DNA Methylation Variation in Blood Cells may Impact Platelet Function

DNA methylation modifies nucleotides, regulating gene expression without sequence change. The effects of DNA methylation within blood cell lineages on the development and function of endomitotic high DNA copy megakaryocytes (MKs) to anucleate platelets remain poorly understood. We sought to characterize this potential relationship by investigating associations between platelet function and methylation in circulating nucleated blood cells. Data were measured in the Framingham Heart Study Third Generation cohort ( n = 1,314). Five bioassays assessed platelet function in response to up to seven agonists in whole blood and platelet-rich plasma, and the Illumina 450K array was used to conduct an epigenome study of blood DNA methylation. In adjusted statistical association models, we found 46 significant associations (false discovery rate-adjusted p < 0.05) across 36 genomic DNA methylation sites, including cg24267699 in a putative regulatory site -742/-743 bases upstream from the ABO transcription start site associated with ristocetin platelet agglutination ( β = 0.21, standard error = 0.03, p < 1.04E-11). The 36 sites collectively reside within genes acting as transcription factors, genes implicated in granule release and exocytosis, cytoskeletal functions, mitochondrial function, and platelet function. The set of associated cytosine-phosphate-guanines was enriched in MKs for markers of regulatory activity, including DNase-I hypersensitivity sites and histone activity. Overall, we report in the first such epigenome scan that blood cell DNA methylation appears to be significantly associated with several platelet reactivity traits, and may drive the regulation of key genes involved in those processes presumably at the upstream level of hematopoietic stem cells or megaerythroid lineage cells.