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Genome Wide Peripheral
Blood Leukocyte DNA
Methylation Microarrays
Identify a Single Association
with Inflammatory Bowel
Diseases
Richard Kellermayer
Pediatrics
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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Pediatrics R. AJMG 2010
Kellermayer
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Increasing prevalence of IBDs argues against primary
role of genes
Before 1960
1960-1980
1980-2008
Molodecky NA et al. Gastroenterology 2011
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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
Autoregulatory proteins
http://www.epigenetics.ch/mirna.html
• Integrated control of transcription independently from the
genetic code
• Mitotically heritable
• Mitotic inheritance: DNA methylation – DNMT1; histone
modifications - ?; ncRNAs - ?
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DNA Methylation, a Nutritionally
Responsive Epigenetic Process
Mammalian one carbon pool
Nutrition/environment
Gene silencing
-p-C-p-G-p(CpG di-nucleotide)
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Nutrition, DNA Methylation, and
Phenotype
Avy/a
Stochasticity
Metastable epiallele
Methyl-donor diet
Waterland RA et al. MCB 2003
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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
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