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Genome-wide peripheral blood leukocyte DNA methylation microarrays identified a single association with inflammatory bowel diseases

Authors

  • R. Alan Harris PhD,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
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    • These authors contributed equally.

  • Dorottya Nagy-Szakal MD,

    1. Department of Pediatrics, Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
    2. USDA/ARS Children's Nutrition Research Center, Houston, Texas
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    • These authors contributed equally.

  • Natalia Pedersen MD,

    1. Gastroenterology Unit, Herlev University Hospital, Herlev, Denmark
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    • These authors contributed equally.

  • Antone Opekun MS,

    1. Department of Pediatrics, Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
    2. Department of Gasteonterology-TMC Digestive Disease Center, Baylor College of Medicine, Houston, Texas
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  • Jiri Bronsky MD,

    1. Department of Pediatrics, Second Medical Faculty, Charles University and University Hospital Motol, Prague, Czech Republic
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  • Pia Munkholm MD, Dr. Med. Sci,

    1. Gastroenterology Unit, Herlev University Hospital, Herlev, Denmark
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  • Cathrine Jespersgaard PhD,

    1. Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark
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  • PaalSkytt Andersen PhD,

    1. Department of Microbiological Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark
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  • Bela Melegh MD, PhD,

    1. Department of Medical Genetics, University of Pecs, Hungary
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  • George Ferry MD,

    1. Department of Pediatrics, Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
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  • Tine Jess M.D, Dr. Med. Sci,

    1. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
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  • Richard Kellermayer MM, PhD

    Corresponding author
    1. Department of Pediatrics, Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
    2. USDA/ARS Children's Nutrition Research Center, Houston, Texas
    • Section of Pediatric Gastroenterology, Hepatology & Nutrition, Baylor College of Medicine, Baylor College of Medicine, Texas Children's Hospital, 6621 Fannin St., CC1010.00, Houston, TX, 77030-2399
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  • R.K. was supported in part by the Broad Medical Research Program, the Broad Foundation (IBD-0252); the Crohn's and Colitis Foundation of America-Children's Digestive Health and Nutrition Foundation/North American Society of Pediatric Gastroenterology Hepatology and Nutrition (CCFA Ref. No. 2426); the Child Health Research Career Development Agency of the Baylor College of Medicine (NIH Grant No. 5K12 HD041648); and a Public Health Service grant DK56338, funding the Texas Medical Center Digestive Diseases Center.

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. (Inflamm Bowel Dis 2012;)

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