Epigenetics of Celiac Disease MEDICEL Malta 2011.

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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.