Genome-wide Peripheral Blood Leukocyte DNA Methylation Microarrays Identified a Single Association with Inflammatory Bowel Diseases

Authors

R. Alan Harris, Baylor College of MedicineFollow
Dorottya Nagy-Szakal, Baylor College of Medicine
Natalia Pedersen, Herlev University HospitalFollow
Antone Opekun, Baylor College of MedicineFollow
Jiri Bronsky, Charles University and University Hospital MotolFollow
Pia Munkholm, Herlev University Hospital
Cathrine Jespersgaard, Statens Serum Institut
Paal Skytt Andersen, Statens Serum InstitutFollow
Bela Melegh, University of PecsFollow
George Ferry, Baylor College of MedicineFollow
Tine Jess, Statens Serum Institut
Richard Kellermayer, Baylor College of MedicineFollow

Document Type

Article

Date of this Version

2012

Citation

Inflamm Bowel Dis 2012;18:2334–2341; DOI 10.1002/ibd.22956

Abstract

Background: Crohn’s disease (CD) and ulcerative colitis (UC) are common forms of inflammatory bowel disease (IBD). Monozygotic (MZ) twin discordance rates and epidemiologic data implicate that environmental changes and epigenetic factors may play a pathogenic role in IBD. DNA methylation (the methylation of cytosines within CpG dinucleotides) is an epigenetic modification, which can respond to environmental influences. We investigated whether DNA methylation might be connected with IBD in peripheral blood leukocyte (PBL) DNA by utilizing genome-wide microarrays.

Methods: Two different high-throughput microarray-based methods for genome-wide DNA methylation analysis were employed. First, DNA isolated from MZ twin pairs concordant (CD: 4; UC: 3) and discordant (CD: 4; UC: 7) for IBD was interrogated by a custom-made methylation specific amplification microarray (MSAM). Second, the recently developed Illumina Infinium HumanMethylation450 BeadChip arrays were used on 48 samples of PBL DNA from discordant MZ twin pairs (CD: 3; UC: 3) and treatment-naive pediatric cases of IBD (CD: 14; UC: 8), as well as controls (n = 14). The microarrays were validated with bisulfite pyrosequencing.

Results: The MSAMs did not yield significant IBD associations. The Methylation BeadChip approach identified a single DNA methylation association of IBD at TEPP (testis, prostate and placenta-expressed protein) when DNA isolated selectively from peripheral blood mononuclear cells was analyzed (8.6% increase in methylation between CD and control, FDR = 0.0065).

Conclusions: Microarray interrogation of IBD-dependent DNA methylation from PBLs appears to have limited ability to detect significant disease associations. More detailed and/or selective approaches may be useful for the elucidation of connections between the DNA methylome and IBD in the future.