceptibility locus of RLS on
chromosome 12 and probable other identified loci will be investigated in the different
RLS populations.Approximately 5 families of each center will be suitable for linkage
analysis and alltogether 30-40 large families will provide data for further genetic
analysis:
As a result from those studies probably involved region in the pathogenesis of RLS
will be investigated by SNP-genotyping. This will be performed in (i) the large
families (ii) small families and (iii) RLS cohorts.
6. In RLS cohorts additional pharmacogenetic studies will be performed testing
dopaminergic and opioidergic therapies and receptor polymorphism of the
dopaminergic and opioidergic receptors.
The search of a gene and genetic susceptibility factors in RLS provide the basis
for future treatments. Large companies of the pharmaceutical industry as well as
biotechnological research companies have already started with collaborations on
genetic research in RLS in search of specifically designed treatments.
The project will be performed within members of the European RLS Study
Group, that has been developing standardized tools for diagnosing and
classifying RLS together with the International RLS Study Group (IRLSSG).
Data exchange with US and Canadian groups working in RLS genetics will be
proposed.
German and other European patient groups as well as the RLSF will be
integrated in the project in identifying large RLS famlies.
7. Innovative aspects
Establishing and use of standardized and recently developed tools of the
IRLSSG to diagnose RLS and document therapy response in RLS to achieve
worldwide comparative clinical and genetic data in RLS.
Investigtion of the dopaminergic system in relation to sleep/wake regulation as
innovative fields of genetics and the role of neurotransmitter systems in sleep
disorders.
Developing a consortium between epidemiologists, clinicians and molecular
geneticists for developing research strategies in RLS genetics and further
neurological disorders involved in specified neurotransmitter systems of
sleep/wake regulation.
8. Existing networks
European Subgroup of the International RLS Study Group
(consists already of RLS specialised centers in Germany, Austria, Switzerland,
Italy, Spain, the Netherlands, Sweden, Finland, England, Scotland)
DGSM German Sleep Society
ESRS European Sleep Research Society
Patient Organisations on RLS in the US (RLS Foundation), Germany (Deutscher
RLS e.V)., Austria, Switzerland, Sweden, the Netherlands.
9. Proposed Partners
Proposed partners are the members of the European RLS Group with additional
specialized sleep centers in Europe and the Dept. of Epidemiology and Social
Medicine, Univ. Münster (Klaus Berger, MD)
The IRLSSG, European Subgroup consists of centers in Germany (Munich,
Göttingen, Marburg, Freiburg) and Austria (Innsbruck, Vienna), Switzerland
(Zürich, Bern), Italy (Milano, Bologna), Spain (Madrid, Barcelona), The
Netherlands (The Hague), Sweden (Orebro), Finland (Turku), England (London)
Genetic Centers will include the GSF in Munich (Thomas Meitinger, MD),
Max-Planck Institute of Psychiatry Munich (Florian Holsboer, MD, PhD) and
Molecular Genetics Laboratory, Univ, Milano, Italy.
10. Budget
Personnel for epidemiological and treatment response studies as technician or
study nurse including one scientist per center for 5 years, computer software for
implementing the database and existing scales for central evaluation, material
for molecular genetic studies in the genetic centers (DNA markers, PCR etc.).
app. 6.5 -7 Mill. EURO ( depending on the number of centers participating).
Address for correspondence:
Claudia Trenkwalder, Dept. Clin Neurophysiology, Univ. of Göttingen (ctrenkw@gwdg.de),
Juliane Winkelmann, Max-Planck Institute of Psychiatry, Munich, AG Neuropharmacology, (janew@mpipsykl.mpg.de),
Klaus Berger, Dept. Epidemiology and Social Medicine, Univ. Münster bergerk@uni-muenster.de
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