What is nature's role in the development of inflammatory bowel disease, psoriasis and ankylosing spondylitis?

July 3, 2019

In an effort to determine what causes immune mediated diseases such as ankylosing spondylitis, inflammatory bowel disease and psoriasis, researchers have focused on learning more about genetic pathogenic pathways responsible for autoimmunity. In this article, we review the data and highlight best practices.

In an effort to determine what causes immune mediated diseases such as ankylosing spondylitis, inflammatory bowel disease and psoriasis, researchers have focused on learning more about genetic pathogenic pathways responsible for autoimmunity.

Published in Arthritis Research & Therapy,  Jessica Whyte and colleagues in Australia present this review of proper experimental design and consistency of approach in future research in an effort to understand the functional role of DNA methylation in immune-mediated disease.

Ankylosing spondylitis, inflammatory bowel disease and psoriasis belong to a group of seronegative autoimmune diseases that are closely related, often co-occur, and share genes that confer susceptibility.

Even though great strides have been made in mapping the genomic basis of autoimmunity, the authors point out that less than 28 percent of the heritability of these diseases has been determined.

RELATED:  Factors that Influence Epigenetics

DNA methylation is an epigenetic or functional modification that occurs throughout life and represents the most robust and tractable epigenetic measurement method we have. Essentially methylation refers to the addition of a methyl group (CH3) to a cytosine on DNA to form 5-methylcytosine (5mC).

DNA methylation is a very stable marker that is maintained through mitosis and is moderately heritable between generations. The loss of methylation on cytosine results in a stable alternative nucleotide thymine. Cytosine to thymine mutations are the most common observed in mammals.

Methylation, or epigenetics, can lead to gene silencing in some cases and gene activation in others. The methylation of DNA may be useful in studying disease as a biomarker for disease outcome/severity, or to uncover transcriptional control and determine the effect of genetic changes on function.

See "Best Practices" next page.

BEST PRACTICES

  • It is important to clearly define an achievable question or goal from the outset.

  • Proper cohort selection in an effort to promote reproducibility and statistical power should be strived for.

  • It is imperative to examine cell types in isolation, to enable comparisons between tissue resident and circulating cells, and to control for cell-specific DNA methylation patterns.

  • Stringent levels of genome-wide significance should be sought by utilizing a properly powered sample size.

  • Methylation-specific PCR can be used when candidate genes are know, otherwise a multi-gene approach should be employed.

  • DNA methylation should be examined in the context of genomic or transcriptomic data as this provides context and functional information.

  • Technical verification is recommended prior to biological validation, as it is generally less time consuming and expensive than biological validation.

“Despite evidence in twin studies that epigenetics is a major mechanism through which immune-mediated disease- associated variants affect function, the role of DNA methylation, the most well-characterized epigenetic mechanism, in immune-mediated diseases remains largely unknown,” the authors wrote.

REFERENCE:

Jessica M. Whyte, Jonathan J. Ellis, Matthew A. Brown,  et al. "Best practices in DNA methylation: lessons from inflammatory bowel disease, psoriasis and ankylosing spondylitis." Arthritis Research & Therapy.  https://doi.org/10.1186/s13075-019-1922-y