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Transcript
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
