DNA Methylation in Whole Blood: Uses and Challenges

Abstract

Due to its convenience, the blood is commonly used in epigenomic studies, but its heterogeneous nature leads to interpretation difficulties, given the now widely recognized potential for confounding by cell composition effects. Many recent publications have reported significant associations between DNA methylation and a variety of health conditions or exposures. In this review, we summarize many of these recent publications, highlighting the findings in the context of potential cell composition effects, particularly findings that are indicative of immune response or inflammation. While there is substantial evidence for confounding by cell composition, there is nevertheless also evidence for differential DNA methylation suggestive of processes that are not cell mediated. We conclude that important biological insights still may be gained from studying DNA methylation in whole blood, either by investigating the cell composition effects themselves or processes that demonstrate associations even after adjusting for cell composition effects.

miRNAs Differentially Expressed by Next-Generation Sequencing in Cord Blood Buffy Coat Samples of Boys and Girls

“…Many well-characterized birth cohorts and other longitudinal studies with banked blood samples rely on them for analysis of DNA methylation and gene expression. Epigenetic changes in blood are relevant even if they do not capture all changes observed in organ-specific tissue [100]. An increasing number of studies have demonstrated that levels of circulating miRNAs released by cells into the bloodstream are correlated with tissue miRNA levels [101,102].…”

Potential epigenetic biomarkers of obesity-related insulin resistance in human whole-blood

“…48 These proteins can associate with protein complexes that contain co-repressors and histone deacetylases, and could influence chromatin structure. 47 Our findings demonstrate that the DNA methylation status associated with SLC19A1 is a promising biomarker for obesity and its underlying insulin resistance, as it is present in both skeletal muscle and blood.…”

“…Whole blood has a heterogeneous cell composition, and potential differences in inflammation between our groups could confound the DNA methylation results. 47 Furthermore, we identified new potential biomarkers for obesityrelated insulin resistance within a limited sample size. Future studies could fractionate blood cell types to avoid confounding composition effects, and will need to replicate our findings in larger cohorts to be considered candidate biomarkers.…”

How to interpret epigenetic association studies: a guide for clinicians

“…Fortunately, several mathematical strategies are emerging that allow adjusting the results for differences in cell composition, even in the absence of a reference epigenome. 43,44 Therefore, in general, researchers should take care in using comparable tissue samples. If they are to draw conclusions about disease-related epigenomic patterns, they must confirm that the differences between groups do not merely depend on cell distributions but indeed reflect different epigenomic signatures.…”