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