Download Epigenetics of Coeliac Disease

Epigenetics of
Celiac Disease
MEDICEL
Malta 2011
Why this project?
• Epigenetics is the first level of integration of genetic and
environmental factors.
• It may translate the effects of risk factors in terms of
molecular events.
• It is feasable with the recent development of micro
arrays/Si RNA knowledge.
• There is no data published to date on this topic (pubmed
september 2011).
What is epigenetics?
• Epigenetics is the a way to transmit gene
regulatory signals through mitosis. It is
required for maintenance of cell
differentiation.
• It is based on
– DNA methylation
– Histone acetylation and phosphorylation
– RNA silencing
Histone acetylation
DNA methylation
RNA silencing
Epigenetics and complex diseases
• Epigenetics is the reflect of
– Environmental factors
– Stochastic events
– Aging
• It is less stable than DNA variations but it is stable
enough to explain chronic diseases. It may add to or
reverse the effect of DNA variations explaining
uncomplete penetrances.
• It may explain
– Altered sex ratio in complex diseases
– Incomplete concordance in monozygotic twins
– Cancers
Ptak et al. 2008
Key questions
• To describe the epigenome of CD (DNA
methylation and Si RNA expression).
• To integrate this information with genetic
and environmental data (disease
modeling).
• To provide disease associated biomarkers
(predictive markers?).
Study design
• 500 CD and 500 controls
• Data collection:
– Clinical data
– Environmental factors
• Biobanquing
– Blood (stored at 20°C)
– Intestinal biopsies (stored at -20°C).
– Intestinal biopsies (stored at -80°C in RNA
later) for few centres.
Procedures design
• Genetic profiling of participants for the 30
known CD polymorphisms.
• DNA methylation (Illumina 450k arrays) on
blood and intestinal samples.
• RNA analyses (siRNA and functional
validation of DNA methylation data for the
most relevant genes).
• Biostatistics/ Mathematical modeling.
Main deliverables/perspectives
• A set of epigenetic biomarkers associated
with the disease to be tested in
prospective studies.
• A comprehensive model of
gene/environment integration at the
epigenetic level.