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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xxx00.#####.ppt 04/10/23 11:42 PMPediatrics Kellermayer R. AJMG 2010

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