Pediatrics
Genome Wide Peripheral Blood Leukocyte DNA Methylation Microarrays Identify a Single Association with Inflammatory Bowel Diseases
Richard Kellermayer
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Etiology of IBD
Intestinal mucosa
Sartor RB. Nat Clin Pract Gastroenterol Hepatol. 2006
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Systems of Key Elements in IBD Pathogenesis
Kellermayer R. AJMG 2010
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Increasing prevalence of IBDs argues against primary role of genes
Molodecky NA et al. Gastroenterology 2011
Before 1960
1960-1980
1980-2008
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Genetic contribution to IBD
40% explained by HLA locus
71 susceptibility loci(Franke A et al. Nat Genet 2010)
49 susceptibility loci (Anderson CA et al. Nat Genet 2011)
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Epigenetic Concept
• Integrated control of transcription independently from the genetic code• Mitotically heritable• Mitotic inheritance: DNA methylation – DNMT1; histone modifications - ?; ncRNAs - ?
http://www.epigenetics.ch/mirna.html
Autoregulatory proteins
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DNA Methylation, a Nutritionally Responsive Epigenetic Process
Gene silencing
Mammalian one carbon pool Nutrition/environment
-p-C-p-G-p-
(CpG di-nucleotide)
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Nutrition, DNA Methylation, and Phenotype
Waterland RA et al. MCB 2003
Avy/a
Methyl-donor diet
Metastable epialleleStochasticity
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Working model
• Transient nutritional/environmental exposures
• Critical periods of development
• Permanent changes in the biological components of IBD
• Nutritionally/environmentally induced predisposition to IBD (if early development – detectable in all tissues – metastable epiallele for IBDs)
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PBL DNA methylation association in IBDs?
• 2 approaches‐ MSAM on MZ twins concordant (CD: 4; UC: 3) and discordant (CD: 4; UC: 7) for IBD
•Validation (bisulfite pyrosequencing in independent cohort of adult patients)
‐ Illumina 450K Infinium Methylation BeadChips: 48 samples: discordant MZ twins (CD:3; UC:3) and treatment naive pediatric cases of IBD (CD:14; UC:8), controls (n=14)
•Validation in expanded cohort
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One single association in PBMCs
TEPP :testis, prostate and placenta-expressed protein
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PBL DNA methylation association in IBD?
•Microarray interrogation of IBD dependent DNA methylation from PBLs is less likely to yield significant results
•More detailed and/or selective approaches may be useful
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Selective Approach from PBL DNA
Inflamm Bowel Dis. 2011 Oct 21. [Epub ahead of print]
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Acknowledgements
•Dorottya Nagy-Szakal
•Ronald A. Harris
•Sabina Mir
•Harry Siegele, Sahna Reddy
•Natalia Pedersen,Jiri Bronsky, Pia Munkholm, Cathrine Jespersgaard, Paal Skytt Andersen, Bela Melegh, Tine Jess
•C. Wayne Smith
•George Ferry
•Mark A. Gilger
•Antone Opekun
•Funding: Broad Foundation, Baylor CHRC