epigenetics in celiac disease medicel istanbul 2012
TRANSCRIPT
Epigenetics inCeliac 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 -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 preferrentiallytheir 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