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.
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