Comparison of DNA Methylation Profiles of Hemostatic Genes between Liver Tissue and Peripheral Blood within Individuals

Abstract

DNA methylation has become increasingly recognized in the etiology of complex diseases, including thrombotic disorders. Blood is often collected in epidemiological studies for genotyping and has recently also been used to examine DNA methylation in epigenome-wide association studies. DNA methylation patterns are often tissue-specific, thus, peripheral blood may not accurately reflect the methylation pattern in the tissue of relevance. Here, we collected paired liver and blood samples concurrently from 27 individuals undergoing liver surgery. We performed targeted bisulfite sequencing for a set of 35 hemostatic genes primarily expressed in liver to analyze DNA methylation levels of >10,000 cytosine-phosphate-guanine (CpG) dinucleotides. We evaluated whether DNA methylation in blood could serve as a proxy for DNA methylation in liver at individual CpGs. Approximately 30% of CpGs were nonvariable and were predominantly hypo- (<25%) or hypermethylated (>70%) in both tissues. While blood can serve as a proxy for liver at these CpGs, the low variability renders these unlikely to explain phenotypic differences. We therefore focused on CpG sites with variable methylation levels in liver. The level of blood–liver tissue correlation varied widely across these variable CpGs; moderate correlations (0.5 ≤ r < 0.75) were detected for 6% and strong correlations (r ≥ 0.75) for a further 4%. Our findings indicate that it is essential to study the concordance of DNA methylation between blood and liver at individual CpGs. This paired blood–liver dataset is intended as a resource to aid interpretation of blood-based DNA methylation results.

Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study

“…Similar approaches using this data have been published recently [32]. Although biomarker discovery that focuses on peripheral whole blood samples is far more feasible than using liver or brain samples, further work is required to understand how DNAm and gene expression differences in the blood might relate to the differences in these tissues of relevance [49,50]. Genetic variations in pharmacokinetic genes have been studied extensively in pharmacogenetic research of antidepressant response and, therefore, are good candidates to study SNP-DNAmgene expression relationships.…”

Methylation analysis by targeted bisulfite sequencing in large for gestational age (LGA) newborns: the LARGAN cohort

“…We recognize that the use of surrogate tissue (blood cells) to identify changes in DNA methylation of inaccessible target tissues in living patients is a drawback but is the only means of study we have to identify epigenomic biomarkers of growth. Recent studies identified subsets of DMCs that correlate between blood and brain [ 83 ] and blood and liver [ 84 ], but further studies need to be done to generate a map of those sites informative of a wider range of tissues and cell types. Although the population studied was composed of diverse ethnicities, they were largely of white European origin.…”