Transcript Epigenetics of Coeliac Disease

Epigenetics in
Celiac Disease
MEDICEL
Istanbul 2012
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 June 2012).
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
Epigenetics and inflammation
• Th1/Th2 ratio:
– Methylation between IL-4 and IL-13 (5q21) reduces
expression of Th2
– Th2 polarization increases methylation and
decreases histone deacetylation of g-IFN promoter
• IL-4/IL-13:
– Demethylation + histone modification
– Allowing GABA and STAT6 fixations
– Lead to IL-4 synthesis that induces IL-13 and IL-15
• FOXP3:
– CpG motifs in promoter : methylted in naif and
activated LT4 but demethylated in Treg.
Lee. Immunity 2002
Jones EMBO J 2006
Epigenetics in lupus
Thabet J Autoimmunol 12
Epigenetics in diabetes
Keating J Cardiovasc Transl res 2012
Epidemic of celiac disease in
children <2 years of age in Sweden
Olsson. Pediatrics 2008
Fathers transmit preferrentially
their DQ2 to their daughters
61% vs 42%, P=0.02
Megiorni.Am J Gastroenterol 2008
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.
Shall we start?
• 500 euros / test
• Conditioning
• Transport : -20 ; -80°C
• Hypothesis of 15% difference :
– 800 patients
– 800.000 to 1.000.000 euros