DNA methylation is associated with von Willebrand factor and coagulation factor VIII plasma levels: the atherosclerosis risk in communities study

Limited information is available on how DNA methylation of cytosine-phosphate-guanine (CpG) sites across the genome regulate circulating von Willebrand Factor (VWF) and factor VIII (FVIII) levels. We performed an epigenome-wide association study to examine the association of leukocyte DNA methylation levels at 483,735 CpG sites with VWF antigen plasma levels and FVIII activity in 2,597 Black and 1,011 White participants from the Atherosclerosis Risk in Communities (ARIC) study. VWF antigen levels and FVIII activity were measured at the baseline exam, while DNA methylation was measured with the Infinium HumanMethylation450 BeadChip array at visit 2 or 3. Discovery analysis was performed in the Black population, with replication in the White population. We identified 55 and 46 significant CpG sites associated with VWF and FVIII (P < 1.03 × 10–7) in the discovery analysis, respectively. Among these, for VWF, 13 were replicated, mapping to one novel (NBEAL2) and one known (ABO) locus. For FVIII, 12 associations were replicated which mapped to 1 novel locus (B3GALT4) and 2 known but previously unreplicated loci (ABO and CORO1A). When we adjusted for the variants previously identified as independently associated with VWF and FVIII at the ABO locus, all attenuated at least 10% towards the null after adjustment for genetic variants. We identified novel epigenetic associations with VWF and FVIII levels at the NBEAL2 and B3GALT4 loci. NBEAL2 is critical for the biosynthesis of platelet alpha granules, which store proteins that enable platelet adhesion initiation, including VWF while B3GALT4 is involved in glycosylation of glycoproteins like VWF and FVIII.